Head of Epigenetic Med Chem Lab - University of Salerno Director of PhD program in Pharmaceutical Sciences, University of Salerno Member of the Patents Commission of the University of Salerno
Education: 1997: Ph.D. in Medicinal Chemistry, University of Rome ''La Sapienza'', Italy 1993: Master degree in Pharmaceutical Chemistry, summa cum laude, University of Rome ''La Sapienza'', Italy
Research experience: 2004: Visiting professor, Department of Chemistry & Biochemistry, UCLA, Los Angeles, CA (USA). 2002-present: Associate Professor, University of Salerno, Italy. 2001: Assistant Professor, University of Salerno, Italy 2001: Research Associate, University of Siena, Italy 2000 : Postdoctoral Fellow, University of Rome ''La Sapienza'', Italy 2000: Italian Pasteur Institute Research Fellow, Medicinal Chemistry Department, University of Rome, Italy 1998-1999: Italian NIH Research Fellow, Medicinal Chemistry Department, Rome, Italy 1997: CNR (Italian National Research Center) Research Fellow, Drug Chemistry Center, University of Rome, Italy
Research Interests: Design, synthesis and optimization of antiviral (HIV and HRVs) and antibacterial agents of MAO-inhibitors and of small-molecule modulators of epigenetic enzymes (HDAC, HAT, HKMT, DNMT, PRMT, LSD1 and PAD4 as well as endogenous non-telomeric RT); pharmacological principles of active drugs, new methodologies for the synthesis of heterocyclic compounds.
Awards 2008: Farmindustria Italian National Award for Research Excellence in Medicinal Chemistry. 1998: Italian Pasteur Institute Award for best Ph.D. thesis 1995: Italian Federation of Chemical Industry (Federchimica) Award 1994: Italian Pasteur Institute Award for best Master Degree thesis
Memberships Italian Chemical Society (SCI) - Medicinal Chemistry Division European Federation for Medicinal Chemistry (EFMC) Epigenetics Society
Abstract: A series of novel 4-phenylquinazoline-2-carboxamides (<b>1-58</b>) were designed as aza-isosters of PK11195, the well-known 18 kDa Translocator Protein (TSPO) reference ligand, and synthesized by means of a very simple and efficient procedure. A number of these derivatives bind to the TSPO with <i>K<sub>i</sub></i> values in the nanomolar/subnanomolar range, show selectivity towards the central benzodiazepine receptor (BzR), and exhibit structure-affinity relationships consistent with a previously published pharmacophore/topological model of ligand-TSPO interaction.
Abstract: A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.
Abstract: Worker and queen bees are genetically indistinguishable. However, queen bees are fertile, larger and have a longer lifespan than their female worker counterparts. Differential feeding of larvae with royal jelly controls this caste switching. There is emerging evidence that the queen-bee phenotype is driven by epigenetic mechanisms. In this study, we show that royal jelly--the secretion produced by the hypopharyngeal and mandibular glands of worker bees--has histone deacetylase inhibitor (HDACi) activity. A fatty acid, (E)-10-hydroxy-2-decenoic acid (10HDA), which accounts for up to 5% of royal jelly, harbours this HDACi activity. Furthermore, 10HDA can reactivate the expression of epigenetically silenced genes in mammalian cells. Thus, the epigenetic regulation of queen-bee development is probably driven, in part, by HDACi activity in royal jelly.
Abstract: A series of Δ(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.
Abstract: Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was N(ε)-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 N(ε)-lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 N(ε)-lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function.
Abstract: Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.
Abstract: A novel class of KAT modulators (long chain alkylidenemalonates, LoCAMs) has been identified. Variations of the alkyl chain length can change the activity profile from inhibition of both KAT3A/KAT2B (as derivative 2a) to the peculiar profile of pentadecylidenemalonate 1b, the first activator/inhibitor of histone acetyltransferases. Together with the powerful apoptotic effect (particularly notable if considering that anacardic acid and other KAT inhibitors are not cell permeable) appoint them as valuable biological tools to understand the mechanisms of lysine acetyltransferases.
Abstract: Histone acetyltransferases (HATs) are a class of epigenetic enzymes crucial for chromatin restructuring and transcriptional regulation in eukaryotic cells, thus being a promising target for therapeutic development. Nonetheless, differently from histone deacetylases (HDACs) inhibitors, there is still paucity of small-molecule modulators of HAT activity. After a decline during past decade, natural products and their derivatives could be once again a valuable tool in the lead discovery process and meet such need of Novel Chemical Entities (NCEs). In this review, we will provide a comprehensive summary on the discovery of small-molecule HAT modulators from naturally occurring molecular scaffolds.
Abstract: Two modern synthetic technologies to perform 1,3-dipolar cycloaddition reactions were compared. This study puts in evidence the power of microwave-assisted and flow-based methodologies compared to the conventional one in terms of reaction time and yield, and demonstrates the potential of flow chemistry in terms of time, automation, and scaling up opportunities.
