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Raffaele Riccio

Dipartimento di Farmacia
Università di Salerno
Via Giovanni Paolo II, 132
84084 Fisciano (SA), Italy
riccio@unisa.it
Prof. of Organic Chemistry
Dean of the Faculty of Pharmacy
University of Salerno, Italy

Vice-President of Italian Chemical Society
http://www.soc.chim.it/

Journal articles

2013
Giuseppe Bifulco, Raffaele Riccio, Gary E Martin, Alexei V Buevich, R Thomas Williamson (2013)  Quantum chemical calculations of 1J(CC) coupling constants for the stereochemical determination of organic compounds.   Org Lett 15: 3. 654-657 Feb  
Abstract: Quantum chemical calculations of one-bond carbon-carbon coupling constants are demonstrated as potential probes for the configurational assignment of organic molecules. The stereochemical analysis of strychnine and its possible stereoisomers is presented as proof of concept.
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Annalisa Vilasi, Maria Chiara Monti, Alessandra Tosco, Simona De Marino, Luigi Margarucci, Raffaele Riccio, Agostino Casapullo (2013)  Differential in Gel Electrophoresis (DIGE) Comparative Proteomic Analysis of Macrophages Cell Cultures in Response to Perthamide C Treatment.   Mar Drugs 11: 4. 1288-1299 04  
Abstract: Secondary metabolites contained in marine organisms disclose diverse pharmacological activities, due to their intrinsic ability to recognize bio-macromolecules, which alter their expression and modulate their function. Thus, the identification of the cellular pathways affected by marine natural products is crucial to provide important functional information concerning their mechanism of action at the molecular level. Perthamide C, a marine sponge metabolite isolated from the polar extracts of Theonella swinhoei and endowed with a broad and interesting anti-inflammatory profile, was found in a previous study to specifically interact with heat shock protein-90 and glucose regulated protein-94, also disclosing the ability to reduce cisplatin-mediated apoptosis. In this paper, we evaluated the effect of this compound on the whole proteome of murine macrophages cells by two-dimensional DIGE proteomics. Thirty-three spots were found to be altered in expression by at least 1.6-fold and 29 proteins were identified by LC ESI-Q/TOF-MS. These proteins are involved in different processes, such as metabolism, structural stability, protein folding assistance and gene expression. Among them, perthamide C modulates the expression of several chaperones implicated in the folding of proteins correlated to apoptosis, such as Hsp90 and T-complexes, and in this context our data shed more light on the cellular effects and pathways altered by this marine cyclo-peptide.
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2012
Luigi Margarucci, Maria Chiara Monti, Maria Giovanna Chini, Alessandra Tosco, Raffaele Riccio, Giuseppe Bifulco, Agostino Casapullo (2012)  The Inactivation Mechanism of Human Group IIA Phospholipase A(2) by Scalaradial.   Chembiochem 13: 15. 2259-2264 Oct  
Abstract: Secretory phospholipases A(2) (sPLA(2) s) are implicated in the pathogenesis of several inflammation diseases, such as rheumatoid arthritis, septic shock, psoriasis, and asthma. Thus, an understanding of their inactivation mechanisms could be useful for the development of new classes of chemical selective inhibitors. In the marine environment, several bioactive terpenoids possess interesting anti-inflammatory activity, often through covalent and/or noncovalent inactivation of sPLA(2) . Herein, we report the molecular mechanism of human group IIA phospholipase A(2) (sPLA(2) -IIA) inactivation by Scalaradial (SLD), a marine 1,4-dialdehyde terpenoid isolated from the sponge Cacospongia mollior and endowed with a significant anti-inflammatory profile. Our results have been collected by a combination of biochemical approaches, advanced mass spectrometry, surface plasmon resonance, and molecular modeling. These suggest that SLD acts as a competitive inhibitor. Indeed, the sPLA(2) -IIA inactivation process seems to be driven by the noncovalent recognition process of SLD in the enzyme active site and by chelation of the catalytic calcium ion. In contrast, covalent modification of the enzyme by the SLD dialdehyde moiety emerges as only a minor side event in the ligand-enzyme interaction. These results could be helpful for the rational design of new PLA(2) inhibitors that would be able to selectively target the enzyme active site.
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Stefania Terracciano, Maria Giovanna Chini, Raffaele Riccio, Ines Bruno, Giuseppe Bifulco (2012)  Design, synthesis, and biological activity of hydroxamic tertiary amines as histone deacetylase inhibitors.   ChemMedChem 7: 4. 694-702 Apr  
Abstract: Herein we describe the design, synthesis, and biological evaluation of new hydroxamic tertiary amines as histone deacetylase (HDAC) inhibitors. These compounds have allowed us to clarify the influence of cap group dimension and hydrophobicity on HDAC inhibitory activity. This report also reveals the recognition pattern between the linear compounds and the histone deacetylase-like protein (HDLP) model receptor, and discusses the synthesis and in vitro evaluation of HDAC inhibitory activity in HeLa cell nuclear extracts. We obtained good qualitative agreement between experimental results and theoretical predictions, confirming that appropriately substituted hydroxamic tertiary amines are potential active HDAC inhibitors.
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Maria Chiara Monti, Luigi Margarucci, Raffaele Riccio, Agostino Casapullo (2012)  Modulation of tau protein fibrillization by oleocanthal.   J Nat Prod 75: 9. 1584-1588 Sep  
Abstract: Among the phenolic compounds extracted from extra virgin olive oil, oleocanthal (1) has attracted considerable attention in the modulation of many human diseases, such as inflammation and Alzheimer's disease (AD). Indeed, 1 is capable of altering the fibrillization of tau protein, which is one of the key factors at the basis of neurodegenerative diseases, and of covalently reacting with lysine ε-amino groups of the tau fragment K18 in an unspecific fashion. In the present study, an investigation of the recognition process and the reaction profile between 1 and the wild-type tau protein has been conducted by a circular dichroism, surface plasmon resonance, fluorescence, and mass spectrometry combined approach. As a result, 1 has been found to interact with tau-441, inducing stable conformational modifications of the protein secondary structure and also interfering with tau aggregation. These findings provide experimental support for the potential reduced risk of AD and related neurodegenerative diseases associated with olive oil consumption and may offer a new chemical scaffold for the development of AD-modulating agents.
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Chiara Cassiano, Maria Chiara Monti, Carmen Festa, Angela Zampella, Raffaele Riccio, Agostino Casapullo (2012)  Chemical proteomics reveals heat shock protein 60 to be the main cellular target of the marine bioactive sesterterpene suvanine.   Chembiochem 13: 13. 1953-1958 Sep  
Abstract: Marine bioactive compounds are potential drug leads because of their diverse pharmacological effects against human diseases. The identification of their cellular targets is crucial for a rational approach to their application in medicinal chemistry. Thus, we have analyzed the cell interactome of suvanine, a sulfated tricyclic terpenoid of marine origin endowed with an interesting anti-inflammatory activity, by application of a chemical proteomic approach. Heat Shock Protein 60, a chaperone involved in the inflammatory response, is the main cellular target of suvanine, which is also able to interfere with protein chaperone activity, giving evidence for its anti-inflammatory properties.
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Maria Giovanna Chini, Rosa De Simone, Ines Bruno, Raffaele Riccio, Friederike Dehm, Christina Weinigel, Dagmar Barz, Oliver Werz, Giuseppe Bifulco (2012)  Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors.   Eur J Med Chem 54: 311-323 Aug  
Abstract: Microsomal prostaglandin E(2) synthase (mPGES)-1 and 5-lipoxygenase (5-LO) are pivotal enzymes in the biosynthesis of the pro-inflammatory PGE(2) and leukotrienes, respectively. The design and synthesis of a second series of mPGES-1 inhibitors based on a triazole scaffold are described. Our studies allowed us to draw a tentative SAR profile and to optimize this series with the identification of compounds 10, 11 and 14-15 which displayed potent mPGES-1 inhibition in a cell-free assay. In addition, compounds 5, 10, 12 and 14-16 also blocked 5-LO activity in cell-free and cell-based test systems, emerging as very promising candidates for the development of safer and more effective anti-inflammatory drugs.
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Rosa De Simone, Ines Bruno, Raffaele Riccio, Katharina Stadler, Julia Bauer, Anja M Schaible, Stefan Laufer, Oliver Werz (2012)  Identification of new γ-hydroxybutenolides that preferentially inhibit the activity of mPGES-1.   Bioorg Med Chem 20: 16. 5012-5016 Aug  
Abstract: Microsomal prostaglandin E(2) synthase-1 (mPGES-1) has been recognized as novel, promising drug target for anti-inflammatory and anticancer drugs. mPGES-1 catalyzes the synthesis of the inducible prostaglandin E(2) in response to pro-inflammatory stimuli, rendering this enzyme extremely interesting in drug discovery process owing to the drastic reduction of the severe side effects typical for traditional non-steroidal anti-inflammatory drugs. In the course of our investigations focused on this topic, we identified two interesting molecules bearing the γ-hydroxybutenolide scaffold which potently inhibit the activity of mPGES-1. Notably, the lead compound 2c that inhibited mPGES-1 with IC(50) = 0.9 μM, did not affect other related enzymes within the arachidonic acid cascade.
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Luigi Margarucci, Maria Chiara Monti, Andrea Mencarelli, Chiara Cassiano, Stefano Fiorucci, Raffaele Riccio, Angela Zampella, Agostino Casapullo (2012)  Heat shock proteins as key biological targets of the marine natural cyclopeptide perthamide C.   Mol Biosyst 8: 5. 1412-1417 Apr  
Abstract: Linking bioactive compounds to their cellular targets is a central challenge in chemical biology. Herein we report the mode of action of perthamide C, a natural cyclopeptide isolated from the marine sponge Theonella swinhoei. Through an emerging mass spectrometry-based chemical proteomics approach, Heat Shock Protein 90 and Glucose Regulated Protein 94 were identified as key targets of perthamide C and this evidence has been validated using surface plasmon resonance. The ability of perthamide C to influence heat shock protein-mediated cell apoptosis revealed that this marine metabolite could be a good candidate for the development of a lead compound with therapeutic applications based on apoptosis modulation.
