Abstract: A series of novel 4-phenylquinazoline-2-carboxamides (1-58) 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 K(i) values in the nanomolar/subnanomolar range, show selectivity toward the central benzodiazepine receptor (BzR) and exhibit structure-affinity relationships consistent with a previously published pharmacophore/topological model of ligand-TSPO interaction.
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 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: 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: 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: A library of 91 heterocyclic compounds composed of 16 distinct scaffolds has been synthesized through a sequence of phosphine-catalyzed ring-forming reactions, Tebbe reactions, Diels-Alder reactions, and, in some cases, hydrolysis. This effort in diversity-oriented synthesis produced a collection of compounds that exhibited high levels of structural variation both in terms of stereochemistry and the range of scaffolds represented. A simple but powerful sequence of reactions thus led to a high-diversity library of relatively modest size with which to explore biologically relevant regions of chemical space. From this library, several molecules were identified that inhibit the migration and invasion of breast cancer cells and may serve as leads for the development of antimetastatic agents.
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: 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: 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: 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: An unusual and efficient method for the synthesis of new quinone-based amine and its derivatives from the corresponding alpha,alpha-amino ester is described. The procedure involves the quinone-based system's oxidative decarboxylation via hydride transfer throughout basic hydrolysis. This synthetic method provides, with good yields, rapid access to new potentially cytotoxic quinones.
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: 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: 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: 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: 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: Four series of 5-aryl-imidazo[2,-c][1,4]benzodiazepine derivatives 1a-f, 2a-f, 3a-f, and 4a-f were synthesized and tested for their affinity at both the peripheral and central benzodiazepine receptors. Among the four series, only N-10 and C-11 sites were changed, mainly [N(CH3)-CO], [N=CH], [NH-CO], [NH-CH2], and in each series the halogen site was varied at the positions C-7, C-2', and C-4'. In particular, 10-methyl-benzodiazepinones 1a and 1b were designed as tricyclic constrained analogues of diazepam and Ro5-4864. All the tested compounds did not show significant binding activity at central benzodiazepine receptors, but relatively good PBzR binding affinities were found for 10-methyl-benzodiazepinone 1c and benzodiazepines 2b, c. Benzodiazepinones 3a-f were prepared by cyclization with 1,1'-carbonyldiimidazole of the corresponding 2-(aryl-imidazol-1-yl-methyl)-arylamines, obtained from the suitable (2-amino-aryl)-aryl-methanols with 1,1'-carbonyldiimidazole in different conditions. N-Alkylation of 3a-f to 1a-f was achieved using dimethylformamide-dimethylacetal. Reduction of 3a-f to 4a-f was accomplished with lithium aluminum hydride or borane and oxidation of 4a-f to 2a-f was performed with manganese (IV) oxide.
Abstract: A new series of 3-phenyl-1-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-yl)propane derivatives 2a-l (related to the antifungal bifonazole) was synthesized and tested for antimicrobial activity. A number of substituents on the phenyl ring were chosen to compare the relative biological properties with those of corresponding aza-analogues, previously described by us. The in vitro antifungal activities of the newly synthesized azoles were tested against several pathogenic fungi responsible for human disease. Test pathogens included representatives of yeasts (Candida albicans, Candida parapsilosis, Criptococcus neoformans), dermathophytes (Tricophyton verrucosum, Tricophyton rubrum, Microsporum gypseum) and moulds (Aspergillus fumigatus). Bifonazole and miconazole were used as reference drugs. Title compounds were prepared by alkylation of 1-biphenyl-4-yl-2-imidazol-1-yl-ethanone with the proper arylmethyl halide and subsequent reduction of corresponding ketones applying the Huang-Minlon modification of the Wolff-Kishner reaction.
Abstract: In the course of a study on 1H-imidazol-1-amine derivatives as antifungal agents, we found that N-[(1,1'-biphenyl)-4-ylmethyl]-N-[(2,4-dichlorophenyl)methyl]-1H-imidazol-1-amine (1a) exhibited promising activities. In order to explore more in detail the structure-activity relationship of this new class of antifungal agents, we report now the synthesis and the biological activity of new analogues (1b-k) of compound 1a. The synthesis was performed using N-[(1,1'-biphenyl)-4-ylmethyl]-1H-imidazol-1-amine as starting material which was reacted with the proper arylmethyl halide. Most of the newly synthesized imidazolamines exhibited both fungal growth inhibition activity and cellular selectivity.
