Abstract: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions.
Abstract: We report the isolation and the structural elucidation of a family of polyhydroxylated steroids from the marine sponge Theonella swinhoei. Decodification of interactions of these family with nuclear receptors shows that these steroids are potent agonists of human pregnane-X-receptor (PXR) and antagonists of human farnesoid-X-receptor (FXR) with the putative binding mode to nuclear receptors (NRs) obtained through docking experiments. By using monocytes isolated from transgenic mice harboring hPXR, we demonstrated that swinhosterol B counter-regulates induction of pro-inflammatory cytokines in a PXR-dependent manner. Exposure of CD4(+) T cells to swinhosterol B upregulates the expression of IL-10 causing a shift toward a T cells regulatory phenotype in a PXR dependent manner. These results pave the way to development of a dual PXR agonist/FXR antagonist with a robust immunomodulatory activity and endowed with the ability to modulate the expression of bile acid-regulated genes in the liver.
Abstract: The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing l-Lys or l-allo-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides.
Abstract: We report the isolation and pharmacological characterization of conicasterol E isolated from the marine sponge Theonella swinhoei. Pharmacological characterization of this steroid in comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a synthetic FXR agonist generated by an improved synthetic strategy, and rifaximin, a potent PXR agonist, demonstrated that conicasterol E is an FXR modulator endowed with PXR agonistic activity. Conicasterol E induces the expression of genes involved in bile acids detoxification without effect on the expression of small heterodimer partner (SHP), thus sparing the expression of genes involved in bile acids biosynthesis. The relative positioning in the ligand binding domain of FXR, explored through docking calculations, demonstrated a different spatial arrangement for conicasterol E and pointed to the presence of simultaneous and efficient interactions with the receptor. In summary, conicasterol E represents a FXR modulator and PXR agonist that might hold utility in treatment of liver disorders.
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 inâ 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.
Abstract: Investigation of roots extracts Pseudrocedrela kotschyi and Trichilia emetica led to identification of 5 limonoid derivatives, Kotschyins D-H, and 11 known compounds. Their structures were elucidated by extensive 1D and 2D NMR experiments in conjunction with mass spectrometry. A surface plasmon resonance (SPR) approach was adopted to screen their Hsp90 binding capability and kotschyin D showed a significant affinity for the chaperone. Therefore, the characterization of the biological activity of kotschyin D by means of a panel of chemical and biological approaches, including limited proteolysis, molecular docking and biochemical and cellular assays, was performed. Our result indicated this compound as a type of client selective Hsp90 inhibitor, directly binding to the middle domain of the protein and possibly preventing its interaction with the activator of Hsp90 ATPase 1 (Aha1).
Abstract: Here we report the first application of combined accurate ROE-distance analysis with DFT calculations of NMR chemical shifts to achieve the relative configuration assignment of a marine natural product, conicasterol F, a new polyhydroxylated steroid isolated from the marine sponge Theonella swinhoei. We demonstrate the substantial advantages of this combined approach as a tool for structural studies of natural products, providing a powerful alternative to, or information to underpin, total synthesis when more classical NMR data analysis fails to provide unequivocal results. In this paper, we also describe the isolation and structure elucidation of conicasterol F and its 24-ethyl derivative, theonellasterol I, and their pharmacological evaluation as human nuclear receptor modulators.
Abstract: The finding of new PXR modulators as potential leads for treatment of human disorders characterized
by dysregulation of innate immunity and with inflammation is of wide interest. In this paper, we report
the identification of the first example of natural marine PXR agonists, solomonsterols A and B, from a
Theonella swinhoei sponge. The structures were determined by interpretation ofNMRand ESIMSdata,
and the putative binding mode to PXR has been obtained through docking calculations.
Abstract: GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation.
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.
Abstract: Two new cyclopeptides, perthamides E and F were isolated from the polar extracts of the sponge Theonella swinhoei. The new structures, featuring an unprecedented beta-amino acid unit (AHMOA), were determined by interpretation of NMR and MS data. The absolute configuration of the AHMOA residue was proposed on the basis of quantum chemical calculation of NMR chemical shifts. Perthamides were proved to inhibit TNF-alpha and IL-8 release in primary human keratinocytes cells and therefore could represent potentially leads for the treatment of psoriasis. (C) 2011 Elsevier Ltd. All rights reserved.
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.
Abstract: Two unprecedented cyclic peptides, solomonamides A and B, were isolated from the marine sponge Theonella swinhoei. The structures were elucidated on the basis of comprehensive 1D and 2D NMR analysis and high-resolution mass spectrometry. A combined approach, involving Marfey's method, QM J based analysis, and DFT J/(13)C calculations, was used for establishing the absolute configuration of the entire molecule. Solomonamide A showed in vivo anti-inflammatory activity.
Abstract: Malaitasterol A, an unprecedented bis-secosterol, was isolated from a Solomon collection of Theonella swinhoei. The structure was elucidated on the basis of a combination of comprehensive 1D and 2D NMR analysis, high-resolution mass spectrometry and DFT (13)C chemical shift calculations. The biological characterization of malaitasterol A provided evidence that this compound is a potent agonist of pregnane-X-receptor and its putative binding mode to PXR has been obtained through docking calculations.
Abstract: 6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a reduction a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.
Abstract: Silica gel column chromatography, followed by HPLC purification on the apolar fraction of the methanol extract of marine sponge Theonella swinhoei, resulted in the isolation of a library of 10 polyhydroxylated steroids which we named theonellasterols B-H (1-7) and conicasterols B-D (8-10). The structures were determined on the basis of extensive spectroscopic data (MS, (1)H and (13)C NMR, COSY, HSQC, HMBC, and ROESY) analysis, and the putative binding mode to nuclear receptors (NRs) has been obtained through docking calculations. Pharmacological and structure-activity relationship analysis demonstrate that these natural polyhydroxylated steroids are potent ligands of human nuclear pregnane receptor (PXR) and modulator of farnesoid-X-receptor (FXR). In addition, the molecular characterization of theonellasterol G allowed the identification of the first FXR modulator and PXR ligand so far identified. Exposure of liver cells to this agent resulted in potent induction of PXR-regulated genes and modulation of FXR-regulated genes, highlighting its pharmacological potential in the treatment of liver disorders.
Abstract: 6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.
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).