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Luigi Margarucci, Alessandra Tosco, Rosa De Simone, Raffaele Riccio, Maria Chiara Monti, Agostino Casapullo (2012)  Modulation of proteasome machinery by natural and synthetic analogues of the marine bioactive compound petrosaspongiolide m.   Chembiochem 13: 7. 982-986 May  
Abstract: Natural or synthetic? Several petrosaspongiolide M natural and synthetic analogues have been tested as proteasome inhibitors and apoptosis modulators. The natural petrosaspongiolide M congeners gave a consistent decrease in activity. Among the synthetic analogues, the introduction of the benzothiophene ring resulted in a bioequivalent alternative of the petrosaspongiolide M terpenoid system.
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Gianluigi Lauro, Milena Masullo, Sonia Piacente, Raffaele Riccio, Giuseppe Bifulco (2012)  Inverse Virtual Screening allows the discovery of the biological activity of natural compounds.   Bioorg Med Chem Apr  
Abstract: A small library of phenolic natural compounds belonging to different chemical classes was screened on a panel of targets involved in the genesis and progression of cancer. The re-investigation of their potential activity was achieved through the Inverse Virtual Screening approach. The normalization of the predicted binding energies permitted the selection of promising compounds on definite targets, avoiding the selection of false positive results. In vitro biological tests revealed the inhibitory activity of xanthohumol and isoxanthohumol on PDK1 and PKC protein kinases. This study validates the robustness of the Inverse Virtual Screening in silico approach as a useful tool for the identification of the specific biological activity of a given set of compounds.
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2011
Simone Di Micco, Frédéric Mazué, Carmelo Daquino, Carmela Spatafora, Dominique Delmas, Norbert Latruffe, Corrado Tringali, Raffaele Riccio, Giuseppe Bifulco (2011)  Structural basis for the potential antitumour activity of DNA-interacting benzo[kl]xanthene lignans.   Org Biomol Chem 9: 3. 701-710 Feb  
Abstract: The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
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Carmen Petronzi, Rosanna Filosa, Antonella Peduto, Maria Chiara Monti, Luigi Margarucci, Antonio Massa, Simona Francesca Ercolino, Valentina Bizzarro, Luca Parente, Raffaele Riccio, Paolo de Caprariis (2011)  Structure-based design, synthesis and preliminary anti-inflammatory activity of bolinaquinone analogues.   Eur J Med Chem 46: 2. 488-496 Feb  
Abstract: As a part of our drug discovery efforts we developed a series of simplified derivatives of bolinaquinone (BLQ), a hydroxyquinone marine metabolite, showing potent anti-inflammatory activity. Thirteen new hydroxyquinone derivatives closely related to BLQ were synthesized and tested on mouse macrophage-like RAW 264.7 cell line in order to investigate their ability to modulate the production of Prostaglandin E2 (PGE2). This optimization process led to the identification of three strictly correlated compounds with comparable and higher inhibitory potency than BLQ on PGE2 production. To evaluate the affinity of BLQ and its analogues for hsPLA2, surface plasmon resonance (SPR) experiments were performed.
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Luigi Margarucci, Maria Chiara Monti, Bianca Fontanella, Raffaele Riccio, Agostino Casapullo (2011)  Chemical proteomics reveals bolinaquinone as a clathrin-mediated endocytosis inhibitor.   Mol Biosyst 7: 2. 480-485 Feb  
Abstract: The emerging field of mass spectrometry-based chemical proteomics provides a powerful instrument in the target discovery of bioactive small-molecules, such as drugs or natural products. The identification of their macromolecular targets is required for a comprehensive understanding of their bio-pharmacological role and for unraveling their mechanism of action. We report the application of a chemical proteomics approach to the analysis of the cellular interactome of the marine metabolite bolinaquinone (BLQ). BLQ was linked to an opportune α,ω-diamino polyethylene glycol chain and then immobilized on a matrix support. The modified beads were then used as a bait for fishing the potential partners of BLQ in a THP-1 macrophage cell lysate. Surprisingly, we identified clathrin, a protein involved in the cell internalization of proteins, viruses and other biologically relevant macromolecules, as a specific and major BLQ partner. In addition, we verified the biochemical role of BLQ testing its ability to inhibit the clathrin-mediated endocytosis of albumin. This finding indicates BLQ as a new biotechnological tool for cell endocytosis studies and paves the way to further investigation on its potential role in modulating internalization process.
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Rosa De Simone, Maria Giovanna Chini, Ines Bruno, Raffaele Riccio, Daniela Mueller, Oliver Werz, Giuseppe Bifulco (2011)  Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents.   J Med Chem 54: 6. 1565-1575 Mar  
Abstract: Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 μM).
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Gianluigi Lauro, Adriana Romano, Raffaele Riccio, Giuseppe Bifulco (2011)  Inverse virtual screening of antitumor targets: pilot study on a small database of natural bioactive compounds.   J Nat Prod 74: 6. 1401-1407 Jun  
Abstract: An inverse virtual screening in silico approach has been applied to natural bioactive molecules to screen their efficacy against proteins involved in cancer processes, with the aim of directing future experimental assays. Docking studies were performed on a panel of 126 protein targets extracted from the Protein Data Bank, to analyze their possible interactions with a small library of 43 bioactive compounds. Analysis of the molecular docking results was performed through the use of tables containing energy data organized in a matrix. The application of this approach may facilitate the prediction of the activity of unknown ligands for known targets involved in the development of cancer and could be applied to other models based on different libraries of ligands and different panels of targets.
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Maria Chiara Monti, Luigi Margarucci, Alessandra Tosco, Raffaele Riccio, Agostino Casapullo (2011)  New insights on the interaction mechanism between tau protein and oleocanthal, an extra-virgin olive-oil bioactive component.   Food Funct 2: 7. 423-428 Jul  
Abstract: Oleocanthal (OLC) is a phenolic component of extra-virgin olive oil, recently supposed to be involved in the modulation of some human diseases, such as inflammation and Alzheimer. In particular, OLC has been shown to abrogate fibrillization of tau protein, one of the main causes of Alzheimer neurodegeneration. A recent interpretation of this mechanism has been attempted on the basis of OLC reactivity with the fibrillogenic tau hexapeptide VQIVYK and SDS-PAGE of OLC/tau incubation mixtures, suggesting that covalent modification events modulate tau fibrillization. In this paper we report a detailed mass spectrometric investigation of the OLC reactive profile with both tau protein fibrillogenic fragment K18 and propylamine in biomimetic conditions. We show that K18 is prone to be covalently modified by OLC through Schiff base formation between the ε-amino group of lysine residues and OLC aldehyde carbonyls. Moreover, as expected from its de-structured conformation, K18 shows a non-selective modification profile, reacting with several lysine residues to give cyclic pyridinium-like stable adducts. These data give new insights on the mechanism of inhibition of tau fibrillization mediated by OLC.
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Maria Chiara Monti, Maria Giovanna Chini, Luigi Margarucci, Raffaele Riccio, Giuseppe Bifulco, Agostino Casapullo (2011)  The binding mode of cladocoran A to the human group IIA phospholipase A(2).   Chembiochem 12: 17. 2686-2691 Nov  
Abstract: The molecular basis for human group IIA phospholipase A(2) inactivation by the marine natural product cladocoran A (CLD A) has been studied in order to elucidate its relevant anti-inflammatory properties. Indeed, secretory phospholipases A(2) are well-known to be implicated in the pathogenesis of inflammation, such as rheumatoid arthritis, septic shock, psoriasis and asthma, thus the understanding of their inactivation mechanism could be useful for the development of new chemical classes of selective inhibitors. Our results, collected by a combination of biochemical approaches, advanced mass spectrometry and molecular modeling, suggest a competitive inhibition mechanism guided by a noncovalent molecular recognition event, and disclose the key role of the CLD A γ-hydroxybutenolide ring in the chelation of the catalytic calcium ion inside the enzyme active site. Moreover, CLD A is able to react selectively with Ser82, although this covalent event seems to play a secondary role in terms of enzyme inhibition.
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2010
Cristian Samorì, Giovanni L Beretta, Greta Varchi, Andrea Guerrini, Simone Di Micco, Serena Basili, Giuseppe Bifulco, Raffaele Riccio, Stefano Moro, Ezio Bombardelli, Franco Zunino, Gabriele Fontana (2010)  Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach.   ChemMedChem 5: 12. 2006-2015 Dec  
Abstract: The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I-mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a-thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I-DNA cleavable complex. These effects were prominent for thio-SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.
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Giulia Palermo, Raffaele Riccio, Giuseppe Bifulco (2010)  Effect of electronegative substituents and angular dependence on the heteronuclear spin-spin coupling constant 3J(C-H): an empirical prediction equation derived by density functional theory calculations.   J Org Chem 75: 6. 1982-1991 Mar  
Abstract: A general carbon-proton vicinal coupling constant ((3)J(C-H)) prediction equation has been empirically derived by a coupling constant database of 2157 (3)J(C-H) calculations (at the hybrid DFT MPW1PW91/6-31G(d,p) level). The equation includes the electronegativity effect of the substituents attached to the (13)C-C-C-(1)H fragment and the dihedral (Phi) dependence of the heteronuclear spin-coupling. A set of butane and pentane models were built, systematically varying both the Phi torsion angle in 30 degree steps and the substitution pattern with several electronegative substituents (Br, NH(2), F, Cl, SH, OH) in order to obtain the coupling constant database. The here reported (3)J(C-H) equation is a quantitative prediction tool, particularly useful as a support in the analysis of NMR data for the structural elucidation of organic compounds characterized by specific substitution patterns. To confirm the accuracy of our equation in the prediction of the experimental (3)J(C-H) couplings, we tested the equation, comparing 114 experimental (3)J(C-H) values obtained from 29 polysubstituted benchmark organic compounds with the predicted data. In addition, a set of (3)J(C-H) coupling bidimensional Karplus-type curves correlating the calculated (3)J(C-H) values to the specific dihedral angle for every substitution pattern considered were built in order to evaluate the magnitude of the electronegativity effect.
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Maria Giovanna Chini, Stefania Terracciano, Raffaele Riccio, Giuseppe Bifulco, Roberta Ciao, Carmine Gaeta, Francesco Troisi, Placido Neri (2010)  Conformationally locked calixarene-based histone deacetylase inhibitors.   Org Lett 12: 23. 5382-5385 Dec  
Abstract: Alkyl- and arylamidocalix[4]arene derivatives 1-11 have been designed and theoretically evaluated by docking studies as potential histone deacetylase inhibitors (HDACi). On the basis of the trimodal distribution of the calculated inhibition constants (K(i)), five alkyl- or arylamido derivatives (3, 7, 8, 9, and 11) were synthesized and tested. A qualitative accordance between the experimental results and the theoretical predictions was obtained, confirming that appropriately substituted arylamidocalix[4]arenes are active HDACi.