Abstract: Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidic moiety; 3) the introduction of a N-containing basic moiety; and 4) the positional isomerization of the aminohydroxynaphthoic moiety. We have assessed the biological activity of these compounds against a panel of arginine methyltransferases (fungal RmtA, hPRMT1, hCARM1, hPRMT3, hPRMT6) and a lysine methyltransferase (SET7/9) using histone and nonhistone proteins as substrates. Molecular modeling studies for a deep binding-mode analysis of test compounds were also performed. The bis-carboxylic acid derivatives 1 b and 7 b emerged as the most effective PRMT inhibitors, both in vitro and in vivo, being comparable or even better than the reference compound (AMI-1) and practically inactive against the lysine methyltransferase SET7/9.
Abstract: Many severe human pathologies are related to alterations of the fine balance between histone acetylation and deacetylation; because not all such diseases involve hypoacetylation, but also hyperacetylation, compounds able to enhance or repress the activities of histone acetyltransferases (HATs) could be promising therapeutic agents. We evaluated in vitro and in cell the ability of eleven natural polyisoprenylated benzophenone derivatives to modulate the HAT activity of p300/CBP, an enzyme that plays a pivotal role in a variety of cellular processes. Some of the tested compounds bound efficiently to the p300/CBP protein: in particular, guttiferone A, guttiferone E and clusianone inhibit its HAT activity, whereas nemorosone showed a surprising ability to activate the enzyme. The ability of nemorosone to penetrate cell membranes and modulate histone acetylation into the cell together with its high affinity for the p300/CBP enzyme made this compound a suitable lead for the design of optimized anticancer drugs. Besides, the studies performed at a cellular and molecular level on both the inhibitors and the activator provided new insights into the modulation mechanism of p300/CBP by small molecules.
Abstract: An inexpensive and regioselective approach to dihydrothieno[3,2-g]quinoline-4,9-dione is reported. A combination of a mild version of Skraup reaction with a sequential substitution/Michael addition allowed the selective preparation in acceptable yield of a pharmacologically important quinone derivative, previously obtained only in trace and together with the other regioisomer.
Abstract: We identified a series of 4-hydroxyquinolines bearing a C1 to C15 alkyl chain at the C2 position and a carbethoxy/carboxy group at the C3 position of the quinoline nucleus (MC compounds), endowed with selective inhibitory activity against the p300/CBP HAT enzymes. Enzyme inhibition was investigated using in vitro HAT assays and by western blot analysis of cellular lysates to examine the acetylation levels of histone H3 and alpha-tubulin. When tested in U937 cells, some compounds displayed pro-apoptotic or cytodifferentiating properties.
Abstract: Several derivatives out of a series of antifungal agents exhibited a good inhibitory potency against aromatase as well as a fairly good selectivity toward CYP17, even if lacking H-bond accepting substituents. Their common structural feature is a flexible backbone that did not fit into previously reported CYP19 models. Thus, a ligand-based approach was exploited to develop a novel statistically robust, self-consistent and predictive 3D-QSAR model herein proposed as a helpful tool to design new aromatase inhibitors.
Abstract: Constrained analogues of procaine were synthesized, and their inhibiting activity against DNMT1 was tested. Among them, the most potent compound, derivative 3b, was also able to induce a recognizable demethylation of chromosomal satellite repeats in HL60 human myeloid leukemia cells and thus represents a lead compound for the development of a novel class of non-nucleoside DNMT1 inhibitors.
Abstract: A number of new compounds bearing two ortho-bromo- and ortho, ortho-dibromophenol moieties linked through a saturated/unsaturated, linear/(poly)cyclic spacer (compounds 1- 9) were prepared as simplified analogues of AMI-5 (eosin), a recently reported inhibitor of both protein arginine and histone lysine methyltransferases (PRMTs and HKMTs). Such compounds were tested against a panel of PRMTs (RmtA, PRMT1, and CARM1) and against human SET7 (a HKMT), using histone and nonhistone proteins as a substrate. They were also screened against HAT and SIRTs, because they are structurally related to some HAT and/or SIRT modulators. From the inhibitory data, some of tested compounds ( 1b, 1c, 4b, 4f, 4j, 4l, 7b, and 7f) were able to inhibit PRMTs, HKMT, HAT, and SIRTs with similar potency, thus behaving as multiple ligands for these epigenetic targets (epi-MLs). When tested on the human leukemia U937 cell line, the epi-MLs induced high apoptosis levels [i.e., 40.7% ( 4l) and 42.6% ( 7b)] and/or massive, dose-dependent cytodifferentiation [i.e., 95.2% ( 1c) and 96.1% ( 4j)], whereas the single-target inhibitors eosin, curcumin, and sirtinol were ineffective or showed a weak effect.
Abstract: Pentadecylidenemalonate 1b, a simplified analogue of anacardic acid, was identified as the first mixed activator/inhibitor of histone acetyltransferases (HATs). It potentiates PCAF HAT activity while inhibiting those of p300/CBP and recombinant CBP. The remarkable apoptotic effect together with the ability to selectively acetylate histone versus non-histone substrates appoint 1b as a lead for the development of anticancer drugs.
Abstract: Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.
Abstract: The screening of the inhibition capabilities of dye-like small molecules from a focused library against both human PRMT1 and Aspergillus nidulans RmtA is reported as well as molecular modeling studies (homology modeling, molecular docking, and 3-D QSAR) of the catalytic domain of the PRMT1 fungal homologue RmtA. The good correlation between computational and biological results makes RmtA a reliable tool for screening arginine methyltransferase inhibitors. In addition, the binding mode analyses of tested derivatives reveal the crucial role of two regions, the pocket formed by Ile12, His13, Met16, and Thr49 and the SAM cisteinic binding site subsite. These regions should be taken into account in the design of novel PRMT inhibitors.