Abstract: We report the biochemical characterization of sulfated polyhydroxysterols isolated from marine invertebrates as potent antagonists of farnesoid-X-receptor (FXR), a ligand-regulated transcription factor involved in the regulation of lipid and glucose homeostasis in mammals. Molecular characterization of a library of sulfated polyhydroxysteroids resulted in the identification of a first FXR antagonist. In contrast to partial antagonists, this compound was endowed with an antagonistic activity on the expression of a subset of FXR-regulated genes in liver cells and abrogated the release of nuclear coreceptor from the promoter of these genes. The putative binding mode to FXR, obtained through docking calculations, suggested the crucial role played by the bent shape of the molecule as well as the presence of one hydroxyl group in its side chain. This compound is a major tool to explore the effect of FXR inhibition in pharmacological settings.
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.
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 degrees 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 polysubstituded 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.
Abstract: Eight new antimicrobial natural products named chrysophaentins A-H belonging to a new structural class have been isolated from the marine chrysophyte alga Chrysophaeum taylori. Their structures were determined by extensive 2D NMR and MS techniques and are characterized by the presence of two polyhalogenated, polyoxygenated omega,omega'-diarylbutene units connected by two ether bonds to form the suite of macrocyclic natural products. Chrysophaentin A, the most potent of these antibiotics, inhibited the growth of clinically relevant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MIC(50) 1.5 +/- 0.7 microg/mL), multidrug-resistant S. aureus (1.3 +/- 0.4 microg/mL), and vancomycin-resistant Enterococcus faecium (MIC(50) 2.9 +/- 0.8 microg/mL). In vitro enzyme assays and transmission electron microscopy showed chrysophaentin A to inhibit the GTPase activity of the bacterial cytoskeletal protein FtsZ with an IC(50) value of 6.7 +/- 1.7 microg/mL, as well as GTP-induced formation of FtsZ protofilaments. Saturation Transfer Difference (STD) NMR experiments further confirmed chrysophaentin A binds to FtsZ, and NMR competition experiments with GTPgammaS showed chrysophaentin A and GTP to bind competitively to FtsZ. Last, molecular docking simulations provided a low energy model in which chrysophaentin A binds in and occludes a large portion of the GTP binding site of FtsZ in a manner that is consistent with the binding epitope determined by STD NMR.
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. (C) 2010 Elsevier Ltd. All rights reserved.
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 (Ki), 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.
Abstract: The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC50 for cytotoxicity in vitro of 3.8 +/- 0.3 nM and an IC50 for NAD depletion of 3.0 +/- 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening.
Abstract: Three new tetracyclic polyisoprenylated xanthones, named oxy-guttiferones M, K2, and 1, along with oxy-guttiferone K and guttiferone M, have been isolated from the fruits of Garcinia cambogia. Their structures were elucidated by MS and NMR spectroscopic experiments. The absolute configurations of oxy-guttiferone K, taken as a model of tetracyclic xanthones, and guttiferone M, as a model of polyisoprenylated benzophenones, have been determined by comparison of their experimentally measured circular dichroism (CD) curves with the TDDFT-predicted curves. (C) 2009 Elsevier Ltd. All rights reserved.
Abstract: The instability of the hydroxylactone Eâ ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomeraseâ 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 16âa-thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in positionâ 17 of the opened Eâ 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 topoisomeraseâ IâDNA 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.
Abstract: Novel macrocyclic peptide mimetics have been synthesized by exploiting a three-component reaction and an azide-alkyne [3 + 2] cycloaddition. The prepared compounds were screened as HDAC inhibitors allowing us to identify a new compound with promising biological activity. In order to rationalize the biological results, computational studies have also been performed.
Abstract: Six new depsipeptides belonging to two different structural classes, termed celebesides A-C and theopapuamides B-D, have been isolated from the marine sponge Siliquariaspongia mirabilis. Their structures were determined using extensive 2D NMR and ESI-MS/MS techniques. Celebesides are unusual cyclic depsipeptides that comprise a polyketide moiety and five amino acid residues, including an uncommon 3-carbamoyl threonine, and a phosphoserine residue in celebesides A and B. Theopapuamides B-D are undecapeptides with an N-terminal fatty acid moiety containing two previously unreported amino acids, 3-acetamido-2-aminopropanoic acid and 4-amino-2,3-dihydroxy-5-methylhexanoic acid. The relative configuration of the polyketide moiety in celebesides was resolved by J-based analysis and quantum mechanical calculations, the results of which were self-consistent. Celebeside A neutralized HIV-1 in a single-round infectivity assay with an IC50 value of 1.9 +/- 0.4 mu g/mL while the nonphosphorylated analog celebeside C was inactive at concentrations as high as 50 mu g/mL. Theopapuamides A-C showed cytotoxicity against human colon carcinoma (HCT-116) cells with IC50 values between 2.1 and 4.0 mu g/mL and exhibited strong antifungal activity against wildtype and amphotericin B-resistant strains of Candida albicans at loads of 1-5 mu g/disk.
Abstract: A series of bisnaphthalimide derivatives were synthesized and evaluated for growth-inhibitory property against HT-29 human colon carcinoma. The N, N â-bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl) ] propane-2-ethanediamine (9) and the N, N â-Bis[2-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benz[de]-isoquinolin-2-yl) ] butylaminoethyl]-2-propanediamine (12) derivatives emerged as the most potent compounds of this series. Molecular modelling studies indicated that the high potency of 12, the most cytotoxic compound of the whole series, could be due to larger number of intermolecular interactions and to the best position of the naphthalimido rings, which favours pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Moreover, 12 was designed as a DNA topoisomerase II poison and biochemical studies showed its effect on human DNA topoisomerase II. We then selected the compounds with a significant cytotoxicity for apoptosis assay. Derivative 9 was able to induce significantly apoptosis (40%) at 0.1 mu M concentration, and we demonstrated that the effect on apoptosis in HT-29 cells is mediated by caspases activation. (c) 2008 Elsevier Ltd. All rights reserved.
Abstract: In the present study, we used a molecular docking as a rapid, interactive method to study the inhibition of fibrillogenesis process by beta-sheet breaker peptide [BSB) (Ac-L-1-V-2 -(NMet)F-3-F-4-A(5)-NH2)- Our aim was to find the complex (A beta:BSB) that blocks the aggregation of the fibrils, and to identify the binding sequences for the small peptides on A beta(1-42). An NIVIR structure solved by Luhrs et at. in 2005 was used to study the interaction of BSB with the amyloid aggregated forms. From our preliminary step-by-step docking studies, the L(17)-D(23) sequence seems to be one of the most common active sites of A beta(1-42), and critical In amylold fibril formation. We note that a single molecule of BSB does not influence the interaction between the two fibrils, while a little excess of BSB (two molecules) with respect to the amyloid does not completely block but undoubtedly obstructs the aggregation process. Copyright (C) 2008 European Peptide Society and John Wiley & Sons, Ltd.