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Rosa De Simone, Rosa M Andrés, Maurizio Aquino, Ines Bruno, María D Guerrero, María C Terencio, Miguel Paya, Raffaele Riccio (2010)  Toward the discovery of new agents able to inhibit the expression of microsomal prostaglandin E synthase-1 enzyme as promising tools in drug development.   Chem Biol Drug Des 76: 1. 17-24 Jul  
Abstract: In our recent studies, we focused our attention on the synthesis of several gamma-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA(2) enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA(2) inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene gamma-hydroxybutenolide 2, which so far represents the only product, together with resveratrol, able to reduce PGE(2) production through the selective downregulation of mPGES-1 enzyme. In consideration that microsomal prostaglandin E synthase 1 (mPGES-1) is one of the most strategic target involved both in inflammation and in carcinogenesis processes, we decided to explore the biological effects of some structural changes of the gamma-hydroxybutenolide 2, hoping to improve its biological profile. This optimization process led to the identification of three strictly correlated compounds 14g, 16g, and 18 with higher inhibitory potency on PGE(2) production on mouse macrophage cell line RAW264.7 through the selective modulation of mPGES-1 enzyme expression.
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Stefania Terracciano, Simone Di Micco, Giuseppe Bifulco, Paola Gallinari, Raffaele Riccio, Ines Bruno (2010)  Synthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222.   Bioorg Med Chem 18: 9. 3252-3260 May  
Abstract: In the course of our ongoing efforts to discover new and more effective HDAC inhibitors useful for the development of promising anticancer candidates, we have recently undertaken a molecular modelling study on a small collection of FR235222 analogues, synthesized by us in the frame of a structure-activity relationship investigation, made in order to identify the key structural elements essential for the activity. Progress made in structure elucidation of HDAC active site, together with accurate docking calculations, provided new structural insights useful for a further refinement of the tetrapeptide scaffold which should assure an optimal interaction between the synthetic ligands and the biological target. Following the computer aided suggestions we synthesized six new cyclotetrapeptide analogues of the lead compound (3-8), bearing a carboxylic or an hydroxamic acid functionality as Zn binding moiety. Herein we describe their synthesis and their inhibition activity on different HDAC isoforms.
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2009
Maria Chiara Monti, Maria Giovanna Chini, Luigi Margarucci, Alessandra Tosco, Raffaele Riccio, Giuseppe Bifulco, Agostino Casapullo (2009)  The molecular mechanism of human group IIA phospholipase A2 inactivation by bolinaquinone.   J Mol Recognit 22: 6. 530-537 Nov/Dec  
Abstract: The molecular basis of the human group IIA secretory phospholipase A(2) inactivation by bolinaquinone (BLQ), a hydroxyquinone marine terpenoid, has been investigated for the comprehension of its relevant antiinflammatory properties, through the combination of spectroscopic techniques, biosensors analysis, mass spectrometry (MS) and molecular docking. Indeed, sPLA(2)s are well known to be implicated in the pathogenesis of inflammation such as rheumatoid arthritis, septic shock, psoriasis and asthma. Our results suggest a mechanism of competitive inhibition guided by a non-covalent molecular recognition event, disclosing the key role of the BLQ hydroxyl-quinone moiety in the chelation of the catalytic Ca(2+) ion inside the enzyme active site.The understanding of the sPLA(2)-IIA inactivation mechanism by BLQ could be useful for the development of a new chemical class of PLA(2) inhibitors, able to specifically target the enzyme active site.
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María Dolores Guerrero, Maurizio Aquino, Ines Bruno, Raffaele Riccio, María Carmen Terencio, Miguel Payá (2009)  Anti-inflammatory and analgesic activity of a novel inhibitor of microsomal prostaglandin E synthase-1 expression.   Eur J Pharmacol 620: 1-3. 112-119 Oct  
Abstract: In a previous study, we reported a new gamma-hydroxybutenolide derivative, 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH), as inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) expression in lypopolysaccharide (LPS) stimulated RAW 264.7 and TPH-1 cells, without affecting cyclooxygenase-2 (COX-2). In this study, we evaluated the in vivo effect of BTH on some acute and chronic inflammatory animal models in relation to its inhibitory profile on mPGES-1 expression. In the zymosan-induced mouse air pouch model, BTH produced a dose-dependent inhibition of prostaglandin E(2) (PGE(2)) production and mPGES-1 protein expression in pouch exudates without any effect on COX-2 protein expression. This behavior was confirmed in the chronic model of collagen-induced arthritis, where administration of BTH (5 mg/kg) clearly reduced PGE(2) and mPGES-1 expression in joint tissues, whereas COX-2 was unaffected. These effects were accompanied by the suppression of clinical and histopathological manifestations of disease such as the loss of proteoglycan, and the destruction of surface cartilage. Other enzymes participating in the metabolism of arachidonic acid, such as prostaglandin I(2) synthase, tromboxane A(2) synthase or 5-lipoxygenase were unaffected by this compound. The acetic acid-induced hyperalgesia model in LPS-sensitized mice showed a dose-dependent analgesic effect of BTH, exerting an ED(50) value of 6.2 mg/kg. Our data suggest that inhibition of mPGES-1 protein expression in acute and chronic inflammatory models by BTH, could provide a potential therapeutic target and a pharmacological tool to discern the role of the inducible enzymes COX-2 and mPGES-1 in inflammatory pathologies.
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Maria Chiara Monti, Raffaele Riccio, Agostino Casapullo (2009)  Effects of petrosaspongiolide R on the surface topology of bee venom PLA(2): a limited proteolysis and mass spectrometry analysis.   Bioorg Chem 37: 1. 6-10 Feb  
Abstract: Petrosaspongiolides are sponge metabolites belonging to the family of the gamma-hydroxybutenolide marine terpenoids. They possess a remarkable in vitro and in vivo anti-inflammatory profile, due to the specific inhibition of group II and III secretory phospholipase A(2) enzymes, and for this reason can be considered as potential lead for the development of anti-inflammatory drugs. The molecular mechanism of bee venom phospholipase A(2) inactivation has been identified, and the ligand-enzyme complex formation is guided by either non-covalent and covalent interactions. In this work we have analyzed the conformational changes induced by petrosaspongiolide R on the bee venom phospholipase A(2) topology during the molecular recognition process, through the application of limited proteolysis and mass spectrometric methodologies. The results are indicative of structural changes at the N- and C-terminal domains producing a more compact conformational arrangement of the enzyme.
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Agostino Casapullo, Oscar Cobar Pinto, Stefania Marzocco, Giuseppina Autore, Raffaele Riccio (2009)  3-Alkylpyridinium alkaloids from the Pacific sponge Haliclona sp.   J Nat Prod 72: 2. 301-303 Feb  
Abstract: The analysis of the polar extracts of the Pacific sponge Haliclona sp. yielded new dimeric (1), trimeric (2), and polymeric 3-alkylpyridinium alkaloids. Their isolation and structural elucidation, based on NMR and MS data, are discussed in detail, along with their cytotoxic activity.
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Maria Chiara Monti, Agostino Casapullo, Claudio N Cavasotto, Alessandra Tosco, Fabrizio Dal Piaz, Arturas Ziemys, Luigi Margarucci, Raffaele Riccio (2009)  The binding mode of petrosaspongiolide M to the human group IIA phospholipase A(2): exploring the role of covalent and noncovalent interactions in the inhibition process.   Chemistry 15: 5. 1155-1163  
Abstract: We report an analysis of the mechanism of human group IIA secretory phospholipase A(2) (sPLA(2)-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a gamma-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA(2)-IIA Lys67 residue, located near the enzyme-membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of sPLA(2)-IIA through several van der Waals/electrostatic complementarities. The two events cannot co-occur on a single PLA(2) molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA(2) supramolecular complexes. These insights could suggest new PLA(2)-inhibition-based therapeutic strategies.
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2008
Maurizio Aquino, Maria D Guerrero, Ines Bruno, María C Terencio, Miguel Paya, Raffaele Riccio (2008)  Development of a second generation of inhibitors of microsomal prostaglandin E synthase 1 expression bearing the gamma-hydroxybutenolide scaffold.   Bioorg Med Chem 16: 19. 9056-9064 Oct  
Abstract: Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, nevertheless we discovered a potent and selective modulator of the expression of microsomal prostaglandin E synthase 1 (mPGES-1), an enzyme highly involved in the inflammatory response, which represents an interesting target for the development of a new class of anti-inflammatory agents. In this paper we report the synthesis of a further collection of nine analogues, having the same scaffold of PM, the gamma-hydroxybutenolide, and bearing, as side chain, more complex aromatic portions, in substitution of the sesterterpene moiety. Their pharmacological behavior against PLA(2) enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and mPGES-1 enzymes is also described.
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Maria Giovanna Chini, Raffaele Riccio, Giuseppe Bifulco (2008)  DFT/NMR integrated approach: a valid support to the total synthesis of chiral molecules.   Magn Reson Chem 46: 10. 962-968 Oct  
Abstract: The analysis of the configuration of kedarcidin chromophore and palau'amine through quantum chemical calculation of Js and chemical shifts suggests a fast and convenient quantum chemical approach that can be applied prior to proceeding to the total synthesis of complex natural compounds in order to avoid loss of time and resources employed in the total synthesis of wrong diastereoisomers.
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Simone Di Micco, Stefania Terracciano, Ines Bruno, Manuela Rodriquez, Raffaele Riccio, Maurizio Taddei, Giuseppe Bifulco (2008)  Molecular modeling studies toward the structural optimization of new cyclopeptide-based HDAC inhibitors modeled on the natural product FR235222.   Bioorg Med Chem 16: 18. 8635-8642 Sep  
Abstract: The natural cyclopeptide FR235222 is a potent HDAC inhibitor displaying relevant multiple anticancer effects and is considered an attractive lead compound for the generation of new and more effective antitumor therapeutics. Recently, we have synthesized a small collection of FR235222 simplified analogues which showed interesting biological activities. These results encouraged us to further explore the structural determinants responsible for the activity of this class of HDAC inhibitors in order to gain guidelines for the rational design of new derivatives with putative higher affinity for this target. In the present paper, we report the results obtained, docking these ligands in the binding pocket of HDLP, an HDAC homologue.