Abstract: Novel triazine analogues of 5-alkyl-2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones (F(2)-DABOs), previously described by us as nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs), were tested for their antiproliferative and cytodifferentiating activity on the A-375 human melanoma cell line. Most of the tested derivatives were effective in decreasing cell proliferation, facilitating morphological differentiation, and reprogramming gene expression. All these effects were reversible upon withdrawal of RT inhibitors. Among the compounds tested, 3 f showed the highest antiproliferative effect, whereas compound 6 c, although not affecting cell proliferation, is endowed with a strong cytodifferentiating effect, which is probably related to a marked upregulation of the e-cad gene. These results support the potential of NNRTIs as valuable antitumor agents.
Abstract: Starting from a yeast phenotypic screening performed on 21 compounds, we described the identification of two small molecules (9 and 18) able to significantly reduce the S. cerevisiae cell growth, thus miming the effect of GCN5 deletion mutant. Tested on a GCN5-dependent gene transcription assay, compounds 9 and 18 gave a high reduction of the reporter activity. In S. cerevisiae histone H3 terminal tails assay, the H3 acetylation levels were highly reduced by treatment with 0.6-1 mM 9, while 18 was effective only at 1.5 mM. In human leukemia U937 cell line, at 1 mM 9 and 18 showed effects on cell cycle (arrest in G1 phase, 9), apoptosis (9), and granulocytic differentiation (18). When tested on U937 cell nuclear extracts to evaluate their histone acetyltransferase (HAT) inhibitory action, both compounds were able to reduce the enzyme activity when used at 500 microM. Another quinoline, compound 22, was synthesized with the aim to improve the activity observed with 9 and 18. Tested in the HAT assay, 22 was able to reduce the HAT catalytic action at 50 and 25 microM, thereby being comparable to anacardic acid, curcumin, and MB-3 used as references. Finally, in U937 cells, compounds 9 and 18 used at 2.5 mM were able to reduce the extent of the acetylation levels of histone H3 (9) and alpha-tubulin (9 and 18). In the same assay, 22 at lower concentration (100 microM) showed the same hypoacetylating effects with both histone and non-histone substrates.
Abstract: Starting from a yeast phenotypic screening performed on 21 chemically different substances we described the discovery of two small molecules as GCN5 inhibitors. The 2-methyl-3-carbethoxyquinoline 9 and its 2-desmethyl analogue 18 were able to significantly reduce the yeast cell growth, thus miming the effect of GCN5 deletion mutant. Tested to evaluate their effect on GCN5-dependent transcription of the HIS3 gene, 9 and 18 showed high inhibitory activity of gene transcription, more evident in activated conditions. Compound 9 was also able to reduce the acetylation levels of H3 and, to a lesser extent, H4 in yeast at 0.6 mM. In human leukemia U937 cells, at 1 mM concentration 9 showed 27% apoptosis induction, while 18 had just a little effect in the same conditions. Further studies on 9 and 18 will be performed to deepen their effects on GCN5-related phenomena.
Abstract: Novel benzyl- and phenyl-isothioureidic derivatives have been synthesised and evaluated as inhibitors of nitric oxide synthesis, induced in lipopolysaccharide (LPS)-activated J774.A1 macrophage cell line. The most potent iNOS inhibitor resulting was 1-methyl-3-phenyl-S-methyl isothiourea 5l.
Abstract: A novel series of 5-substituted-3-(1H-pyrrol-2-yl)-2-oxazolidinones 2a-s has been described as pyrrole analogues of toloxatone and befloxatone, two phenyl-oxazolidinones active as anti-MAO agents and used in antidepressant therapy. Tested against MAO-A and MAO-B enzymes, the majority of 2a-s show highly potent inhibitory effect against the A isoform of the enzyme, with Ki values in the range 0.52-0.004 microM, whilst their anti-MAO-B activity is considerably lower (Ki = >100-0.5 microM). Structurally, 2a-s differs for the substituent inserted at the C5 position of the 2-oxazolidinone ring (hydroxymethyl (2a-d), methoxymethyl (2e-h), azidomethyl (2i-l), methylaminomethyl (2m-p), and aminomethyl (2q-s)), and the size of the alkyl chain at the pyrrole N1 position (methyl, ethyl, allyl, or benzyl). As a rule, apart from the C5 substitution, the bulkier is the alkyl group at the pyrrole-N1, the lower is the anti-MAO-A activity of the compounds, being the N1-methyl derivatives 2a, 2e, 2i, and 2q among the most potent (K(iMAO-A) = 0.087-0.004 microM) and A-selective (A-selectivity ratio: >11,111-41) compounds in this series. Exceptions are represented by the N1-benzyl derivative 2d (K(iMAO-A) = 0.009 microM) and the N1-allylpyrrole 2o (K(iMAO-A) = 0.04 microM). In comparison with the reference drugs, these highly active derivatives are more potent than toloxatone, slightly less potent than befloxatone, and several times more A-selective than both the references. Such results indicate that 2a-s may represent a new promising series of antidepressant agents.