Abstract: HDAC inhibitors show great promise for the treatment of cancer. AS part of a broader effort to explore the SAR of HDAC inhibitors, synthesis, biological evaluation, and molecular docking of novel Ugi products containing a zinc-chelating moiety are presented. One compound shows improved inhibitory potencies compared to SARA, demonstrating that hindered lipophilic residues grafted on the peptide scaffold of the alpha-aminoacylamides can be favorable in the interaction with the enzyme.
Abstract: The preparation of a new class of backbone-modified PNA mimetic incorporating thymine is described. Target dipeptoid monomer 21 was synthesised from an N-[2-(thymin-1-yl)ethyl]glycinate ester and a properly protected iminodiacetic acid. The distinctive structural motif in the backbone is a carboxy group, inserted to impart water solubility to the oligomer. Two achiral oligopeptoid sequences (8-mer and 12-mer), characterised by the shift of the amide carbonyl group away from the nucleobase, were efficiently assembled according to solid-phase synthesis protocols. Thermal denaturation studies showed that the two homopyrimidine oligopeptoids do not effectively hybridise with complementary sequences of DNA and RNA or fully synthetic (2,4-diamino)triazin-6-yl-tagged peptoid 22. A possible reason could reside in the concurrent unfavourable influence of the anionic N-(carboxymethyl) moieties and the flexible nucleobase/backbone ethylene linker. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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 Ca2+ 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. Copyright (C) 2009 John Wiley & Sons, Ltd.
Abstract: We report on the use of a diversity oriented synthesis (DOS) approach that resulted in the generation of a set of libraries of compounds presenting novel structural cores. These chemical cores have been employed to design potential antagonists of the antiapoptotic protein Bcl-x(L) through reiterated steps of molecular docking calculations followed by experimental verification of binding. Our data suggest that the DOS approach is suitable to generate novel scaffolds, which can be employed to target protein-protein interactions.
Abstract: N-Benzyloxyethyl macrocyclic peptoids 3 and 4 were synthesized and subjected to alkali metal binding studies; these compounds, plus the known 1 and 2, when subjected to ion transport studies, demonstrated size-dependent selectivity for the first group alkali metals cation transport.
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. (C) 2008 Elsevier Ltd. All rights reserved.
Abstract: The analysis of the configuration of kedarcidin chromophore and palauâamine 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. Copyright (C) 2008 John Wiley & Sons, Ltd.
Abstract: H-1-H-1 scalar coupling across two stacked (parallel and eclipsed) aromatic rings has been revealed through the 1D and 2D H-1 NMR analysis of a [2,2]paracyclophane and rationalized by means of density functional theory (DFT) calculation of the J values. Copyright (c) 2008 John Wiley & Sons, Ltd.
Abstract: N-Benzyloxyethyl cyclic alpha-peptoids of various size were prepared and their conformational features were investigated by means of computational, spectroscopic, and X-ray crystallographic studies.
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 pro. le 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 pro. le is also described. (c) 2008 Elsevier Ltd. All rights reserved.
Abstract: (+)-Yatakemycin is a new and potent member of a class of natural antitumor compounds that derive their biological activities from specific alkylation of adenine residues in the minor grooves of AT-rich tracts. We have analyzed the covalent complex 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 H-1 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. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).
Abstract: Calix[4]arenes bearing aromatic amide (aramid) moieties at the upper rim display interesting recognition properties toward anions and in particular versus planar trigonal nitrate and Y-shaped benzoate. Molecular modeling and DFT calculations indicate that the high affinity displayed by aramidocalix[4]arenes 3 and 4 for nitrate anion is likely due to the planar arrangement of the NH groups, which form an unusual six-hydrogen-bond scheme with nitrate anion. (c) 2007 Elsevier Ltd. All rights reserved.
Abstract: QM GIAO calculations of C-13 and H-1 chemical shift values of the ArCH2Ar 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.
Abstract: On the basis of the biological activities exhibited by the phenolic constituents of Yucca schidigera, the antioxidant activity of the methanol extract of Yucca gloriosa roots was evaluated in the TEAC assay. The strong activity exerted by this extract prompted investigation of its phenolic constituents, yielding three new phenolic derivatives, gloriosaols C, D, and E, along with gloriosaols A and B previously isolated from Y. gloriosa roots and yuccaols C-E isolated from Y. schidigera. ESIMS and NMR data of gloriosaols C-E closely resembled those reported for gloriosaols A and B, two diasteroisomers characterized by unusual spirostructures. Careful inspection of ROESY spectra revealed that gloriosaols C-E are diastereoisomers of gloriosaols A and B. A possible assignment of the relative configuration of gloriosaols C-E, derived according to an integrated NMR-quantum mechanical (QM) approach, which was already applied to the determination of the stereostructures of gloriosaols A and B, is also proposed. Gloriosaols A-E exhibited potent antioxidant activity measured by the TEAC assay, showing the potential use of Y. gloriosa as a source of antioxidant principles.
Abstract: Two novel triterpenoids, aplysiols A (5) and B (6), have been isolated, together with structurally related known metabolites, from a South China Sea collection of the anaspidean mollusc Aplysia dactylomela. The structures of 5 and 6 were determined mainly by spectroscopic NMR techniques. The absolute stereochemistry of compound 5 was deduced by Mosherâs method as well as by biogenetical consideration, whereas the absolute stereochemistry of compound 6 was established also using an integrated NMR-QM (Quantum Mechanical) approach, based on the combination of C-13 NMR chemical shifts and (2,3)JC-H coupling constant DFT (density functional theory) calculations. (c) 2007 Published by Elsevier Ltd.