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Stefania Terracciano, Ines Bruno, Elisabetta D'Amico, Giuseppe Bifulco, Angela Zampella, Valentina Sepe, Charles D Smith, Raffaele Riccio (2008)  Synthetic and pharmacological studies on new simplified analogues of the potent actin-targeting Jaspamide.   Bioorg Med Chem 16: 13. 6580-6588 Jul  
Abstract: In the recent years, we focused our attention on the cyclodepsipeptide Jaspamide 1, an interesting marine metabolite, possessing a potent inhibitory activity against breast and prostate cancer, as a consequence of its ability to disrupt actin cytoskeleton dynamics. Although its biological profile has been well determined, many mechanistic details are still missing in terms of molecular target identification. For this reason, we decided to synthetically modify the natural metabolite, obtaining small arrays of unnatural variants useful to illuminate the structural requirements essential for the activity. Here, we report the synthesis of seven new Jaspamide analogues 2-8, containing, as the parent compound, a beta-amino acid in the cyclopeptide backbone. Their biological profile is also described.
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SIMONE DI MICCO, DALE L BOGER, Raffaele RICCIO, AND GIUSEPPE BIFULCO (2008)  Structural Features of the (+)-Yatakemycin/d(GACTAATTGAC)-(GTCAATTAGTC) Complex – Quantum Mechanical Calculation of NMR Parameters as a Tool for the Characterization of Ligand/DNA Interactions   EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2008 (14): 2454-2462  
Abstract: Abstract: (+)-Yatakemycin is a new and potent member of a class of natural antitumor compounds that derive their biological activitiesfrom specific alkylation of adenine residues in the minor grooves of AT-rich tracts. We have analyzed the covalentcomplex formed between (+)-yatakemycin and the d(GACTAATTGAC)-(GTCAATTAGTC) duplex, and have established that the ligand covalently binds to the A5 residue.For this purpose we used a hybrid approach based on 2D-NMR spectroscopy and quantum mechanical (QM) calculations of 1H chemical shifts at the DFT/MPW1PW91 level. In this study we also show that the calculation of NMR parameters can be a useful tool for the structural characterization of ligand–receptor interactions.
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2007
Giuseppe Bifulco, Raffaele Riccio, Carmine Gaeta, Placido Neri (2007)  Quantum mechanical calculations of conformationally relevant 1H and 13C NMR chemical shifts of N-, O-, and S-substituted calixarene systems.   Chemistry 13: 25. 7185-7194  
Abstract: QM GIAO calculations of (13)C and (1)H chemical shift values of the ArCH(2)Ar group in N-, O-, and S-substituted calixarene systems were performed with a hybrid DFT functional MPW1PW91 and 6-31G(d,p) basis set. A good reproduction of experimental data was obtained for some representative calixarenes and for a series of simplified calixarene models. This allowed the derivation of chemical shift surfaces versus phi and chi dihedral angles. The applicability of chemical shift surfaces in the study of calixarene conformational features is illustrated.
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Maria Chiara Monti, Agostino Casapullo, Claudio N Cavasotto, Assunta Napolitano, Raffaele Riccio (2007)  Scalaradial, a dialdehyde-containing marine metabolite that causes an unexpected noncovalent PLA2 Inactivation.   Chembiochem 8: 13. 1585-1591 Sep  
Abstract: Several marine terpenoids that contain at least one reactive aldehyde group, such as manoalide and its congeners, possess interesting anti-inflammatory activities that are mediated by the covalent inactivation of secretory phospholipase A(2) (sPLA(2)). Scalaradial, a 1,4-dialdehyde marine terpenoid that was isolated from the sponge Cacospongia mollior, is endowed with a relevant anti-inflammatory profile, both in vitro and in vivo, through selective sPLA(2) inhibition. Due to its peculiar dialdehyde structural feature, it has been proposed that scalaradial exerts its enzymatic inactivation by means of an irreversible covalent modification of its target. In the context of our on-going research on anti-PLA(2) natural products and their interaction at a molecular level, we studied scalaradial in an attempt to shed more light on the molecular mechanism of its PLA(2) inhibition. A detailed analysis of the reaction profile between scalaradial and bee venom PLA(2), a model sPLA(2) that shares a high structural homology with the human synovial enzyme, was performed by a combination of spectroscopic techniques, chemical reactions (selective modifications, biomimetic reactions), and classical protein chemistry (such as proteolytic digestion, HPLC and mass spectrometry), along with molecular modeling studies. Unexpectedly, our data clearly indicated the noncovalent forces to be the leading event in the PLA(2) inactivation process; thus, the covalent modification of the enzyme emerges as only a minor side event in the ligand-enzyme interaction. The overall picture might be useful in the design of SLD analogues as new potential anti-inflammatory compounds that target sPLA(2) enzymes.
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Maria D Guerrero, Maurizio Aquino, Ines Bruno, María C Terencio, Miguel Paya, Raffaele Riccio, Luigi Gomez-Paloma (2007)  Synthesis and pharmacological evaluation of a selected library of new potential anti-inflammatory agents bearing the gamma-hydroxybutenolide scaffold: a new class of inhibitors of prostanoid production through the selective modulation of microsomal prostaglandin E synthase-1 expression.   J Med Chem 50: 9. 2176-2184 May  
Abstract: As a part of our drug discovery effort, recently we clarified the molecular basis of phospholipase A2 (PLA2) inactivation by petrosaspongiolide M (PM), an interesting metabolite belonging to a marine sesterterpene family, containing in its structural architecture a gamma-hydroxybutenolide moiety and showing potent anti-inflammatory activity. In the attempt to expand structural diversity as well as to simplify crucial synthetic features of the parent compound, we decided to develop a selected library based on the densely functionalized gamma-hydroxybutenolide scaffold. The synthesized products were tested for their ability to inhibit PLA2 enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), two key enzymes highly involved in the inflammatory event, in order to discover new promising anti-inflammatory agents with better pharmacological profiles. This led us to the discovery of a promising inhibitor (4e) of prostanoid production acting by in vitro and in vivo selective modulation of microsomal prostaglandin E synthase 1 expression.
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Nakia Maulucci, Maria Giovanna Chini, Simone Di Micco, Irene Izzo, Emiddio Cafaro, Adele Russo, Paola Gallinari, Chantal Paolini, Maria Chiara Nardi, Agostino Casapullo, Raffaele Riccio, Giuseppe Bifulco, Francesco De Riccardis (2007)  Molecular insights into azumamide e histone deacetylases inhibitory activity.   J Am Chem Soc 129: 10. 3007-3012 Mar  
Abstract: Azumamide E, a cyclotetrapeptide isolated from the sponge Mycale izuensis, is the most powerful carboxylic acid containing natural histone deacetylase (HDAC) inhibitor known to date. In this paper, we describe design and synthesis of two stereochemical variants of the natural product. These compounds have allowed us to clarify the influence of side chain topology on the HDAC-inhibitory activity. The present contribution also reveals the identity of the recognition pattern between azumamides and the histone deacetylase-like protein (HDLP) model receptor and reports the azumamide E unprecedented isoform selectivity on histone deacetylases class subtypes. From the present studies, a plausible model for the interaction of azumamides with the receptor binding pocket is derived, providing a framework for the rational design of new cyclotetrapeptide-based HDAC inhibitors as antitumor agents.
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2006
CARLA BASSARELLO, ANGELA ZAMPELLA, MARIA CHIARA MONTI, LUIGI GOMEZ-PALOMA, MARIA VALERIA DAURIA, Raffaele RICCIO, GIUSEPPE BIFULCO (2006)  Quantum Mechanical Calculation of Coupling Constants in the Configurational Analysis of Flexible Systems : Determination of the Configuration of Callipeltin A   EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2006 (3): 604-609  
Abstract: Abstract: An integrated NMR-quantum mechanical (QM) approach, relying on the comparison between calculated and experimental J-values, was applied to the analysis of the relative configuration of four amino acid units (known as AGDHE, DaThr1, D-aThr2 and ?-OMeTyr) contained in callipeltin A, a cyclopeptide endowed with a powerful inhibitory activity on the cardiac sodium/calcium exchanger and also showing interesting antiviral and antifungal properties. In this paper we report the first example of the application of this method to a real case, which allowed the assignment of the relative configuration of the ?-OMeTyr residue and the revision of the configuration of the Thr2 unit in callipeltin A.
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Paola Cimino, Giuseppe Bifulco, Raffaele Riccio, Luigi Gomez-Paloma, Vincenzo Barone (2006)  On the role of stereo-electronic effects in tuning the selectivity and rate of DNA alkylation by duocarmycins.   Org Biomol Chem 4: 7. 1242-1251 Apr  
Abstract: The role of local geometric and stereo-electronic effects in tuning the alkylation of DNA by duocarmycins has been analyzed by an integrated computational tool rooted in the density functional theory and the polarizable continuum model. Our study points out that together with steric accessibility, different electronic delocalisations also contribute to determine the higher reactivity of adenine with respect to guanine. Also the effect of the methyl ester group on the alkylating agent has an electronic origin. Furthermore, deviations from the planarity in the drug structure (conformational catalysis) could be less important than currently accepted since, according to our computations, compounds with strongly different reactivity have nearly constant and very similar out of plane distortions before and after the reaction. Model computations suggest, instead, that specific non covalent interactions could discriminate between different drugs selectively reducing some activation energies with respect to the corresponding processes in solution.
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Maria Di Marzo, Agostino Casapullo, Giuseppe Bifulco, Paola Cimino, Alessia Ligresti, Vincenzo Di Marzo, Raffaele Riccio, Luigi Gomez-Paloma (2006)  Synthesis, conformational analysis and CB1 binding affinity of hairpin-like anandamide pseudopeptide mimetics.   J Pept Sci 12: 9. 575-591 Sep  
Abstract: We have designed, synthesized and evaluated the CB(1) binding affinity of a number of new conformationally restricted lipopeptides (1-17). All of them present some of the AEA key structural elements incorporated in a hairpinlike peptide framework. Among them, compounds 1-3 and 8 showed CB(1) affinities in competitive binding assays with K(i) values in the micromolar range (K(i) of AEA = 0.8 microM in the same assay). The remaining pseudopeptides showed little binding to the CB(1) receptor (with K(i) values >or= 50 microM). Conformational analysis on two representative compounds, performed by a combination of NMR studies, restrained molecular dynamics and QM calculations, allowed us to shed light on the structure-activity relationships (SAR), pointing to a correlation between the predominance of the hairpin-like structural motif and the CB(1) binding affinity. In a more general context, the present study may also prove useful in gaining additional insight into the biological relevance of the various AEA conformations.