Abstract: Two 2,6-difluoro-DABO derivatives (MC 1047, 1, and MC 1220, 2, respectively) were tested against endogenous, nontelomeric reverse transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compounds significantly reduced cell proliferation and facilitated the morphological differentiation of cells. These results propose F(2)-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies and as antiproliferative drugs in tumor therapy.
Abstract: Histone acetyltransferases are key chromatin regulators responsible for transcriptional activation and cell cycle progression. We propose a simple yeast-based assay to determine the specificity and targets of novel Gcn5p inhibitors. Here, we report the finding of a novel, small molecule, MC1626, which is able to inhibit yeast cell growth, Gcn5p-dependent gene transcription and acetylation of the histone H3 N-terminal tail in vivo. Because HATs misregulation is invariably associated with human diseases, the identification of MC1626 as a novel cell-permeable Gcn5p inhibitor suggests that it may be a very useful starting tool for the further development of new molecules to be applied to expression profiling of genes regulated by histone H3 acetylation. In addition, our results demonstrate that MC1626 is a Gcn5p-dependent yeast growth inhibitor.
Abstract: 2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.
Abstract: Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) are a family of potent NNRTIs developed in the past decade. Attempts to improve their potency and selectivity led to thio-DABOs (S-DABOs), DATNOs, and difluoro-thio-DABOs (F(2)-S-DABOs). More recently, we reported the synthesis and molecular modeling studies of a novel conformationally constrained subtype of the S-DABO series characterized by the presence of substituents on the methylene linkage connecting the pyrimidine ring to the aryl moiety (Mai, A., et al. J. Med. Chem. 2001, 44, 2544-2554). Now we report the computer-aided design, synthesis, and biological evaluation of four new DABO prototypes (5-alkyl-2-cyclopentylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones, F(2)-NH-DABOs) in which the sulfur atom of the related F(2)-S-DABOs is replaced by an amino group. For these studies, we used as a reference model the cocrystallized MKC-442/RT complex. Docking studies with Autodock of the newly designed F(2)-NH-DABOs on the ligand-derived RT confirmed the findings previously described for the F(2)-S-DABOs. The F(2)-NH-DABO binding mode resembles that reported for F(2)-S-DABOs, with the difference that the NH moiety at the C-2 position represents a new anchor site for ligand/enzyme complexation. The predicted inhibition constant (K(i)) values by the internal scoring function of Autodock, and the predicted IC(50) values by the application of a VALIDATE II/HIV-RT model strongly suggested the synthesis of the designed amino-DABOs. F(2)-NH-DABOs were shown to be highly active in both anti-RT and anti-HIV biological assays with IC(50) and EC(50) comparable with that of the reference compound MKC-442. Interestingly, 2-cyclopentylamino-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl pyrimidin-4(3H)-one (9d) was active against the Y181C HIV-1 mutant strain at submicromolar concentration, with a resistance value similar to that of efavirenz, the last FDA-approved NNRTI for AIDS therapy, and 2-fold lower than that of its 2-cyclopentylthio counterpart 8d. The introduction in 9d of a new anchor point (pyrimidine C-2 NH group), with the formation of a new hydrogen bond with Lys101, could compensate for the lack of positive hydrophobic ligand/NNBP interactions due to the Tyr181 to Cys181 mutation.
Abstract: Pursuing our searches on quinolonecarboxylic acids we used a simple three-step one pot procedure to synthesize novel 1,7-disubstituted-6-nitroquinolones. The new derivatives were tested against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) as well as against both gram-positive and gram-negative bacteria. In vitro assays showed some derivatives were endowed with good inhibiting activities against tested mycobacteria. Some derivatives were also found more potent than ciprofloxacin and ofloxacin (used as reference drugs) against gram-positive bacteria.
Abstract: Pursuing our search program for new antitubercular drugs we decided to explore the potentiality of oxazolidinone moiety by synthesizing novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480. The new derivatives were tested against atypical mycobacteria as well as against drug resistant Mycobacterium tuberculosis and some of them exhibited a fairly good activity against Mycobacterium avium complex (MAC).
Abstract: Due to the key role played by monoamine oxidases (MAOs) in the metabolism of neurotransmitters, MAO inhibitors (MAOIs) represent an useful tool for the treatment of several neurological diseases. Among selective MAOIs, MAO-A inhibitors (e.g. clorgyline) are used as antidepressant and antianxiety drugs and are claimed to protect neuronal cells against apoptosis, and selective MAO-B inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson's disease either alone or in combination with L-DOPA. However, they engender covalent bonds with the active site of the enzyme and induce irreversible inhibition; moreover, they tend to lose their initial selectivity at high dosages or with repeated administrations. Phenyloxazolidinones belong to third-generation-MAOIs, characterized by a selective and reversible inhibition of the enzyme. Among these molecules, the most representative are toloxatone and befloxatone, two selective and reversible MAO-A inhibitors used in therapy as antidepressant drugs. Going on our searches on CNS potentially active compounds containing a pyrrole moiety we prepared 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and -3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted selective and reversible MAO-A inhibitors. The most potent compound is (R)-5-methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), endowed with very high potency (K(iMAO-A) = 4.9 nM) and A-selectivity (A-selectivity = 10,200, about 116-fold greater than that of befloxatone).