Abstract: In the context of a research program aimed at elucidating the properties of the 5H-imidazo[2,1-c][1.4]benzodiazepine system, a series of 11-aryl-5H-imidazo[2,1-c][1,4]benzodiazepines (3a-i) and their 10,11-dihydro-derivatives (4a-i) has been synthesized. The synthetic strategy includes the preparation of the aryl-[1-(2-nitrobenzyl)-1H-imidazol-2-yl]methanones (5a-i) followed by their reduction and subsequent cyclization. Affinities of compounds 3a-i and 4a-i for central benzodiazepine as well as for adenosine A1-receptors were determined by radioligand binding assays. Among the unsaturated analogues, the highest activity at both receptors is displayed by 1H-(2-thienyl) derivative 3e. The hydrogenated analogues 4a-i do not exhibit considerable binding affinity either for central benzodiazepine or for adenosine A1-receptors.
Abstract: A series of isoxazole derivs. structurally related to broxaterol has been prepd. and tested for their potency to beta 1 and beta 2 adrenergic receptors. At variance with broxaterol, none of the tested compds. displayed agonistic activity. The 3-isopropenyl deriv. is the most potent antagonist both in the trachea and atria prepns.
Notes: CAN 133:296394 xD;Heterocyclic Compounds (More Than One Hetero Atom) xD;76596-57-1 (Broxaterol) Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), BIOL (Biological study) (prepn. and beta 1 and beta 2 adrenergic receptor activities of broxaterol analogs); 115697-55-7P; 115697-57-9P; 115697-60-4P; 301168-33-2P; 301168-34-3P; 301168-35-4P; 301168-36-5P; 301168-37-6P; 301168-38-7P Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (prepn. and beta 1 and beta 2 adrenergic receptor activities of broxaterol analogs); 684-88-8; 2028-63-9 (3-Butyn-2-ol); 5471-68-1; 14630-40-1 (Bis(trimethylsilyl)acetylene); 76596-55-9; 135325-36-9 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. and beta 1 and beta 2 adrenergic receptor activities of broxaterol analogs); 5930-98-3P; 68659-04-1P; 301168-22-9P; 301168-23-0P; 301168-24-1P; 301168-26-3P; 301168-27-4P; 301168-28-5P; 301168-29-6P; 301168-30-9P; 301168-31-0P; 301168-32-1P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and beta 1 and beta 2 adrenergic receptor activities of broxaterol analogs); 301168-25-2P Role: SPN (Synthetic preparation), PREP (Preparation) (prepn. and beta 1 and beta 2 adrenergic receptor activities of broxaterol analogs)
Abstract: [structure] Two water-soluble fullerene derivatives have been computer-designed and synthesized. They may exhibit interesting anti-HIV activity owing to the presence of two ammonium groups strategically located on the spheroid surface.
Abstract: The synthesis and the biological activity of (+/-)-cis- and (+/-)-trans-[4-[[2-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-ylmethyl)-1, 3-dioxolan-4-yl]methylthio]phenyl]carbamic acid ethyl esters (2a and 2b) are discussed. They were designed as structural analogues of Tubulozole, a synthetic tubulin polymerisation inhibitor with antimitotic properties. Biological tests were carried out on PC12, a neuronal-like cell line derived from rat pheochromocytoma, and on GL15, a cell line derived from human glioblastoma. The exposure (from 5 to 20 h) of GL15 and PC12 cells to different concentrations (0.1-1000 microM; IC50 approximately 1 microM) of 2a or 2b resulted in a drastic decrease in the number of viable cells without an apparent effect on the cell distribution in the various phases of the cell cycle. Compound 2a or 2b (10 microM) induced cell death by activating apoptosis. This was correlated with the activation of an oscillating Ca(2+)-dependent mechanism which increased the intracellular calcium concentration ([Ca2+]i) via Ca(2+)-release from internal stores. Moreover, 2a (10 microM) also induced severe damage of cytoskeletal F-actin filaments after a 5 h incubation in GL15 cells. This was also observed but to a smaller extent, for 2b. Under the same experimental conditions, PC12 cells showed similar actin deregulation.
Abstract: In this study we extended our exploration of the N-azolylamine moiety for its antifungal activity. We prepared a number of N-azolylamino derivatives. The synthetic sequence includes the preparation of aminoazole Schiff bases, and the reduction and the alkylation of the corresponding secondary amines. The title compounds were evaluated in vitro against several pathogenic fungi responsible for human disease. The most potent antimicrobial compound was the N-(biphenyl-4-yl)methyl-N-(2,4-dichlorophenyl)methyl-1H-imidazol-l-yl amine (21), which was found to be active against yeasts and dermatophytes; its potency and selectivity were comparable to those of miconazole.
Abstract: The methyl group of naftifine (1) and butenafine (2) was replaced by an azolic nucleus to obtain the new compounds 3-8 which exhibit the characteristics of both allylamine (or benzylamine) and azole antifungals. The title compounds were evaluated in vitro against several pathogenic fungi responsible for human disease. Among these, compounds 5, 6, and 8 were found to inhibit the growth of dermatophytes with a potency comparable to that of naftifine. The synthetic sequence includes the preparation of aminoazole Schiff bases, reduction, and alkylation of the corresponding secondary amines.