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Maria Chiara Monti, Agostino Casapullo, Cosima Santomauro, Maria Valeria D'Auria, Raffaele Riccio, Luigi Gomez-Paloma (2006)  The molecular mechanism of bee venom phospholipase A2 inactivation by bolinaquinone.   Chembiochem 7: 6. 971-980 Jun  
Abstract: The molecular basis of the inactivation of bee venom PLA2 by the marine natural product bolinaquinone (BLQ) was studied by several spectral techniques (CD, fluorescence, and NMR spectroscopy, mass spectrometry), biomimetic reactions, and molecular modeling. Our data suggest competitive inhibition based on a BLQ-PLA2 noncovalent molecular recognition. However, BLQ is also able to react selectively with Lys133 through conjugate addition followed by a beta elimination. The biological implications of both the covalent and noncovalent molecular events are discussed.
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Stefania Terracciano, Maurizio Aquino, Manuela Rodriquez, Maria Chiara Monti, Agostino Casapullo, Raffaele Riccio, Luigi Gomez-Paloma (2006)  Chemistry and biology of anti-inflammatory marine natural products: molecules interfering with cyclooxygenase, NF-kappaB and other unidentified targets.   Curr Med Chem 13: 16. 1947-1969  
Abstract: The majority of the anti-inflammatory drugs routinely used nowadays are COX (cyclo-oxygenase) inhibitors. The important role of this enzyme, once known as prostaglandin synthase, in inflammation came a consequence of the discovery by the Nobel prize winner John Vane with his path-breaking discovery that aspirin and similar drugs exert their action by blocking the biosynthesis of the prostaglandin group of lipid mediators. (John R. Vane, Nobel Lecture, December 8, 1982 and references cited therein) In the last five years it has become clear that there are two such enzymes involved. One of the "cyclo-oxygenases", called COX1 is responsible for making prostaglandins, which among other things, protect the stomach and kidney from damage. It is now clear that inhibition of COX1 accounts for the unwanted side effects of aspirin-like drugs such as gastric irritation and renal damage. The other enzyme, COX2, is induced by inflammatory stimuli and it is prostaglandins made by this enzyme that contribute to the inflammation in diseases such as rheumatoid arthritis. However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes. In recent years, it has steadily become more clear, that modulation in the expression of genes underlies most cellular responses, and inflammation is certainly not an exception in this sense. It does not come as surprise that molecules showing ability to interfere with factors involved in the modulation of genes expression, such as NF-kB, have also to be considered potential anti-inflammatory agents. Also in this respect, marine natural products (MNP) have brought a collection of novel molecular entities displaying ability to target COX1/COX2, NF-kappaB or acting through molecular mechanisms yet-to-be-discovered. Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-molecular targets. Chemical synthesis of particular relevant molecules will be also discussed, especially in those cases where the natural products can be considered as lead compounds for the development of simplified derivatives or analogues of potential pharmaceutical interest.
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M Aquino, I Bruno, R Riccio, L Gomez-Paloma (2006)  Regioselective entry to bromo-gamma-hydroxybutenolides: useful building blocks for assemblying natural product-like libraries.   Org Lett 8: 21. 4831-4834 Oct  
Abstract: [reaction: see text] We report a regioselective entry to 3-bromo- and 4-bromo-5-hydroxy-5H-furan-2-ones by photooxidation of 3-bromofuran with a singlet oxygen in the presence of a suitable base. By this procedure, a variety of 3-substituted gamma-hydroxybutenolides have become for the first time easily accessible. Strategies employing these highly functionalized building blocks for the preparation of focused libraries of natural-like molecules are also discussed.
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2005
Giuseppe Bifulco, Luigi Gomez-Paloma, Raffaele Riccio, Carmine Gaeta, Francesco Troisi, Placido Neri (2005)  Quantum mechanical calculations of conformationally relevant 1H and 13C NMR chemical shifts of calixarene systems.   Org Lett 7: 26. 5757-5760 Dec  
Abstract: [graphs: see text] QM GIAO calculations of 13C and 1H chemical shift values of the ArCH2Ar group have been performed, using the hybrid DFT functional MPW1PW91 and the 6-31G(d,p) basis set, on some representative calixarenes and on a series of simplified calixarene models allowing derivation of chemical shift surfaces versus phi and chi dihedral angles. A good reproduction of experimental data was obtained. The applicability of chemical shift surfaces in the study of calixarene conformational features is illustrated.
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Maria Chiara Monti, Agostino Casapullo, Raffaele Riccio, Luigi Gomez-Paloma (2005)  The inactivation of phospholipase A2 by scalaradial: a biomimetic study by electrospray mass spectrometry.   Rapid Commun Mass Spectrom 19: 3. 303-308  
Abstract: A biomimetic approach was employed to shed light on the nature of chemical reactions occurring in the covalent inactivation of phospholipase A(2) (PLA(2)) by scalaradial (1), a marine dialdehyde terpenoid endowed with potent anti-inflammatory activity. To this end, a detailed study of the reaction profile between the nitrogenous nucleophile isopropylamine and scalaradial was performed under biologically relevant conditions.
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Stefania Terracciano, Ines Bruno, Giuseppe Bifulco, Elvira Avallone, Charles D Smith, Luigi Gomez-Paloma, Raffaele Riccio (2005)  Synthesis, solution structure, and bioactivity of six new simplified analogues of the natural cyclodepsipeptide jaspamide.   Bioorg Med Chem 13: 17. 5225-5239 Sep  
Abstract: Recently, we described the synthesis and the biological evaluation of three modified analogues of jaspamide (1), a natural cyclodepsipeptide possessing a potent antitumor activity as a consequence of its ability to interfere with actin cytoskeleton. To obtain additional information on the potential pharmacophoric core of the target molecule, which is of fundamental importance to discover new and more effective anticancer products, we decided to explore the biological effects of further structural modifications carried out on the parent molecule. The synthesis and the chemical characterization of six jaspamide analogues (2-7) are reported and their conformational and biological properties are described.
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2004
Paola Cimino, Luigi Gomez-Paloma, Dario Duca, Raffaele Riccio, Giuseppe Bifulco (2004)  Comparison of different theory models and basis sets in the calculation of 13C NMR chemical shifts of natural products.   Magn Reson Chem 42 Spec no: S26-S33 Oct  
Abstract: The influence of the calculation method in mimicking experimental (13)C NMR chemical shifts of 15 low-polarity natural products singularly containing 10-20 carbon atoms was investigated by employing different quantum chemistry approaches and basis sets, both in the preliminary geometry optimizations and in the following single-point (13)C GIAO calculations of the NMR chemical shifts. The geometries of the involved species were optimized at the PM3, HF, B3LYP and mPW1PW91 levels whereas the (13)C NMR parameters were determined at the HF, B3LYP and mPW1PW91 levels. Different combinations of basis sets were also tested. The consistency and efficiency of the considered combinations of geometry optimizations and GIAO (13)C NMR calculations were thoroughly checked by the analysis of statistical parameters concerning computed and experimental (13)C NMR chemical shift values.
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Stefania Terracciano, Ines Bruno, Giuseppe Bifulco, Jean E Copper, Charles D Smith, Luigi Gomez-Paloma, Raffaele Riccio (2004)  Synthesis, conformational analysis, and cytotoxicity of new analogues of the natural cyclodepsipeptide jaspamide.   J Nat Prod 67: 8. 1325-1331 Aug  
Abstract: Three analogues of the natural bioactive cyclodepsipeptide jaspamide (3-5) were efficiently synthesized using a combination of solid and solution phase techniques. The preliminary design of the molecules has involved the rational substitution and/or simplification of the most critical structural features of the lead compound. The synthetic products were subjected to pharmacological assays, and the conformational properties were investigated by MM (molecular mechanics) and MD (molecular dynamics) calculations, to describe the potential pharmacophoric core responsible for the observed activities.
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Carla Bassarello, Silvia Lazzaroni, Giuseppe Bifulco, Pietro Lo Cantore, Nicola S Iacobellis, Raffaele Riccio, Luigi Gomez-Paloma, Antonio Evidente (2004)  Tolaasins A--E, five new lipodepsipeptides produced by Pseudomonas tolaasii.   J Nat Prod 67: 5. 811-816 May  
Abstract: Pseudomonas tolaasii, the causal organism of brown blotch disease of Agaricus bisporus and of the yellowing of Pleurotus ostreatus, was shown to produce in culture tolaasin I (1), tolaasin II (2), and five other minor metabolites, tolaasins A, B, C, D, and E (3-7). These compounds were demonstrated to be important in the development of the disease symptoms. This paper reports on the structural elucidation, based essentially on NMR studies and MS spectra, and biological activity of the above lipodepsipeptides (3-7). All the above analogues showed differences in the peptide moiety, as observed in other lipodepsipeptides of bacterial origin, and maintained the beta-hydroxyoctanoyl phi chain at the N-terminus, except tolaasin A, in which the acyl moiety was a gamma-carboxybutanoyl phi moiety. Among the target microorganisms used (fungi, yeast, and bacteria) the Gram-positive bacteria were the most sensitive, although the antimicrobial activity appeared to be correlated to the structural modification in the different analogues. The structure-activity relationships of these toxins are discussed.