Abstract: The binding mode of 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides 1a-c, belonging to a recently reported class of synthetic histone deacetylase (HDAC) inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072), into the new modeled HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. HDAC1 X-ray coordinates were obtained by virtual "mutation" of those of histone deacetylase-like protein, a bacterial HDAC homologue. In in vitro antimaize HD2 as well as antimouse HDAC1 assay, compounds 1a-c showed inhibitory activities in the low micromolar range. Similarly, 1a-c are endowed with anti-HDAC activity in vivo: on mouse A20 cells, 1a-c induced histone hyperacetylation leading to a highly increased acetylation level of H4 as compared to control histones. Results obtained with acid-urea-triton polyacrylamide gel electrophoresis have been confirmed by Western Blot experiments. Finally, compound 1a, chosen as a representative member of this class of HDAC inhibitors, resulted endowed with antiproliferative (45 and 85% cell growth inhibition at 40 and 80 microM, respectively) and cellular differentiation (18 and 21% of benzidine positive cells at the same concentrations) activities in murine erythroleukemic cells.
Abstract: 3-(1H-Pyrrol-1-yl)-2-oxazolidinones 1aminus signi have been synthesized as pyrrole analogues of toloxatone (Humoryl), an antidepressant agent belonging to the 3-phenyl-2-oxazolidinone class, and their monoamine oxidase (MAO) type A and B inhibitory activities have been evaluated. The majority of 1aminus signi showed inhibitory activity against the A isoform of the enzyme higher than that exerted against the MAO-B, the sole exception being the (S)-5-aminomethylderivative 1d. (R)-5-Methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone 1b, the most potent among test derivatives, was 78-fold more potent than toloxatone.
Abstract: rac-2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047) is a potent inhibitor of HIV-1 multiplication in acutely infected cells. MC-1047 racemate has been resolved by chiral HPLC using, as chiral stationary phase (CSP), a commercially available (R,R)-Whelk-01 column. The optical purity and the circular dichroism (CD) of the two resolved enantiomers were determined and their biological activities tested in in vitro assays. Molecular modeling inspection of the binding of (R) and (S) enantiomers to the non-nucleoside binding site (NNBS) of reverse transcriptase (RT) using the defined model of F(2)-S-DABO/RT complex indicates the (R) enantiomer as the more active isomer.
Abstract: Several 5-alkyl, 5-alkenyl, 5-iso-alkyl, 5-halo, 5-aminomethyl and 5-carboxy derivatives of S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-benzyloxopyrimidines), DATNOs (dihydro-alkylthionaphthylmethyl-oxopyrimidines) and F2-S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-2,6-difluorobenzyl-oxopyrimidines) have been prepared and tested as anti-HIV-1 agents. S-DABO derivatives bearing at C-6 position monosubstituted phenylmethyl or heteroarylmethyl units have also been synthesized. 2-Alkylthio-3,4-dihydropyrimidin-4(3H)-one derivatives of F2-S-DABO series bearing small alkyl groups at C-5 proved to be potent inhibitors of HIV-1 replication in vitro with selectivity indexes ranging from 250 to >2,500.
Abstract: 5-Alkyl-2-(alkylthio)-6-(2,6-difluorobenzyl)-3,4-dihydropyrimidin-4(3H)-ones (S-DABOs, 2) have been recently described as a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) active at nanomolar concentrations (Mai, A. et al. J. Med. Chem. 1999, 42, 619-627). In pursuing our lead optimization efforts, we designed novel conformationally restricted S-DABOs, 3, featuring a methyl at the benzylic carbon (Y = Me) and at the pyrimidine 5-position (R = Me). Conformational analyses and docking simulations suggested that the presence of both methyls would significantly reduce conformational flexibility without compromising, in the R enantiomers, the capability of fitting into the RT non-nucleoside binding pocket. To develop structure-activity relationships, we prepared several congeners of type 3 belonging to the thymine (R = Me) and uracil (R = H) series, featuring various 2-alkylthio side chains (X = Me, i-Pr, n-Bu, i-Bu, s-Bu, c-pentyl, and c-hexyl) and aryl moieties different from the 2,6-difluorophenyl (Ar = phenyl, 2,6-dichlorophenyl, 1-naphthyl). Moreover, alpha-ethyl derivatives (Y = Et) were included in the synthetic project in addition to alpha-methyl derivatives (Y = Me). All of the new compounds were evaluated for their cytotoxicity and anti-HIV-1 activity in MT-4 cells, and some of them were assayed against highly purified recombinant wild-type HIV-1 RT using homopolymeric template primers. The results were expressed as CC(50) (cytotoxicity), EC(50) (anti-HIV-1 activity), SI (selectivity, given by the CC(50)/EC(50) ratio), and IC(50) (RT inhibitory activity) values. In the 2,6-difluorobenzylthymine (R = Me) series, methylation of the benzylic carbon improved anti-HIV-1 and RT inhibitory activities together with selectivity. Compound 3w (Ar = 2,6-F(2)-Ph, R = Y = Me, X = c-pentyl) turned out the most potent and selective among the S-DABOs reported to date (CC(50) > 200 microM, EC(50) = 6 nM, IC(50) = 5 nM, and SI > 33 333). Assays performed on the pure enantiomer (+)-3w, much more active than (-)-3w, yielded the following results: CC(50) > 200 microM, EC(50) = 2 nM, IC(50) = 8 nM, and SI > 100 000, under conditions wherein MKC-442 was less active and selective (CC(50) > 200 microM, EC(50) = 30 nM, IC(50) = 40 nM, SI > 6666). The 2,6-difluorophenylethylthymines (R = Me) were generally endowed with higher potency compared with the uracil counterparts (R = H). In the 2,6-difluorophenyl series the best and the least performant 2-alkylthio side chains were the 2-c-pentylthio and the 2-methylthio, respectively. When the methyl at the benzylic carbon was replaced by an ethyl, activity was retained or decreased slightly, thus suggesting that the dimensions of the cavity within the RT hosting this substituent would not be compatible with groups larger than ethyl. Aryl moieties different from the 2,6-difluorophenyl (phenyl, 1-naphthyl, 2,6-dichlorophenyl) were generally detrimental to activity, consistent with a favorable electronic effect exerted by the 2,6-fluorines on a putative charge-transfer interaction between the aromatic moieties of the inhibitor and Tyr188.