Abstract: Two novel tricyclic triazepinones, 5,10-dihydro-5-ethyl-11H-pyrrolo[1,2-b][1,2,5]benzotriazepin-11-one 5 and 5,11-dihydro-11-ethyl-6H-pyrido[3,2-f]pyrrolo[1,2-b][1,2,5]triazepin-6-one 6, structurally related to the reverse transcriptase inhibitor nevirapine were prepd. from N-(2-nitrophenyl)- and N-(3-nitro-2-pyridinyl)-1H-pyrrol-1-amine 7a, b. The synthetic sequence includes ethylation with EtBr, redn. of the nitro group, triphosgene reaction followed by intramol. cyclization. Activity of the two compds. against the HIV-1 multiplication in acutely infected cells is also reported, with 5 (EC50 = 48 micro M) being more potent than 6 (EC50 >200 micro M), but less so than nevirapine itself (EC50 = 0.1 micro M).
Notes: CAN 134:280817 xD;Heterocyclic Compounds (More Than One Hetero Atom) xD;765-39-9 (1-Aminopyrrole); 5470-18-8 (2-Chloro-3-nitropyridine) Role: RCT (Reactant), RACT (Reactant or reagent) (arylation of aminopyrrole with chloro(nitro)pyridine); 79700-48-4 Role: RCT (Reactant), RACT (Reactant or reagent) (ethylation of); 332379-52-9P; 332379-53-0P Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (prepn. and activity of, against HIV-1 multiplication in acutely infected cells); 332379-49-4P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and ethylation of); 332379-51-8P; 332379-57-4P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and reaction with triphosgene); 332379-50-7P; 332379-55-2P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and redn. of nitro group in); 332379-59-6P; 332379-61-0P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and thermal cyclization of); 32315-10-9 (Triphosgene) Role: RCT (Reactant), RACT (Reactant or reagent) (reaction with (aminopyridinyl)- or (aminophenyl)(ethyl)pyrrolamines); 129618-40-2 (Nevirapine) Role: MSC (Miscellaneous) (synthesis of tricyclic triazepinones related to nevirapine)
Abstract: Positively charged fullerene derivatives, moderately soluble in water:DMSO 9:1, have been tested using three strains of Mycobacterium spp. Some compounds inhibit the growth of Mycobacterium tuberculosis, a human clinical isolate, particularly virulent and resistant, at doses as low as 5 microg/mL.
Abstract: The four stereoisomers of Delta 2-isoxazoline I, a beta -adrenergic receptor antagonist structurally related to Falintolol, were prepd. by an enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc. CH2:CHCH(OH)CH2OSiPh2CMe3, followed by its cycloaddn. to pyruvonitrile oxide. Through this strategy, diastereomeric amino alcs. (+)-I/(-)-I and (-)-2a/(+)-2b were obtained in 99 and 92% enantiomeric excess, resp. The abs. configuration to the target compds. was assigned via chem. correlation to the enantiomers of epoxides 4a and 4b, whose stereochem. had been previously established.
Notes: CAN 133:309859 xD;Heterocyclic Compounds (More Than One Hetero Atom) xD;267236-53-3P; 267236-54-4P Role: BPN (Biosynthetic preparation), BIOL (Biological study), PREP (Preparation) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.); 91376-49-7P; 267236-50-0P; 267236-51-1P; 267236-52-2P; 301670-75-7P Role: BPN (Biosynthetic preparation), PUR (Purification or recovery), RCT (Reactant), BIOL (Biological study), PREP (Preparation), RACT (Reactant or reagent) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.); 301670-76-8P; 301670-77-9P Role: BPN (Biosynthetic preparation), RCT (Reactant), BIOL (Biological study), PREP (Preparation), RACT (Reactant or reagent) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.); 9001-62-1 (Lipase) Role: CAT (Catalyst use), USES (Uses) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.); 497-06-3 (3-Butene-1,2-diol); 3282-30-2 (Pivaloyl chloride); 5471-68-1 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.); 177032-63-2P; 177032-64-3P; 191800-37-0P; 301670-78-0P; 301670-79-1P; 301670-80-4P; 301670-81-5P; 301670-82-6P; 301670-83-7P; 301670-84-8P; 301670-85-9P; 301670-86-0P; 301670-87-1P; 301670-88-2P; 301670-89-3P; 301670-90-6P; 301670-91-7P; 301670-92-8P; 301670-93-9P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.); 62214-39-5P; 86106-09-4P; 301670-95-1P; 301670-97-3P; 301670-99-5P; 301671-01-2P Role: SPN (Synthetic preparation), PREP (Preparation) (prepn. of stereoisomers of Delta 2-isoxazoline via enzyme-catalyzed kinetic resoln. of the unsatd. secondary alc.)
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 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: 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.