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P Cimino, R Improta, G Bifulco, R Riccio, L Gomez-Paloma, V Barone (2004)  Nucleophilic cyclopropane ring opening in duocarmycin SA derivatives by methanol under acid conditions: a quantum mechanical study in the gas-phase and in solution.   J Org Chem 69: 8. 2816-2824 Apr  
Abstract: We present a quantum-mechanical study of the S(N)2 acid-catalyzed solvolysis with methanol of seven simplified duocarmycin SA (DNA alkylating agent) derivatives characterized by spirocyclic systems of increasing complexity, all containing the cyclopropyl/cyclohexadienone substrate. The reaction has been studied at the DFT-PBE0/6-31G(d) level in the gas phase and in methanol solution, using in the latter case the polarizable continuum model (PCM) to describe solvent effects. The results delivered by this computational protocol are in full agreement with the available experimental evidences and are not modified by extension of the basis set or by using a second-order many-body treatment (MP2) in place of DFT. This allows investigation of substituent effects in terms of structure/reactivity relationships and evaluation of the role of stereoelectronic effects. Furthermore, reactivity indices (hardness, electrophilicity) have been computed and shown to correlate well with activation energies. Together with their intrinsic interest, the details of the mechanism of the acid-catalyzed nucleophilic addition to the activated cyclopropane issuing from the present study pave the route for a deeper understanding of the molecular basis for the remarkable profile of the DNA-alkylation by DSA derivatives.
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M C Monti, A Casapullo, R Riccio, L Gomez-Paloma (2004)  PLA2-mediated catalytic activation of its inhibitor 25-acetyl-petrosaspongiolide M: serendipitous identification of a new PLA2 suicide inhibitor.   FEBS Lett 578: 3. 269-274 Dec  
Abstract: 25-Acetyl-petrosaspongiolide M (PMAc) (1), a mild non-covalent PLA(2) inhibitor, unexpectedly recovers, after incubation with bvPLA(2), the ability to covalently modify the enzyme target. This study demonstrates the catalytic effect of bvPLA(2) in converting 1 in its deacetylated congener petrosaspongiolide M (PM) (2), a strong covalent PLA(2) inhibitor whose molecular mechanism of inhibition has already been clarified. Moreover, our findings outline the potential role of PMAc as anti-inflammatory pro-drug, by virtue of its ability of delivering the active PM agent at the site of inflammation, functioning as a suicide inhibitor.
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Giuseppe Bifulco, Carla Bassarello, Raffaele Riccio, Luigi Gomez-Paloma (2004)  Quantum mechanical calculations of NMR J coupling values in the determination of relative configuration in organic compounds.   Org Lett 6: 6. 1025-1028 Mar  
Abstract: [structure: see text] An approach relying on quantum mechanical calculations of proton-proton and proton-carbon J coupling values is proposed as a tool for assigning the relative configuration on chiral organic compounds. The method is suitable for carbon frameworks containing several adjacent stereogenic centers and may allow significant advances in the extensive use of spin-spin couplings in structural elucidation.
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Maria Chiara Monti, Agostino Casapullo, Raffaele Riccio, Luigi Gomez-Paloma (2004)  Further insights on the structural aspects of PLA(2) inhibition by gamma-hydroxybutenolide-containing natural products: a comparative study on petrosaspongiolides M-R.   Bioorg Med Chem 12: 6. 1467-1474 Mar  
Abstract: Petrosaspongiolides M-R (PM-PR, 1-5) are marine sesterterpenes structurally characterised by a gamma-hydroxybutenolide moiety. They have shown an in vitro and in vivo potent anti-inflammatory activity, mediated by specific inhibition of secretory phospholipase A(2) (sPLA(2) enzymes). The molecular mechanism underlying the sub-micromolar irreversible inhibition of the bee-venom PLA(2) (bvPLA(2)) by PM has been clarified combining mass spectrometry (MS) and molecular modelling approaches. The N-terminal amino group (Ile-1 residue), recently identified as the unique PM covalent binding site on this enzyme, selectively delivers a nucleophilic attack onto the masked aldehyde at C-25 of the pharmacophoric gamma-hydroxybutenolide ring of PM, giving rise to a Schiff base. In the attempt of broadening the knowledge of the mechanism at molecular level of PLA(2) inactivation by this family of compounds, we performed a comparative analysis on petrosaspongiolides M-R, whose results are discussed in this paper. Firstly, the amount of bvPLA(2) enzyme covalently modified after incubation with each of petrosaspongiolides M-R was measured and resulted to be in good agreement with pharmacological in vitro data. Then, a full characterisation of the bvPLA(2) adduct with PR, one of the least active and most structurally different among petrosaspongiolides, by LC-MS, MS(n), and computational methods, confirmed the same inhibition mechanism and covalent binding site already found for PM. Finally, extensive molecular docking studies performed in comparison on the PM-PLA(2) and PR-PLA(2) complexes provided critical insight on how the balance between non-covalent and covalent inhibitor-enzyme interactions may affect the final potency exhibited by the various compounds of the petrosaspongiolide family.
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2003
2002
L Ciasullo, A Cutignano, A Casapullo, R Puliti, C A Mattia, C Debitus, R Riccio, L Gomez-Paloma (2002)  A new cycloamphilectene metabolite from the Vanuatu sponge Axinella sp.   J Nat Prod 65: 8. 1210-1212 Aug  
Abstract: A new diterpene, N-formyl-7-amino-11-cycloamphilectene (1), was isolated from the apolar extract of the Vanuatu sponge Axinella sp. The structure and relative stereochemistry were established by spectroscopic and single-crystal X-ray studies.
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Linda Ciasullo, Agostino Casapullo, Adele Cutignano, Giuseppe Bifulco, Cécile Debitus, John Hooper, Luigi Gomez-Paloma, Raffaele Riccio (2002)  Renieramide, a cyclic tripeptide from the Vanuatu sponge Reniera n. sp.   J Nat Prod 65: 3. 407-410 Mar  
Abstract: The polar extract of the Vanuatu sponge Reniera n. sp., which showed immunomodulating activity in preliminary tests, was found to contain a cyclic tripeptide, which we named renieramide (1). This metabolite is identical to a synthetic derivative mentioned in a patent concerning the preparation of cyclic peptides of the OF4949 family of anticancer agents. We describe here the first isolation of this metabolite from natural sources and its complete characterization by spectroscopic and chemical approaches. Renieramide (1) possesses a 17-membered cyclic side-chain-linked biphenyl ether skeleton, typical of the class that includes the natural products OF4949 I-IV, K13, and eurypamides. A tridimensional model of 1, obtained by NMR restrained molecular mechanics and dynamics, is also presented.
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Giampaolo Barone, Luigi Gomez-Paloma, Dario Duca, Arturo Silvestri, Raffaele Riccio, Giuseppe Bifulco (2002)  Structure validation of natural products by quantum-mechanical GIAO calculations of 13C NMR chemical shifts.   Chemistry 8: 14. 3233-3239 Jul  
Abstract: Geometry optimization and GIAO (gauge including atomic orbitals) (13)C NMR chemical shift calculations at Hartree-Fock level, using the 6-31G(d) basis set, are proposed as a tool to be applied in the structural characterization of new organic compounds, thus providing useful support in the interpretation of experimental NMR data. Parameters related to linear correlation plots of computed versus experimental (13)C NMR chemical shifts for fourteen low-polar natural products, containing 10-20 carbon atoms, were employed to assess the reliability of the proposed structures. A comparison with the hybrid B3LYP method was carried out to evaluate electron correlation contributions to the calculation of (13)C NMR chemical shifts and, eventually, to extend the applicability of such computational methods to the interpretation of NMR spectra in apolar solutions. The method was tested by studying three examples of revised structure assignments, analyzing how the theoretical (13)C chemical shifts of both correct and incorrect structures matched the experimental data.
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Giampaolo Barone, Dario Duca, Arturo Silvestri, Luigi Gomez-Paloma, Raffaele Riccio, Giuseppe Bifulco (2002)  Determination of the relative stereochemistry of flexible organic compounds by Ab initio methods: conformational analysis and Boltzmann-averaged GIAO 13C NMR chemical shifts.   Chemistry 8: 14. 3240-3245 Jul  
Abstract: Ab initio calculations at the Hartree-Fock level with full-geometry optimization using the 6-31G(d) basis set, and GIAO (gauge including atomic orbitals) (13)C NMR chemical shifts, are presented here as a support in the study of the stereochemistry of low-polar organic compounds having an open-chain structure. Four linear stereoisomers, fragments of a natural product previously characterized by experimental (13)C NMR spectra, which possesses three stereogenic centers, 11 carbon atoms, and 38 atoms in total, were considered. Conformational searches, by empirical force-field molecular dynamics, pointed out the existence of 8-13 relevant conformers per stereoisomer. Thermochemical calculations at the ab initio level in the harmonic approximation of the vibrational modes, allowed the evaluation, at 298.15 K, of the standard Gibbs free energy of the conformers. The (13)C NMR chemical shift of a given carbon atom in each stereoisomer was considered as the average chemical shift value of the same atom in the different conformers. The averages were obtained by the Boltzmann distribution, using the relative standard free energies as weighting factors. Computed parameters related to linear correlation plots of experimental (13)C chemical shifts versus the corresponding computed average data allowed us to distinguish among the four stereoisomers.
Notes:
Fabrizio Dal Piaz, Agostino Casapullo, Antonio Randazzo, Raffaele Riccio, Piero Pucci, Gennaro Marino, Luigi Gomez-Paloma (2002)  Molecular basis of phospholipase A2 inhibition by petrosaspongiolide M.   Chembiochem 3: 7. 664-671 Jul  
Abstract: Petrosaspongiolide M (PM) is an anti-inflammatory marine metabolite that displays a potent inhibitory activity toward group II and III secretory phospholipase A(2) (PLA(2)) enzymes. The details of the mechanism, which leads to a covalent adduct between PLA(2) and gamma-hydroxybutenolide-containing molecules such as PM, are still a matter of debate. In this paper the covalent binding of PM to bee venom PLA(2) has been investigated by mass spectrometry and molecular modeling. The mass increment observed for the PM-PLA(2) adduct is consistent with the formation of a Schiff base by reaction of a PLA(2) amino group with the hemiacetal function (masked aldehyde) at the C-25 atom of the PM gamma-hydroxybutenolide ring. Proteolysis of the modified PLA(2) by the endoprotease LysC followed by HPLC MS analysis allowed us to establish that the PLA(2) alpha-amino terminal group of the Ile-1 residue was the only covalent binding site for PM. The stoichiometry of the reaction between PM and PLA(2) was also monitored and results showed that even with excess inhibitor, the prevalent product is a 1:1 (inhibitor:enzyme) adduct, although a 2:1 adduct is present as a minor component. The 2:1 adduct was also characterized, which showed that the second site of reaction is located at the epsilon -amino group of the Lys-85 residue. Similar results in terms of the reaction profile, mass increments, and location of the PLA(2) binding site were obtained for manoalide, a paradigm for irreversible PLA(2) inhibitors, which suggests that the present results may be considered of more general interest within the field of anti-inflammatory sesterterpenes that contain the gamma-hydroxybutenolide pharmacophore. Finally, a 3D model, constrained by the above experimental results, was obtained by docking the inhibitor molecule into the PLA(2) binding site through AFFINITY calculations. The model provides an interesting insight into the PM-PLA(2) inhibition process and may prove useful in the design of new anti-inflammatory agents that target PLA(2) secretory enzymes.