Abstract: The title compd. (I) was prepd. by reacting suberic acid with acetic anhydride to give suberic anhydride. The latter was condensed with aniline to give suberanilic acid, which reacted with ClCO2Et and NH2OH to give I in 58% overall yield.
Abstract: Novel 3-(4-aroyl-2-pyrrolyl)-N-hydroxy-2-propenamides are disclosed as a new class of histone deacetylase (HDAC) inhibitors. Three-dimensional structure-based drug design and conformational analyses into the histone deacetylase-like protein (HDLP) catalytic core suggested the synthesis and biological evaluation of compounds 7a-h. Experimental pK(i) values are in good agreement with VALIDATE predicted pK(i) values of new derivatives. All compounds 7a-h show HDAC inhibitory activity in the micromolar range, with 7e as the most potent derivative (IC(50) = 1.9 microM). The influence of the 4'-substituent in the aroyl moiety is not significant for the inhibitory activity, as all compounds 7a-g show IC(50) values between 1.9 and 3.9 microM. Otherwise, the unsaturated chain linking the pyrrole ring to the hydroxamic acid group is clearly important for the anti-HDAC activity, the saturated analogue 7h being 10-fold less active than the unsaturated counterpart 7a.
Abstract: S-DABO derivs. contg. the methylthiomethyl (MTM) group have been synthesized and tested for anti-HIV-1 activity in cell based assay (MTT and p24 assays) and for their capability to target the HIV-1 reverse transcriptase in enzyme assays. Data of expts. lead to the conclusion that the introduction of a 2-MTM-thio side chain is not sufficient per se to significantly increase S-DABO's potency. Nevertheless, potent MTM-S-DABOs can be obtained by introducing a 2,6-difluorophenylmethyl moiety as a C-6 substituent.
Abstract: Molecular modeling analysis of compounds belonging to the recently published series of dihydro-alkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2, 6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2, 6-dichloro(or 2,6-difluoro)phenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to >/=5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.
Abstract: Various N-derivs. of 4-(4-thiomorpholinyl)aniline and 4-(4-thiomorpholinylmethyl)aniline were synthesized and tested for in vitro antibacterial activities against Mycobacterium avium CIP 103317 and other mycobacteria including M. tuberculosis CIP 103471. Appropriate substituents were introduced at the nitrogen of aniline portion in order to exploit their potential antimycobacterial activities. Only derivs. with the biphenylylmethyl group bound to the 4-(4-thiomorpholinylmethyl)aniline moiety were found to possess appreciable antibacterial activities against atypical mycobacteria and M. tuberculosis. Several compds. were two and sixteen times more potent than azithromycin and isoniazid, resp., in the in vitro assays against M. avium.
Abstract: During search on quinolonecarboxylic acids we used a facile, convenient two- or three-step procedure to synthesize new quinolone analogs, bearing at the C-7 position alkylamino substituents, and at the C-6 position a fluorine or alternatively a nitro group. The new derivatives were tested against both Gram-positive and Gram-negative bacteria and against a number of different mycobacteria. In vitro assays showed 1-tert-butyl-7-tert-butylamino-6-nitro-1,4-dihydro-4-quinolone-3-carboxy lic acid to be a potent inhibitor of Streptococcus and Staphylococcus with potencies superior to those of ofloxacin and ciprofloxacin, used as reference drugs. Some 6-nitroquinolones were found to exert good inhibiting activities against Mycobacterium tuberculosis and various atypical mycobacteria, whereas the 6-fluoro counterparts showed poor or no activity against this bacterium.
Abstract: Thiomorpholine analogues of U-100480 with the biphenylmethyl group replacing the acetamidomethyloxazolidinone moiety have been synthesized and tested as antimycobacterial agents together with various related derivatives. Some biphenyl derivatives were endowed with high activity against Mycobacterium tuberculosis and other non-tuberculous mycobacteria.
Abstract: S-DABO 618 is monoclinic, space group C2/c, a 26.327(1), b 8.315(2), c 15.118(2) .ANG., .beta. 90.75(6), Z = 8, R = 0.069, Rw = 0.080 for 1199 reflections. DATNO 774 is triclinic, space group P.hivin.1, a 10.2592(9), b 11.113(3), c 8.040(1) .ANG., .alpha. 99.65(2), .beta. 101.770(9), .gamma. 101.14(1), Z = 2, R = 0.075, Rw = 0.097 for 1288 reflections. At. coordinates are given. Both compds. crystd. with difficulty giving poor quality crystals. A short on the bonding, torsion angles and conformation is given.