Abstract: The complex between distamycin A and the parallel DNA quadruplex [d(TGGGGT)](4) has been studied by H-1 NMR spectroscopy and isothermal titration calorimetry (ITC). To unambiguously assert that distamycin A interacts with the grooves of the quadruplex [d(TGGGGT)](4), we have analyzed the NMR titration profile of a modified quadruplex, namely [d(TGG(Me)GGT)](4), and we have applied the recently developed differential frequency-saturation transfer difference (DF-STD) method, for assessing the ligand - DNA binding mode. The three-dimensional structure of the 4:1 distamycin A/[d(TGGGGT)](4) complex has been determined by an in-depth NMR study followed by dynamics and mechanics calculations. All results unequivocally indicate that distamycin molecules interact with [d(TGGGGT)](4) in a 4:1 binding mode, with two antiparallel distamycin dinners that bind simultaneously two opposite grooves of the quadruplex. The affinity between distamycin A and [d(TGGGGT)](4) enhances (similar to 10-fold) when the ratio of distamycin A to the quadruplex is increased. In this paper we report the first three-dimensional structure of a groove-binder molecule complexed to a DNA quadruplex structure.
Abstract: Two new cyclized C-geranylated flavonoids, the dihydroflavonol bonanniol C (4a) and the flavanone bonannione B (6a), were isolated as minor compounds from the aerial parts of Bonannia graeca (Umbelliferae). Their structures were elucidated by a combined approach of extensive spectroscopic means and quantum mechanical methods. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).
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.
Abstract: Gloriosaols A (1) and B (2), two novel phenolic derivatives characterized by unusual spirostructures made UP Of two C-15 units linked via a gamma-lactone to a central stilbenic portion were isolated from the roots of Yucca gloriosa. On the basis of an extensive NMR analysis, the same basic structure was established for the two compounds but no further information about their structural difference could be deduced. Thus two hypotheses were formulated: (1) gloriosaols A and B could be atropisomers caused by a restriction of the free rotation around the double bond due to a steric congestion of the bulky phenolic portions; (2) gloriosaols A and B could be two configurational isomers, indicating, in this case, a nonstereoselective biogenetic formation of the stereogenic center C-2. Semi-empirical calculations of the potential energy surfaces on gloriosaols A and B, together with the H-1 NMR spectra recorded at various temperatures, allowed us to unambiguously exclude the hypothesis of two restricted rotational conformers of a single configurational isomer. Finally, quantum mechanical calculations of the geometries and of the 1H chemical shifts on the gloriasols A and B in combination with the analysis of the ROE data allowed us to deduce a diastereomeric relation between the two compounds and to assess the relative configuration of the two diastereomers. (c) 2006 Published by Elsevier Ltd.
Abstract: Peptide T (ASTTTNYT), a segment corresponding to residues 185-192 of gp120, the coat protein of HIV, has several important biological properties in vitro that have stimulated the search for simpler and possibly more active analogs. We have previously shown that pseudocyclic hexapeptide analogs containing the central residues of peptide T retain considerable chemotactic activity. We have now extended the design of this type of analogs to peptides containing different aromatic residues and/or Ser in lieu of Thr. The complex conformation-activity relationship of these analogs called for a reexamination of the basic conformational tendencies of peptide T itself. Here, we present an exhaustive NMR conformational study of peptide T in different media. Peptide T assumes a gamma-turn in aqueous mixtures of ethylene glycol, a type-IV beta-turn conformation in aqueous mixtures of DMF, and a type-II beta-turn conformation in aqueous mixtures of DMSO. The prefer-red conformations for the analogs were derived from modeling, starting from the prefer-red conformations of peptide T. The best models derived from the gamma-turn conformation of peptide T are those of peptides XII (DSNYSR), XIII (ETNYTK) and XVI (ESNYSR). The best models derived from the type-IV beta-turn conformation of peptide T are those of peptides XIV (KTTNYE) and XV QSSNYR). No low-energy models could be derived starting from the type-II beta-turn conformation of peptide T. The analogs with the most favored conformations are also the most active in the chemotactic test. Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.
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, D-aThr1, D-aThr2 and beta-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 P-OMeTyr residue and the revision of the configuration of the Thr2 unit in callipeltin A. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Abstract: The RuO4-catalyzed oxidative polycyclization of some selected linear polyenes, possessing a repetitive 1,5-diene structural motif, has been investigated. The all-traps triene (E,E,E)-acetic acid henicosa-2,6,10-trienyl ester gave the expected bis-tetrahydrofuranyl diol product possessing a threo-cis-threo-cis-threo relative configuration, along with a mixture of the corresponding bis-THF ketols. These compounds can be seen as useful intermediates in the synthesis of the bis-THF diol core of adjacent bis-THF antitumour acetogenins possessing a threocis-threo-cis-erythro relative configuration, such as rolliniastatiin-1, membranacin, rollimembrin and membrarollin. Oxidation of the related all-traps tetraene (E,E,E,E)-acetic acid pentacosa-2,6,10,14-tetraenyl ester stops at the second cyclization step giving a mixture of a threo-cisthreo-cis-threo bis-THF diol and the corresponding ketol products. Oxidation of the triene (E,E,E,E)-acetic acid 12-acetoxy-dodeca-2,6,10-trienyl ester stops at the monocyclization level failing to give bis-cyclized products, as previously observed for the related isoprenoid triene (E,Z)-farnesyl acetate. This result confirms the difficulty of closing a second THF ring when the central double bond of the triene possesses a cis configuration. Based on the collected results, a plausible model is proposed that both explains the observed cis/traps stereoselectivity for each ring-closing step in these processes, and rationalize the stereochemical course of the previously studied polycyclization of the isoprenoid polyenes (E,E)-farnesyl acetate, geranylgeranyl acetate and squalene. (c) 2006 Elsevier Ltd. All rights reserved.
Abstract: We have designed, synthesized and evaluated the CB, 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 CB1 affinities in competitive binding assays with K-i values in the micromolar range (K-i of AEA = 0.8 mu m in the same assay). The remaining pseudopeptides showed little binding to the CB, receptor (with K-i values >= 50 mu m). 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 hairpinlike structural motif and the CB, 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. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.
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.
Abstract: Capitalizing on an oxidation-alkylation approach, a non-diastereoselective entry into 2â-methyl taxanes was developed. The issue of configurational assignment at the newly formed side-chain quaternary stereocenter was solved and put into a more general context by integrating information from, an alternative diastereoselective synthesis of model compounds and from spectroscopic measurements, critically comparing the J-Based and the Universal NMR Database approaches. (c) 2005 Elsevier Ltd. All rights reserved.