Notes:
Assunta Napolitano, Ines Bruno, Paolo Rovero, Rut Lucas, Miguel Payà Peris, Luigi Gomez-Paloma, Raffaele Riccio (2002)  Synthesis and biological properties of the seven alanine-modified analogues of the marine cyclopeptide hymenamide C.   J Pept Sci 8: 8. 407-417 Aug  
Abstract: The synthesis and biological activity of the marine cyclopeptide hymenamide C(1), showing an inhibitory effect on human neutrophil elastase degranulation release, were recently described. Based on this result, it was decided to undertake a systematic structure-activity relationship study of this cyclopeptide, based on the Ala-scan technique, in order to obtain useful information for the rational design of additional analogues. The synthesis and characterization of the seven Ala modified analogues are reported and their biological and pharmacological properties are described.
Notes:
Paola Cimino, Giuseppe Bifulco, Antonio Evidente, Mohamed Abouzeid, Raffaele Riccio, Luigi Gomez-Paloma (2002)  Extension of the J-based configuration analysis to multiple conformer equilibria: an application to sapinofuranone A.   Org Lett 4: 16. 2779-2782 Aug  
Abstract: [structure: see text] A new strategy that extends the application of the J-based configuration analysis to systems characterized by multiple conformer equilibria is described and applied to sapinofuranone A (1), a phytotoxic molecule produced by three strains of Sphaeropsis sapinea. This method, based on a combination of computational techniques and NMR spectroscopy, uses ab initio calculations to predict a set of theoretical homo- and heteronuclear J values which can be compared against experimental NMR data.
Notes:
2001
P Cimino, G Bifulco, A Casapullo, I Bruno, L Gomez-Paloma, R Riccio (2001)  Isolation and NMR characterization of rosacelose, a novel sulfated polysaccharide from the sponge Mixylla rosacea.   Carbohydr Res 334: 1. 39-47 Aug  
Abstract: Rosacelose, a new anti-HIV polysaccharide composed of glucose and fucose sulfate, has been isolated from an aqueous extract of the marine sponge Mixylla rosacea. Extensive use of 1H and 13C multidimensional NMR spectroscopy, combined with chemical analysis were used to establish a linear polysaccharide structure composed mainly of 4,6-disulfated 3-O-glycosylated alpha-D-glucopyranosyl and 2,4-disulfated 3-O-glycosylated alpha-L-fucopyranosyl residues (in a 3:1 molar ratio).
Notes:
A Casapullo, A Cutignano, I Bruno, G Bifulco, C Debitus, L Gomez-Paloma, R Riccio (2001)  Makaluvamine P, a new cytotoxic pyrroloiminoquinone from Zyzzya cf. fuliginosa.   J Nat Prod 64: 10. 1354-1356 Oct  
Abstract: A new pyrroloiminoquinone alkaloid (1) belonging to the makaluvamine family has been isolated from the sponge Zyzzya cf. fuliginosa collected in the waters off the Vanuatu Islands. The compound, designated makulavamine P, was characterized on the basis of its spectral data and displayed cytoxicity in the microM range on KB cells and antioxidant activity.
Notes:
2000
A Casapullo, G Bifulco, I Bruno, R Riccio (2000)  New bisindole alkaloids of the topsentin and hamacanthin classes from the Mediterranean marine sponge Rhaphisia lacazei.   J Nat Prod 63: 4. 447-451 Apr  
Abstract: Chemical investigation of the Et(2)O extract of the marine sponge Rhaphisia lacazei resulted in the isolation of 13 pure bisindole alkaloids (1-13). Compounds (1-6) belong to the class of topsentins and have already been described. Compounds 7-13 are new products, closely related to the class of hamacanthins. The major compounds 1-3 were tested in vitro for antitumor activity; compounds 2 and 3 showed antiproliferative activity against human bronchopulmonary cancer cells (NSCLC-N6) with an IC(50) of 12 and 6.3 microg/mL, respectively.
Notes:
1999
1996
L Minale, M Iorizzi, E Palagiano, R Riccio (1996)  Steroid and triterpenoid oligoglycosides of marine origin.   Adv Exp Med Biol 404: 335-356  
Abstract: Saponins have been considered for a long time typical metabolites of plant origin. It has been only in the last two decades that the world-wide investigation of marine organisms as sources of new bioactive metabolites disclosed the wide distribution of these molecules also among marine animals. Today saponins are recognized as the most common characteristic metabolites in two classes of the phylum Echinodermata (Holothuroidea and Asteroidea). Furthermore, several steroid and triterpenoid oligoglycosides have been isolated from different species of marine sponges, more rarely Anthozoans, and also from fishes of the genus Pardachirus, where they have been shown to act as shark repellents. This communication offers a general view of the distribution of steroid and triterpenoid oligoglycosides among marine organisms and focuses on a number of recent examples to discuss structural characteristics, biological activities, and methods of investigation.
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1995
M Iorizzi, G Bifulco, F de Riccardis, L Minale, R Riccio, F Zollo (1995)  Starfish saponins, Part 53. A reinvestigation of the polar steroids from the starfish Oreaster reticulatus: isolation of sixteen steroidal oligoglycosides and six polyhydroxysteroids.   J Nat Prod 58: 1. 10-26 Jan  
Abstract: A reinvestigation of the starfish Oreaster reticulatus has led to the isolation of sixteen steroidal oligoglycosides and six polyhydroxysteroids. One steroidal monoglycoside has been identified as asterosaponin-1 [5], previously isolated from the same organism, and one pentaglycoside steroidal sulfate has been identified with the known ophidianoside F [1], previously isolated from starfish species of the family Ophidiasteridae. The novel pentaglycoside steroidal sulfates reticulatosides A [3] and B [4] represent the second examples of asterosaponins containing the 5 alpha-cholesta-9(11)-en-3 beta,6 alpha,20,22-tetraol aglycone. Of the remaining new steroidal oligoglycosides, the majority are characterized by the common (24S)-5 alpha-cholesta-3 beta,6 alpha,8,15 alpha,24-pentaol aglycone, with some having a sulfate group at C-6, and differing in the sugar moiety. Compounds 11, 12, 15, and 16 represent major departures from the more common structural features encountered in steroidal glycosides from starfish with the presence in 11 and 12 of a rare 5-O-methylgalactofuranosyl unit and in 15 and 16 of a 3-O-methyl-2-O-sulfate-xylopyranosyl unit. The latter was shown by nmr data combined with molecular dynamics calculations to exist in an 8:2 equilibrium mixture of the 1C4 and 4C1 conformations.
Notes:
M Iorizzi, P Bryan, J McClintock, L Minale, E Palagiano, S Maurelli, R Riccio, F Zollo (1995)  Chemical and biological investigation of the polar constituents of the starfish Luidia clathrata, collected in the Gulf of Mexico.   J Nat Prod 58: 5. 653-671 May  
Abstract: Ten new [1-10] and three known [11-13] polyhydroxysteroids were isolated, along with four known asterosaponins [14-17], from the starfish Luidia clathrata, collected from the offshore waters of the northern Gulf of Mexico. The EtOH extracts of this starfish showed feeding-deterrent properties against marine fish, and inhibited the settlement of larvae of barnacles and bryozoans, as well as the growth of several bacteria. The structures of the new compounds were determined by interpretation of their nmr spectral data and by comparison with the spectral data of known compounds. The assignment of the configurations of the side-chain stereogenic centers of compounds 1 and 3-10 were based on the comparison of their nmr data with those of the stereoisomeric model compounds after derivatization with the chiral auxiliary MTPA reagent. Larval settlement assays conducted on ten isolated compounds revealed they are all potent inhibitors of settlement. Two of these isolated compounds inhibited the growth of several bacteria.
Notes:
G Bifulco, I Bruno, R Riccio, J Lavayre, G Bourdy (1995)  Further brominated bis- and tris-indole alkaloids from the deep-water New Caledonian marine sponge Orina Sp.   J Nat Prod 58: 8. 1254-1260 Aug  
Abstract: Two tris-indole alkaloids, (+/-) gelliusines A and B [1], have been isolated for the first time from a marine source, the New Caledonian sponge, Orina sp. (or Gellius sp.), along with five further indole constituents [2-6]. Compound 6 has been identified as 2,2-bis-(6'-bromo-3'-indolyl(-ethylamine, previously isolated from the tunicate Didemnum candidum, but the remaining four indoles [2-5] are novel compounds. These showed anti-serotonin activity and a strong affinity for somatostatin and neuropeptide Y receptors in receptor-binding assays.
Notes:
1994
G Bifulco, I Bruno, L Minale, R Riccio, A Calignano, C Debitus (1994)  (+/-)-Gelliusines A and B, two diastereomeric brominated tris-indole alkaloids from a deep water new caledonian marine sponge (Gellius or Orina sp.).   J Nat Prod 57: 9. 1294-1299 Sep  
Abstract: Two new diastereomeric brominated tris-indole alkaloids occurring as enantiomeric pairs, (+/-)-gelliusines A [1] and B [2], have been isolated from a deep water New Caledonian sponge (Gellius or Orina sp.), whose crude extract exhibited cytotoxicity against KB cells. Their structures were elucidated by spectroscopic methods including one- and two-dimensional nmr spectroscopy. The major compound, (+/-) gelliusine A [1], which showed very weak cytotoxicity, proved to be active at the serotonin receptor.
Notes:
T C McKee, J H Cardellina, R Riccio, M V D'Auria, M Iorizzi, L Minale, R A Moran, R J Gulakowski, J B McMahon, R W Buckheit (1994)  HIV-inhibitory natural products. 11. Comparative studies of sulfated sterols from marine invertebrates.   J Med Chem 37: 6. 793-797 Mar  
Abstract: A total of 22 sulfated sterols isolated from marine sponges, ophiuroids (brittle stars), and asteroids (sea stars) were comparatively evaluated for their antiviral activity against HIV-1 and HIV-2. In general, sterols with sulfate groups at position 2, 3, or 6 were the most active, with EC50 values of 3-13 microM against HIV-1 (RF) and 2-8 microM against HIV-2 (CBL20). Those compounds which were sulfated on the sterol D ring were completely inactive against both HIV-1 and HIV-2. Overall, sulfated sterols active against HIV-1 were also active against HIV-2.