Abstract: Arylketotetramethylene analogs of disoxaril (WIN 51711) were synthesized by reaction of 1-aryl-5-chloropentan-1-ones with 2-(4-hydroxyphenyl)-4,5-dihydro oxazoles, Et 4-hydroxybenzoates and 4-hydroxybenzontrile. The new derivs. were tested for antiviral activity against various human rhinovirus (HRV) serotypes. The best activity was exhibited by the ethoxycarbonyl derivs., whereas the oxazoline counterparts were less active and the cyano derivs. totally inactive. 5-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]-1-(4-methoxyphenyl)pentan-1-one and Et 4-[5-(4-methylthiophenyl)-5-oxopentoxy] benzoate were more active than, and as active as, disoxaril, resp., against HRV-14. Moreover, they were 10 times less cytotoxic.
Abstract: Novel compounds related to 2-(cyclohexylthio)-3,4-dihydro-5-methyl-6-(3-methylbenzyl)-4-ox opyrimidine (3c, MC 639) have been synthesized and tested as inhibitors of human immunodeficiency virus type-1 (HIV-1). Reaction of thiourea with ethyl arylmethylacetoacetates furnished 5-alkyl-6-(arylmethyl)-3,4-dihydro-2-mercapto-4-oxopyrimidines which were then alkylated at the sulfur atom to afford the required 2-alkylthio or 2-cycloalkylthio derivatives (S-DABOs). Chemical modifications at N-3, C-4, and C-6 of the pyrimidine ring were attempted with the aim of improving antiretroviral activity. In particular, replacement of the benzyl group with the 1-naphthylmethyl moiety enhanced the activity of S-DABOs, whereas N-3 alkylation and C=O transformation into C=S at position 4 of the pyrimidine ring led to compounds devoid of anti-HIV-1 activity. Lower activity was generally observed when 1-naphthylmethyl was replaced by the isomeric 2-naphthylmethyl moiety. The most active compounds showed activity in the low micromolar range with EC50 values comparable to that of nevirapine.
Abstract: 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) have emerged as non-nucleoside inhibitors of human immunodeficiency virus type 1 [Artico et al (1993), Antiviral Chem Chemother 4: 361-368]. With a view to increasing their potency, a new series of DABO derivs., differently substituted at positions C-2 and/or C-5 of the pyrimidine ring and 3' or 3',5' of the benzyl moiety, have been synthesized. DABOs were prepd. by reacting O-methylisourea with the appropriate Me 2-alkyl-4-phenylacetylacetate, with formation of 3,4-dihydro-2-methoxy-6-arylmethyl-4-oxopyrimidines. Subsequent displacement of the methoxy group linked at the 2-position of the pyrimidine ring by treatment with alkoxy and cycloalkoxy potassium salts led to the required derivs.
Abstract: Various thio analogues of dihydroalkoxybenzyloxopyrimidines (DABOs), a new class of non-nucleoside reverse transcriptase inhibitors, were found to selectively inhibit the HIV-1 multiplication in vitro. Among the C-5 H-substituted 6-benzyl-3,4-dihydro-4-oxopyrimidines, the introduction of alkylthio or cycloalkylthio substituents at C-2 of the pyrimidine ring led to derivatives (S-DABOs) which were up to 10-fold more potent than the alkyloxy or cycloalkyloxy counterparts. The further introduction of a methyl group at the 3'-position of the benzyl portion of 2-(alkylthio)-6-benzyluracils reduced the cytotoxicity leading to more selective compounds. Among C-5 methyl-substituted S-DABOs, numerous derivatives showed EC50 values as low as 0.6 microM and lacked cytotoxicity at doses as high as 300 microM. In the C-5 double methyl-substituted series, a more pronounced cytotoxicity was observed and the further introduction of a methyl at the 3'-position in the benzylidene group resulted in total loss of antiviral activity. S-DABOs, namely 2-(alkylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidines, were synthesized by reacting proper methyl (phenylacetyl)acetates or their 2-methyl compounds with thiourea to afford 6-benzyl-4-oxo-1,2,3,4-tetrahydro-2-thiaoxopyrimidines or the related 5-methyl derivatives. Treatment of the latter derivatives with alkyl or cycloalkyl halides in alkaline medium gave the required title compounds.
Abstract: A review. Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) were disclosed as NNRTIs by the authors' group in 1993. Although not very potent (EC50 ranged from 3.0 to 40.0 .mu.M), they resulted scarcely cytotoxic (CC50 was >200 .mu.M) thus encouraging further studies with the aim to increase their potency. As a result, a new series of DABO derivates bearing 3-Me or 3, 5-dimethylbenzyl moiety as substituent at the C-6 position of the pyrimidine ring have been prepd. and tested for anti-HIV-1 activity. In vitro, the most potent compds. had an EC50 of 0.8 .mu.M and a selective index of 400. The next step was to evaluate the effect on antiviral activity produced by replacing the alkyloxy chain with the corresponding alkylthio chain(S-DABOs). Among these novel derivs. many showed EC50 values as low as 0.6 .mu.M and lacked cytotoxicity at doses as high as 200 .mu.M. Further improvement in potency was obtained through the substitution of the benzyl moiety with a naphthylmethyl group (DATNOs). More recently, mol. modeling studies prompted the synthesis and biol. evaluation of novel DABOs bearing fluorine or chlorine atoms at positions 2 and 6 of the benzene ring. The most potent derivs. the authors obtained were 2,6-difluorobenzyl analogs of S-DABOs, some of which were found to be endowed with anti HIV-1 activity at nanomolar concns. (EC505nM,SI>40,000).