Abstract: An efficient preparation of a series of secondary amines, structurally related to the kainic acid scaffold, is described. Naturally occurring (-)-alpha-kainic acid was hydroformylated with complete terminal selectivity and high stereoselectivity. The stereochemistry of the product was investigated through the ROESY and FIETLOC spectra of the corresponding 2,4-dinitrophenyl hydrazone, showing the presence of a single diastereoisomer with rotamers related to the presence of the Boc group. The aldehyde was used as a platform to prepare amines by reductive amination in ionic liquids.
Abstract: The configuration of the alpha-substituted alpha-hydroxy-beta-aminoester moiety in a series of 2â-substituted taxanes was analyzed according to the recently proposed Universal NMR Database (UDB) approach. A critical analysis of the results showed that modifications regarding chemical shift adjustment (so as to render the shifts virtually connectivity independent) were necessary to get consistent stereoassignments in this set of compounds. On this basis, a modified UDB-based strategy, especially tailored to the configurational assignment of densely substituted diastereomeric fragments, is proposed.
Abstract: Eight new 14,15-secopregnane glycosides, namely argelosides C-J, possessing two ketal functions involved in three five-membered rings, have been isolated from the hairy seeds of Solenostemma argel. Their structures have been established by MS and NMR experiments, combined with quantum mechanical calculations of the C-13 chemical shifts for the interpretation of the experimental data. On the basis of the obtained results, the structures of argelosides A and B have been revised. Additionally, the effect of these compounds on the VEGF-induced in Kaposiâs sarcoma cell proliferation was evaluated. Results indicated that all the compounds reduced the cell proliferation in a dose-dependent manner. (c) 2005 Elsevier Ltd. All rights reserved.
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. (c) 2005 Elsevier Ltd. All rights reserved.
Abstract: QM GIAO calculations of C-13 and H-1 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.
Abstract: The methodology of J-based analysis applied to 1,3-methylcarboamido systems allowed us to deduce the relative configurations of the two leucine-like fragments of a new tetrachloro, amino acid derivative dysithiazolamide, which was isolated from an unidentified sponge of the genus Dysidea. Furthermore, the absolute configuration was also proposed by comparison with analogous systems. (c) 2005 Elsevier Ltd. All rights reserved.
Abstract: The configuration of the penta-tetrahydrofuranyl diol (penta-THF) product obtained by a single-step, RuO4-catalyzed oxidative polycyclization of squalene, has been determined as cis-threo-cis-threo-trans-threo-trans-threo-trans. The cis-cis-trans-trans-trans sequence for the five contiguous THF rings has been established through extensive 2D-NMR spectroscopic studies carried out both on the intact molecule and on some of its derivatives, including the oxidative cleavage products obtained by degradation of the penta-THF with PCC/AcOH. Four different chemical approaches were devised to determine each of the four threo relationships within each carbon pair connecting adjacent THF rings in the molecule. To this aim, studies have been carried out either on some intermediates of the process leading to penta-THF, obtained by stopping the oxidation of squalene prior to completion, or on a degradation product of the penta-THF, obtained from the latter through a bidirectional double oxidative degradation with PCC. (C) 2004 Elsevier Ltd. All rights reserved.
Abstract: Stemmosides C and D, two novel pregnane glycosides characterized by an unusual C-17alpha side chain were isolated from the pericarps of Solenostemma argel. In addition, stemmoside D displays an uncommon 14beta proton configuration, apparently being the first pregnane isolated from plants known to have a 15 keto, cis CD ring junction. Their structures have been established by ESIMS and NMR experiments. The relative configuration of the molecules was determined using a strategy based on the simulation of H-1, C-13, and J coupling NMR parameters. DFT calculations of H-1 and C-13 chemical shifts, and of the H homonuclear spin-spin coupling constants were performed with the mPW1PW91 functional using the 6-31G(d,p) basis set on the fully optimized geometries of all the possible stereoisomers. (C) 2004 Elsevier Ltd. All rights reserved.
Abstract: SCSA is an algorithm designed to get information on molecular conformational properties. The most stable conformers are determined by the homemade SCSA code, performing a multistep systematic conformational search, which involves energy and structure quantum chemical optimizations at low-level and high-level. The SCSA method was employed to analyze the conformational space of the in vacuo cyclopeptide renieramide at AM1 and B3LYP/6-31G(d) levels. Calculations at B3LYP level of the GIAO C-13 NMR chemical shifts were also performed on the final conformers. In fact, to validate the conformational search results experimental and calculated C-13 NMR spectra of renieramide were compared. Slight disagreements observed between experimental and calculated spectra could be attributed to solute-solvent interactions, which were not taken into account in the algorithm proposed here.
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-PBEO/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.
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 1 (1), tolaasin 11 (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.
Abstract: The (17R,20S,22S,24S) C-20-C-29 segment of contignasterol has been stereoselectively prepared in 8 steps and 40% overall yield from (S)-carvone. Synthetic studies towards contignasterolâs C/D ring functionalization/isomerization are also reported. (C) 2004 Elsevier Ltd. All rights reserved.
Abstract: The influence of the calculation method in mimicking experimental C-13 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 C-13 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 C-13 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 C-13 NMR calculations were thoroughly checked by the analysis of statistical parameters concerning computed and experimental C-13 NMR chemical shift values. Copyright (C) 2004 John Wiley Sons, Ltd.
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.
Abstract: 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.
Abstract: The stereochemical study of flexible stereogenic carbon chains, such as those of many novel natural products, is a particularly challenging task. Recent applications of our group on the so-called âJ-based approachâ, a methodology relying on a detailed analysis of homonuclear (H-H) and heteronuclear (C-H) (2,3)J couplings, include the study of the sphinxolide family of antitumor macrolides, a group of molecules characterized by a flexible macrocyclic framework bearing a number of oxygenated and methylated undetermined stereocenters, and of ascaulitoxin, a nitrogen-containing phytotoxin with herbicidal activity produced by a phytopathogenic fungus. An extension of the original procedure, relying on a Hartree-Fock (HF) ab initio calculation of conformational equilibrium and an estimate of the Boltzmann averaged (2,3)J(HH) and (2,3)J(CH) couplings, has been applied to the stereochemical study of sapinofuranone A, where the conformational equilibrium among existing rotamers had initially led to controversial results. C-13 NMR chemical shifts are additional useful parameters in the study of complex organic molecules. Along these lines, we have lately proposed the use of Hartree-Fock gauge including atomic orbitals (GIAO) calculated C-13 NMR chemical shift values as a supporting tool for the validation of the structure of new natural products and the determination of the relative stereochemistry of diastereomeric flexible compounds that are characterized by multiple conformer equilibria.