Notes:
G Bifulco, I Bruno, L Minale, R Riccio (1994)  Novel HIV-inhibitory halistanol sulfates F-H from a marine sponge, Pseudoaxinissa digitata.   J Nat Prod 57: 1. 164-167 Jan  
Abstract: Three new steroid sulfates 2-4 related to halistanol sulfate [1] were isolated along with the known halistanol sulfate C [5] from the marine sponge Pseudoaxinissa digitata. Halistanol sulfates F [2] and G [3] proved to be cytoprotective against HIV.
Notes:
1993
M Iorizzi, F de Riccardis, L Minale, R Riccio (1993)  Starfish saponins, 52. Chemical constituents from the starfish Echinaster brasiliensis.   J Nat Prod 56: 12. 2149-2162 Dec  
Abstract: This paper reports an analysis of the chemical constituents from the Caribbean starfish Echinaster brasiliensis collected at Grand Bahama Island. This species is completely devoid of cyclic steroidal glycosides, previously isolated from two species of the genus Echinaster in place of the more common penta- and hexa-glycoside steroidal sulfates ("asterosaponins"). Two typical "asterosaponins" and ten glycosides of polyhydroxysteroids were instead isolated in relatively large amounts from E. brasiliensis. The asterosaponins include the known marthasteroside A1 [1] and the new brasiliensoside [2], while the glycosides of polyhydroxysteroids include seven new compounds (six monoglycosides and one diglycoside). The known echinasteroside A, previously found in Echinaster sepositus and in the related Henricia laeviuscula (both belonging to the family Echinasteridae), and laeviusculosides C and I from H. laeviuscula were also isolated. Most of the glycosides from E. brasiliensis are 3-O-beta-xylopyranosides of delta 4-3 beta,6 beta,8,15 alpha,16 beta pentahydroxysteroid aglycones, having different side chains and sometimes a sulfate group at C-15, structural features which are typical of steroidal glycosides from starfishes of the family Echinasteridae. Continuing the analysis of the constituents of E. brasiliensis, we have also isolated a series of anthraquinones, known animal pigments found only in echinoderms and particularly in Crinoidea and in the Echinasteridae family of Asteroidea.
Notes:
R G Berlinck, J C Braekman, D Daloze, I Bruno, R Riccio, S Ferri, S Spampinato, E Speroni (1993)  Polycyclic guanidine alkaloids from the marine sponge Crambe crambe and Ca++ channel blocker activity of crambescidin 816.   J Nat Prod 56: 7. 1007-1015 Jul  
Abstract: Four pentacyclic guanidine derivatives (crambescidin 800 [5], crambescidin 816 [6], isocrambescidin 800 [9], and crambine [10]) related to ptilomycalin A [11] have been isolated from the Mediterranean sponge Crambe crambe. Isocrambescidin 800 and crambidine are new derivatives, the structures of which have been determined on the basis of their spectral properties. The absolute configuration of crambescidin 816 at the stereogenic center C-43 has been determined by applying Mosher's method. Pharmacological and biological activities of the Crambe crambe alkaloids are reported. In particular, crambescidin 816 was found to have a potent Ca++ antagonist effect and to inhibit the acetylcholine-induced contraction of guinea pig ileum at very low concentrations.
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M Iorizzi, L Minale, R Riccio, T Yasumoto (1993)  Starfish saponins, Part 51. Steroidal oligoglycosides from the starfish Distolasterias nipon.   J Nat Prod 56: 10. 1786-1798 Oct  
Abstract: A reinvestigation of the extracts from the starfish Distolasterias nipon, collected at Mutsu Bay, Japan, has led to the isolation of six glycosides of polyhydroxysteroids and six asterosaponins. Four steroidal glycosides have been identified as distolasterosides D1 [1] and D2 [2] (previously isolated from the same organism), and pycnopodioside C [5] and pisasteroside A [6], previously found in the related species Pycnopodia helianthoides and Pisaster ochraceus (family Asteridae), respectively. Two asterosaponins have been identified as the common versicoside A [7] and thornasteroside A [7a]. The two remaining glycosides of polyhydroxysteroids, named distolasterosides D4 [3] and D5 [4], and four asterosaponins designated nipoglycosides A [8], B [9], C [10], and D [11] are new compounds, and their structures have been elucidated mainly by interpretation of spectral data and comparison with known compounds.
Notes:
I Bruno, L Minale, R Riccio, L Cariello, T Higa, J Tanaka (1993)  Starfish saponins, Part 50. Steroidal glycosides from the Okinawan starfish Nardoa tuberculata.   J Nat Prod 56: 7. 1057-1064 Jul  
Abstract: This paper describes a complete analysis of the glycoside and polyhydroxysteroid constituents of the starfish Nardoa tuberculata, collected at Zampa, Okinawa, Japan. Besides a group of known non-sulfated steroidal diglycosides, halitylosides A [5], B [6], D [7], E [8], and F [9], and two known polyhydroxysteroids 10 and 11, N. tuberculata also contains four new sulfated steroidal glycosides 1-4 closely related to the previous halitylosides. The antifungal activities and the effects on the development of fertilized sea urchin eggs of some steroid components from this starfish were examined.
Notes:
1992
M Iorizzi, L Minale, R Riccio, T Yasumoto (1992)  Starfish saponins, 48. Isolation of fifteen sterol constituents (six glycosides and nine polyhydroxysteroids) from the starfish Solaster borealis.   J Nat Prod 55: 7. 866-877 Jul  
Abstract: This paper reports a complete steroid glycoside and polyhydroxysteroid analysis of the starfish Solaster borealis, collected at Mutsu Bay, Japan. The glycosides include a new pentaglycoside steroid sulfate ("asterosaponin"), designated solasteroside A [1], two new sulfated 24-O-diglycosides, both with the common 5 alpha-cholesta-3 beta,6 alpha,8,15 alpha, 24-pentaol aglycone, borealosides A [2] and B [3], two new 24-O-(3-O-methyl)xylosides, borealosides C [4] and D [5], having the same aglycone with an additional hydroxy group at 4 beta-position in 5, and the known amurensoside B, previously isolated from Asterias amurensis. Among the polyhydroxysteroid constituents, four (7-10) are new, and five (11-15) have previously been isolated from starfishes.
Notes:
1991
1990
1989
L Andersson, L Bohlin, M Iorizzi, R Riccio, L Minale, W Moreno-López (1989)  Biological activity of saponins and saponin-like compounds from starfish and brittle-stars.   Toxicon 27: 2. 179-188  
Abstract: Twenty-four saponins and saponin-like compounds, isolated from starfish and brittle-stars, have been tested in four in vitro tests, based upon bacterial and cell tissue cultures. Saponin-like compounds from brittle-stars have previously not been tested for biological activity. In an antibacterial test based on an agar diffusion test, the Gram positive bacterium S. aureus was affected by the polyhydroxylated steroidal glycosides, polyhydroxylated sterols and disulfated sterols. However, none of the 21 compounds tested were active against the Gram negative bacterium E. coli. In a cytotoxicity test all 21 compounds tested influenced the cells at a concentration of 100 micrograms/ml, while the cells were unaffected at 1 microgram/ml. In an antitumor test, 16 compounds were tested on two lymphoma cell lines. Inhibition of cell growth, at a concentration of 5 ng/ml, was seen for three polyhydroxylated sterols, in one cell line. Weak activity was seen in an antiviral test at a concentration of 10 micrograms/ml.
Notes:
1988
1977
L Minale, R Riccio, O Scalona, G Sodano, E Fattorusso, S Magno, L Mayol, C Santacroce (1977)  Metabolism in porifera. VII. Conversion of [7,7-3H2]-fucosterol into calysterol by the sponge Calyx niceaensis.   Experientia 33: 12. 1550-1552 Dec  
Abstract: The sponge Calyx niceaensis metabolizes administered [7,7--(3)H2]-fucosterol to produce labelled calysterol, the principal sterol component of the sponge, possessing the unique feature of a cyclopropene ring bridging C23,24.
Notes:

Book chapters

2012
2008
Agostino Casapullo, Maria Chiara Monti, Raffaele Riccio (2008)  Results and Perspectives on Anti-inflammatory Marine Natural Products   In: Natural Products as Future Medicinal Agents Edited by:Susan Hawthorne. 165-194 Transworld Research Network (KERALA, INDIA) ISBN: 978-81-7895-394-6  
Abstract: Marine organisms are rich sources of small molecules with unique chemical skeletons and potent bioactivities. In the last years anti-inflammatory marine natural products have received considerable attention inside the scientific community and above all, the major phospholipase A2 (PLA2) inhibitors, contignasterol and its congeners, pseudopterosins, and the cyclomarins will be discussed here.
Notes:
1999
1996
Raffaele RICCIO, G BIFULCO, L GOMEZ PALOMA (1996)  A basic introduction to one-dimensional multi-pulse NMR spectroscopy   SocietÃa' Chimica Italiana, Divisione di Chimica Organica, ROMA  
Abstract:
Notes: In “Seminars in Organic Synthesis”, XXI Summer School “A. Corbella”
L GOMEZ PALOMA, G BIFULCO, Raffaele RICCIO (1996)  Two-dimensional heteronuclear NMR correlation techniques   Societa'  Chimica Italiana, Divisione di Chimica Organica, ROMA  
Abstract:
Notes: In “Seminars in Organic Synthesis”, XXI Summer School “A. Corbella”.
1995
1994
1993

Conference papers

1995

Other

2004
2001
A NAPOLITANO, I BRUNO, P ROVERO, L GOMEZPALOMA, RAFFAELE RICCIO Raffaele RICCIO, 26th, Montpellier, France European Peptide Symposium (2001)  Synthesis, structural aspects and bioactivity of the marine cyclopeptide hymenamide C.    
Abstract:
Notes: Editor(s): Martinez, Jean; Fehrentz, Jean-Alain. Publisher: Editions EDK, Paris, Fr CODEN: 69EDWK
1998
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