Abstract: Histone methylation is (together with phosphorylation, acetylation and ubiquitination) one of the post-translational covalent modifications that regulates a broad range of DNA and chromatin-templated nuclear events, including transcription. Histones (preferentially H3 and H4) tails can be methylated on the terminal amino groups of lysine as well as on the guanidine moieties of arginine residues, the latter being mediated by a family of S-adenosylmethionine-dependent enzymes named protein arginine N-methyltransferases (PRMTs). The fact that PRMTs are known coactivators for nuclear receptors and likely overexpressed in prostate and breast cancers makes novel small mol. selective inhibitors of PRMTs highly longed for. Recently, employing a fungal PRMT for screening and a human enzyme for validation, several mols. were described as reversible arginine methyltransferase inhibitors. Herein we report updated structure-based 3-D QSAR models with improved robustness and predictive ability. Details and exptl. procedure will be reported.
Abstract:
The acetylation of proteins is a dynamic event involving the enzymic activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs primarily acetylate (and prevent pos. charges from forming on) the .epsilon.-amino groups of specific lysines in histones, as well as in transcription factors (i.e., p53) and other nuclear proteins (i.e., .alpha.-tubulin), thus regulating transcription, histone deposition during nucleosome assembly, DNA repair and other genomic processes. The impairment of this cellular regulatory system (for example, after treatment with HDAC inhibitors) can have a significant impact on cell functions, including altered gene expression, growth arrest, differentiation and cell death, and is, therefore, a promising target for therapeutic development. Yet a limited no. of HAT inhibitors have been described so far, with various degrees of selectivity and cell permeability. The pentadecylidenemalonate 1b, a simplified analog of anacardic acid, was identified as the first mixed activator/inhibitor of histone acetyltransferases (HATs). It potentiates PCAF HAT activity while inhibiting those of p300/CBP and recombinant CBP. The remarkable apoptotic effect together with the ability to selectively acetylate histone vs. non histone substrates appoints 1b as a lead for the development of anticancer drugs.
Abstract: Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. They not only occur early in carcinogenesis but also are found in virtually all cases of cancer. Importantly, epigenetic alterations do not involve changes in the DNA sequence and, thus, are potentially reversible. Of the epigenetic changes seen in cancer, the most extensively studied is the increase of CpG dinucleotide methylation at CpG islands in the proximal promoter regions of genes. This change in DNA methylation characteristically results in the transcriptional silencing of important cancer genes such as tumor suppressors and caretaker genes. Nucleoside analogs like 5-azacytidine or 2-pyrimidone-1-.beta.-D-riboside (zebularine), though effective in inducing DNA demethylation and reactivation of hypermethylated genes, carry considerable concerns about toxicity. These concerns have led to consideration of non-nucleoside inhibitors of DNA methyltransferases. Procainamide, originally approved by the U.S. Food and Drug Administration for the treatment of cardiac arrhythmias, specifically inhibits the maintenance methyltransferase activity of DNMT1 and reactivates genes silenced by promoter CpG island hypermethylation. Herein we report the synthesis of frozen analogs of procainamide and their inhibitory activity towards DNA methyltransferases in vitro and in vivo.
Abstract: The DNA methyltransferase (DNMT) enzyme family represents one of the most promising targets for the development of novel anticancer drugs. Using an homol. model of the catalytic domain of human DNMT1 we report herein mol. modeling studies of several small-mol. DNMT1 inhibitors including hydralazine, procaine, procainamide [Singh, N. et al.]. The docking models suggest key interactions between the inhibitors and the binding pocket that can be exploited in structure-based design. We also present our findings of docking-based virtual screening of large compd. databases for novel DNMT1 inhibitors.
Abstract: A pharmaceutical compn. comprising a compd. of formula I and a pharmaceutically acceptable carrier. Methods for treating a proliferative disorder mediated by a Me transferase comprising administering an anti-proliferative effective amt. of the compd. of formula I are also presented. Compds. of formula I wherein R1 - R8 are independently H, C1-7 alkyl, C2-6 alkenyl;, C2-6 alkynyl, C2-7 alkanoyl, etc.; X is C and S; and their N-oxide derivs., prodrug derivs., protected derivs., isomers, mixt. of isomers, pharmaceutically acceptable salts, and solvates thereof, are claimed. Example compd. II.bul.HCl was prepd. by olefination of 3-nitrobenzaldehyde with 2-(triphenylphosphoranylidene)butanedioic acid 1-Me ester; the resulting 3-(methoxycarbonyl)4-(3-nitrophenyl)-3-butenoic acid underwent cyclization to give compd. II.bul.HCl. All the invention compds. were evaluated for their transferase inhibitory activity (some data given).