Abstract: Further studies on the RuO4-catalyzed oxidative polycyclization of isoprenoid polyenes have been carried out. The configuration of the tris-THF product from the oxidation of geranylgeranyl acetate has been determined by a combination of spectral and chemical correlation methods. The oxidation of (EZ)-farnesyl acetate, synthesized from nerol, has been carried out. This process stops at the first cyclization indicating that an E configuration of the Delta(6) double bond is needed for the second cyclization to occur. The results are discussed in comparison with previous knowledge on the related Re(VII) polycyclization of polyenic bis-homoallylic alcohols. (C) 2003 Elsevier Science Ltd. All rights reserved.
Abstract: Quantum chemical calculations at mPW1PW91 level, with full geometry optimization, using the 6-31 g(d) basis set, and GIAO (gauge including atomic orbitals) C-13 NMR chemical shifts using the 6-31g(d,p) basis set, are here utilized as a support to define the configurational features of the natural product passifloricin A, whose previously proposed relative configuration has been recently shown, by synthetic studies. to be incorrect. This study suggests that the relative stereostructure for passifloricin A corresponds to the delta-lactone of the (5R,7R,9S,11R)-tetrahydroxyhexttcos-2-enoic acid. (C) 2003 Elsevier Ltd. All rights reserved.
Abstract: The absolute configuration of the seven stereogenic centers contained in the C23-C35 portion of reidispongiolide A is determined by asymmetric synthesis of the corresponding fragment obtained by ozonolysis of the natural macrolide. (C) 2003 Elsevier Science Ltd. All rights reserved.
Abstract: Argeloside A and B, two novel 14,15-secopregnane glycosides characterized by the presence of two hemiketal functions involved in two five-membered rings, were isolated from Solenostemma argel fruits. Their structures have been established by ESIMS and NMR experiments. In particular the relative configuration of the molecules has been defined by combining the available NMR data with quantum chemical calculations of the geometries and C-13 chemical shifts. (C) 2003 Elsevier Ltd. All rights reserved.
Abstract: We report the NMR solution structure of (+)-CPI-indole (CPI, 1,2,8,8a-tetrohydrocyclopropa[c]pyrrolo[3,2-e]indol-4(5H)-one), an agent belonging to the CC-1065/duocarmycin family of antitumor compounds. This (+)-CPI-indole structure is covalently bound to d(G(1)ACTAATTGTC(11))-d(G(12)TCAATTAGTC(22)), a synthetic DNA duplex containing a high-affinity binding site. The three-dimensional structure has been determined by several cycles of restrained molecular dynamics calculations with a total of 563 NMR-derived constraints, both in vacuo and by using the generalized Born solvent continuum model. In-depth analysis of the structure of this ligand-DNA complex led to a detailed knowledge of the bound state conformation of the CPI-indole, the most simplified agent related to CC-1065 and duocarmycins, the parent members of a family of extremely potent antitumor compounds. Comparison of the CPI-indole bound conformation with those previously found for (+)-duocarmycin SA (DSA), its unnatural enantiomer (-)-DSA, and the demethoxylated analogue (+)-DSI in their DNA complexes provided additional evidence of the tight correlation between the catalytic effect exerted by DNA on the alkylation reaction and the extent of angular twist between the two planar heteroaromatic subunits of these agents. Additionally, comparison of the structural features of the DNA-bound state of a ânakedâ ligand, such as CPI-indole, with those of various other duocarmycin agents provided useful information for the interpretation of the observed effects on chemical reactivity of the different substitution patterns at the hemispheres of these types of complex.
Abstract: Simulation of 2D H-1 homo- and H-1-C-13 heteronuclear NMR spectra of organic molecules are here suggested as a tool in the structure elucidation of organic compounds. DFT calculations of H-1 and C-13 chemical shifts are performed on a sample compound, the ethyl ester of the exo-2-norbornanecarbamic acid, with the mPW1PW91 method using the 6-31G(d) basis set, following a full optimization of the geometry. Homo and heteronuclear spin-spin coupling constants are also calculated, providing full prediction of the common 2D H-1-H-1 COSY, 2D H-1-C-13 HSQC, and 2D H-1-C-13 HMBC. (C) 2003 Elsevier Ltd. All rights reserved.
Abstract: Geometry optimization and GIAO (gauge including atomic orbitals) C-13 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 C-13 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 C-13 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 C-13 chemical shifts of both correct and incorrect structures matched the experimental data.
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) C-13 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 C-13 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 C-13 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 C-13 chemical shifts versus the corresponding computed average data allowed us to distinguish among the four stereoisomers.
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.
Abstract: Five fragments, 2a-4b, embedding all the stereogenic centers of reidispongiolide A (1), have been prepared by a controlled ozonolysis of the natural compound. The absolute stereochemistry of the asymmetric centers of fragment 3, corresponding to the C17-C22 portion of reidispongiolide A, was determined by enantioselective synthesis and application of the advanced Mosher method.
Abstract: The Structural revision of the anti-inflammatory marine metabolites halipeptin A (1) and B (2) along with the isolation of the new related product halipeptin C (3) are reported. In particular, the heterocyclic portion of the molecule. incorrectly assigned as an oxazetidine ring, has now been characterised as a thiazoline unit by comparison of the spectral data of the natural products (1-3) with an appropriate synthetic model (10). GIAO calculated C-13 NMR chemical shifts for oxazetidine and thiazoline model compounds provide additional support to the revised structure. (C) 2002 Elsevier Science Ltd. All rights reserved.
Abstract: Four new triterpenoid estersaponins, tentatively designated as IIIA(2) (1), IIIA(3) (2), 111132 (3), and IIIC4 (4) have been isolated from fruits of Pittosporum tobira AIT. and their structures elucidated by spectroscopic and chemical analyses. All the four compounds consist of an acylated pentacyclic triterpenoid aglycone which bears the same oligosaccharide portion. The crude saponin mixture (CIDI) was found to show significant in vitro and in vivo cytotoxicity in different human cancer cell lines. (C) 2002 Elsevier Science Ltd. All rights reserved.
Abstract: A new, very unusual, phenolic constituent based on a spiro benzopyran-4-cyclopentan-3-one system has been isolated from Yucca schidigera bark and its structure has been established by ESI-MS and NMR experiments. In particular the relative configuration of the molecule has been defined combining the NMR data with ab initio conformational studies; the minimum energy conformers for the eight possible diastereomers were compared to the NMR experimental data in order to assess the diastereomer fitting of all the J coupling values and the dipolar values. (C) 2002 Elsevier Science Ltd. All rights reserved.
Abstract: Isoprenoid polyenes farnesyl acetate, geranylgeranyl acetate and squalene undergo oxidative polycyclization to bis-, tris-, and penta-tetrahydrofurane products, respectively, in the presence of catalytic amounts of RuO4 (from RuO4.2H(2)O) and NaIO4 as primary oxidant. The stereochemistry of the bis-cyclization product was established as cis-threo-cis-threo through chemical methods and 2D-NMR experiments, and a cascade mechanism was proposed that explains the reactivity exhibited by all the related polyenes. A similarity with rhenium(VII) chemistry has emerged. (C) 2002 Elsevier Science Ltd. All rights reserved.
Abstract: [GRAPHICS] 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.
Abstract: The J-based NMR configurational analysis was applied to the determination of relative stereochemistry of the ascaulitoxin molecule (1), a phytotoxic metabolite with herbicidal activity against Chenopodium album. This method is particularly suitable for acyclic structures containing hydroxy(alkoxy) groups, because in this kind of system, besides (3)J(H-H) and (3)J(C-H), (2)J(C-H) values can also be used to extract additional angular information. Ascaulitoxin (1), with its bis-amino acid side chain containing four stereocenters, two of which with nitrogen substituents, required a more careful analysis of heteronuclear J-couplings, also in comparison with theoretical values obtained by ab initio methods. (C) 2001 Elsevier Science Ltd. All rights reserved.
Abstract: Two new metabolites, named halipeptins A and B, have been isolated from the marine sponge Haliclona sp. Their structures were determined by extensive use of one- and two-dimensional NMR experiments, mass spectrometry, and UV and IR spectroscopy. Halipeptin A is a novel 17-membered cyclic depsipeptide, consisting of five residues including two alanines (with L stereo chemistry) and three new residues that appear to be previously undescribed from natural sources: 1,2-oxazetidine-4-methyl-4-carboxylic acid, 3-hydroxy-2,2,4-trimethyl-7-methoxydecanoic acid (HTMMD), and N-methyl-delta -hydroxyisoleucine. The HTMMD residue is substituted with 3-hydroxy-2,2,4-trimethyl-7-hydroxydecanoic acid in halipeptin B. Halipeptin A was found to possess very potent anti-inflammatory activity in vivo, causing about 60% inhibition of edema in mice at the dose of 300 mug/kg (i.p.).
Abstract: An improved Version of the J-based NMR configurational analysis of flexible organic molecules, that relies on extensive use of HSQC-TOCSY spectra, was applied to the stereochemical study of sphinxolide, a potent anti-tumor marine macrolide acting on cell microfilaments that has lately proven to circumvent multi-drug-resistance (MDR) in cancer cells. NMR data allowed stereochemical assignment of all molecular segments except the C18-C19 unit, whose configuration had to be addressed by a chemical/degradative approach.
Abstract: Dactylolide (1), a new cytotoxic 20-membered macrolide, was isolated from a marine sponge of the genus Dactylospongia collected off the coast of the Vanuatu islands. It co-occurred with other known bioactive macrolides: latrunculin A (2), laulimalide (3), isolaulimalide (4) and with the anthelminthic mycothiazole (5). The structure of 1, which is a minor metabolite, was elucidated by spectroscopy (mainly by 1D/2D NMR and MS techniques). It showed cytotoxic activity against the L1210 and SK-OV-3 tumor cell lines (63% and 40% inhibition at 3.2 mug/mL).
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 H-1 and C-13 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). (C) 2001 Elsevier Science Ltd. All rights reserved.
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 muM range on KB cells and antioxidant activity.
Abstract: A new bromoindole alkaloid, named dragmacidin F (1) and structurally related to other dragmacidins previously described, was isolated from a marine sponge of the genus Halicortex collected off the southern coast of Ustica Island (Italy). Structural elucidation of 1 was achieved by an extensive spectroscopic study (mainly by 1D/2D-NMR and MS techniques). Compound 1, containing an unprecedented carbon skeleton that is very likely derived from cyclization of a partially oxidized form of dragmacidin D (2), showed in vitro antiviral activity against HSV-1 (EC50=95.8 mu M) and HIV-1 (EC50=0.91 mu M), thus proving to be responsible for the antiviral property exhibited by Halicortex extracts. (C) 2000 Elsevier Science Ltd. All rights reserved.
Abstract: Chemical investigation of the Et2O 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 broncopulmonary cancer cells (NSCLC-NG) with an IC50 of 12 and 6.3 mu g/mL, respectively.
Abstract: Duocarmycin SA is a member of a growing class of interesting lead compounds for chemotherapy, distinguished by the manner in which they bind to and react with DNA substrates. The first three-dimensional structure of a DNA adduct of an unnatural enantiomer from this family has been determined by H-1 NMR methods. Comparison to the previously determined structure of the natural enantiomer bound in the same DNA-binding site provides unique insights into the similarities and critical distinctions producing the respective alkylation products and site selectivities. The results also support the hypothesis that the duocarmycin SA alkylation reaction is catalyzed by the binding to DNA, and provide a deeper understanding of the structural basis for this unique mode of activation. (C) 2000 Academic Press.
Abstract: The head-to-tail dimer of the calicheamicin oligosaccharide domain exhibits substantially higher DNA binding affinity and sequence selectivity and greater bioactivity than the monomer from which it is derived. To determine the structural basis for these functional properties, the solution structure of the 1:1 complex between the head-to-tail dimer of the calicheamicin oligosaccharide and the oligonucleotide duplex d(GCACCTTCCTGC). d(GCAGGAAGGTGC) has been solved by restrained molecular dynamics calculations using NMR-derived distance and torsion angle constraints. The final input data consisted of 562 internuclear distance and 114 dihedral angle constraints, an average of 27 constraints per residue. In contrast to observations made for a complex between a DNA duplex and the head-to-head dimer of calicheamicin oligosaccharide, the head-to-tail dimer exhibits a unique binding mode in the DNA minor groove. A comparative analysis of the carbohydrate-DNA interactions at the two different binding sites explains at the atomic level how calicheamicin derivatives are able to effectively recognize both d(ACCT) and d(TCCT) sites. This study brings deeper insight into the factors governing DNA-binding affinity and the sequence preferences of calicheamicin and its derivatives.
Abstract: Hydrophobic core residues have a marked influence on the Ca2+-binding properties of calbindin D-9k, even though there are no direct contacts between these residues and the bound Ca2+ ions. Eleven different mutants with substitutions in the hydrophobic core were produced, and their equilibrium Ca2+ binding constants measured from Ca2+ titrations in the presence of chromophoric chelators. The Ca2+ dissociation rate constants were estimated from Ca2+ titrations followed by H-1 NMR1 and were measured more accurately using stopped-flow fluorescence. The parameters were measured at four KCI concentrations to assess the salt dependence of the perturbations. The high similarity between the NMR spectra of mutants and wild-type calbindin D-9k suggests that the structure is largely unperturbed by the substitutions. More detailed NMR investigations of the mutant in which Va161 is substituted by Ala showed that the mutation causes only very minimal perturbations in the immediate vicinity of residue 61, Substitutions of alanines or glycines for bulky residues in the center of the core were found to have significant effects on both Ca2+ affinity and dissociation rates. These substitutions caused a reduction in affinity and an increase in off-rate. Small effects, both increases and decreases, were observed for substitutions involving residues far from the Ca2+ sites and toward the outer part of the hydrophobic core. The mutant with the substitution Phe66 â> Trp behaved differently from all other mutants, and displayed a 25-fold increase in overall affinity of binding two Ca2+ ions and a 6-fold reduction in calcium dissociation rate. A strong correlation (R = 0.94) was found between the observed Ca2+-dissociation rates and affinities, as well as between the salt dependence of the off-rate and the distance to the nearest Ca2+-coordinating atom. There was also a strong correlation (R = 0.95) between the Ca2+ affinity and stability of the Ca2+ state and a correlation (R = 0.69) between the Ca2+ affinity and stability of the apo state, as calculated from the results in the present and preceding paper in this issue [Julenius, K., Thulin, E., Linse, S,, and Finn, B. E, (1998) Biochemistry 37, 8915-8925]. The change in salt dependencies of k(off) and cooperativity were most pronounced for residues completely buried in the core of the protein (solvent accessible surface area approximate to 0), Altogether, the results suggest that the hydrophobic core residues promote Ca2+ binding both by contributing to the preformation of the Ca2+ sites in the apo state and by preferentially stabilizing the Ca2+-bound state.
Abstract: An unusual sulfated mannose homopolysaccharide (1) showing in vitro anti-HIV activity has been isolated from the mucous secretion of the Pacific tunicate Didemnum molle. Analysis of H-1 and C-13 NMR data polysaccharide and its desulfated derivative 2 revealed that it consists of a sequence of 2,3-disulfated mannose units joined through beta (1,6) glycosidic linkages.
Abstract: The head-to-head dimer of the calicheamicin oligosaccharide domain exhibits an impressive nanomolar affinity for its specific DNA recognition sites and a substantially higher degree of sequence selectivity relative to the oligosaccharide monomer. In an effort to detennine the structural basis for these binding properties, the solution structure of the 1:1 complex between the head-to-head dimer and the self-complementary oligonucleotide d(CGTAGGATATCCTACG)(2) has been solved using H-1 NMR-derived distance and torsion angle constraints and molecular dynamics calculations. Complete sequence specific proton assignments of both the DNA duplex and the carbohydrate have been obtained by 2D-NMR. A total of 607 experimentally derived constraints were identified including 452 proton-proton distance constraints derived from NOESY cross peaks intensities and assigned hydrogen bonds, along with 155 dihedral angle constraints obtained from a detailed analysis of the multiplet structure of cross-peaks for the sugar rings and from qualitative analysis of nuclear Overhauser effects for the DNA backbone. The final conformation of the complex is represented by an ensemble of seven structures (the average all-atom root mean square deviation from the mean is 1.07 Angstrom in the well-defined region) obtained by refining 14 initial conformations with widely different nonstandard DNA geometries. A number of favorable interactions are found to stabilize the structure of the complex and account for binding sequence preferences. Overall, the binding mode of each oligosaccharide unit of the head-to-head dimer in the DNA minor groove seems to be very close to that observed in the case of the monomeric calicheamicin oligosaccharide bound to its corresponding TCCT recognition site. Variable temperature NMR studies have shown that this dimer binds to d(CGTAGGATATCCTACG)(2) in two subtly different conformations, probably differing in the positioning of rings E and Eâ, interconverting with a rate constant of similar to 0.35 s(-1). The solution structure of this carbohydrate-DNA complex provides confirmation of design principles for new calicheamicin-based DNA-binding agents and confirms insights obtained previously into the molecular basis for oligosaccharide recognition within the DNA minor groove.
Abstract: Prenylhydroquinone sulfates have been isolated from a marine sponge, Ircinia sp., collected off New Caledonia. These compounds bind to the neuropeptide Y receptor, inhibit the tyrosine protein kinase and HIV-integrase enzymes, and co-occur with a mixture of sulfated prenylated chromanols and chromenols, prenylhydroquinones, and the corresponding quinones and chromenols. A hydroxylated heptaprenylhydroquinone, which proved to be active against tyrosine protein kinase, was also isolated, as well as a novel C-31 furanoterpene alcohol sulfate, named ircinol sulfate.
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-(6â-bromo-3â-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.
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 C-1(4) and C-4(1) conformations.
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.
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.
Abstract: We report the isolation and the structural elucidation of a family of polyhydroxylated steroids from the marine sponge Theonella swinhoei. Decodification of interactions of these family with nuclear receptors shows that these steroids are potent agonists of human pregnane-X-receptor (PXR) and antagonists of human farnesoid-X-receptor (FXR) with the putative binding mode to nuclear receptors (NRs) obtained through docking experiments. By using monocytes isolated from transgenic mice harboring hPXR, we demonstrated that swinhosterol B counter-regulates induction of pro-inflammatory cytokines in a PXR-dependent manner. Exposure of CD4(+) T cells to swinhosterol B upregulates the expression of IL-10 causing a shift toward a T cells regulatory phenotype in a PXR dependent manner. These results pave the way to development of a dual PXR agonist/FXR antagonist with a robust immunomodulatory activity and endowed with the ability to modulate the expression of bile acid-regulated genes in the liver.
