RESUMEN
Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.
Asunto(s)
Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Sirtuina 2/antagonistas & inhibidores , Cromonas/síntesis química , Cromonas/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Sirtuina 2/metabolismo , Relación Estructura-ActividadRESUMEN
Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3-10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.
Asunto(s)
Antocianinas , Simulación del Acoplamiento Molecular , Sirtuinas , Antocianinas/química , Antocianinas/farmacología , Sitios de Unión , Células CACO-2 , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Polifenoles , Estructura Secundaria de Proteína , Sirtuinas/antagonistas & inhibidores , Sirtuinas/química , Sirtuinas/metabolismoRESUMEN
Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.
Asunto(s)
Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Etiquetas de Fotoafinidad/química , Sirtuina 2/antagonistas & inhibidores , Sitios de Unión/efectos de los fármacos , Cromonas/síntesis química , Cromonas/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Sirtuina 2/metabolismo , Relación Estructura-Actividad , Espectrometría de Masas en TándemRESUMEN
Sirtuins are NAD(+)-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Sirtuinas/metabolismo , Proliferación Celular , Supervivencia Celular , Senescencia Celular , Reparación del ADN , Epigénesis Genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Sirtuinas/antagonistas & inhibidoresRESUMEN
Sirtuinâ 6 (SIRT6) is an NAD+-dependent histone deacetylase enzyme that is involved in multiple molecular pathways related to aging. Initially, it was reported that SIRT6 selectively deacetylated H3K9Ac and H3K56Ac; however, it has more recently been shown to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups in vitro. Subsequently, fatty acids were demonstrated to increase the catalytic activity of SIRT6. In this study, we investigated whether a series of N-acylethanolamines (NAEs), quercetin, and luteolin could regulate SIRT6 activity. NAEs increased SIRT6 activity, with oleoylethanolamide having the strongest activity (EC50 value of 3.1 µm). Quercetin and luteolin were demonstrated to have dual functionality with respect to SIRT6 activity; namely, they inhibited SIRT6 activity with IC50 values of 24 and 2 µm, respectively, and stimulated SIRT6 activity more than sixfold (EC50 values of 990 and 270 µm, respectively).
Asunto(s)
Etanolaminas/química , Sirtuinas/química , Etanolaminas/metabolismo , Humanos , Estructura Molecular , Sirtuinas/aislamiento & purificación , Sirtuinas/metabolismoRESUMEN
Control of histone acetylation is a part of the epigenetic mechanism that regulates gene expression and chromatin architecture. The members of the bromodomain and extra terminal domain (BET) protein family are a group of epigenetic readers that recognize histone acetylation, whereas histone deacetyl- ases such as sirtuinâ 1 (SIRT1) function as epigenetic erasers. We observed that BET inhibition by the specific inhibitor JQ1 upregulated SIRT1 expression and activated SIRT1. Moreover, we observed that BET inhibition functionally reversed the pro-inflammatory effect of SIRT1 inhibition in a cellular lung disease model. SIRT1 activation is desirable in many age-related, metabolic and inflammatory diseases; our results suggest that BET protein inhibition would be beneficial in treatment of those conditions. Most importantly, our findings demonstrate a novel mechanism of SIRT1 activation by inhibition of the BET proteins.
Asunto(s)
Azepinas/farmacología , Inflamación/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Sirtuina 1/genética , Factores de Transcripción/antagonistas & inhibidores , Triazoles/farmacología , Regulación hacia Arriba/efectos de los fármacos , Animales , Proteínas de Ciclo Celular , Línea Celular , Línea Celular Tumoral , Epigénesis Genética , Células HEK293 , Humanos , Inflamación/genética , Inflamación/inmunología , Células MCF-7 , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Interferencia de ARN , ARN Interferente Pequeño/genética , Sirtuina 1/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
Sirtuins (SIRT1-SIRT7) are NAD dependent deacetylases and intriguing drug targets in for example neurodegenerative diseases and cancer. Virtual screening has been shown to be a fast and efficient method of discovering new sirtuin inhibitors. In this study, a new putative binding site on the zinc binding domain of sirtuins was utilized to screen the ZINC database virtually in order to discover new sirtuin inhibiting scaffolds. Altogether 26 compounds were tested in vitro and initially 15 inhibitors displayed >30% SIRT3 inhibition. However, the evaluation of raw data from in vitro assay revealed that many of the compounds had intrinsic property to interfere with the fluorescence signal at the assay wavelengths resulting in false positives. All compounds with over 30% SIRT3 inhibition were studied more closely for their behavior in the assay and eventually, three compounds were identified as novel sirtuin inhibitors. They displayed 32-40% SIRT3 and 21-60% SIRT2 inhibition. The inhibitors display two new scaffolds, the smaller of which can be considered as a promising fragment, which offers a base for structural optimization.
Asunto(s)
Diseño Asistido por Computadora , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Simulación del Acoplamiento Molecular , Sirtuina 2/antagonistas & inhibidores , Sirtuina 3/antagonistas & inhibidores , Regulación Alostérica , Artefactos , Sitios de Unión , Dominio Catalítico , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/metabolismo , Unión Proteica , Conformación Proteica , Sirtuina 2/química , Sirtuina 2/metabolismo , Sirtuina 3/química , Sirtuina 3/metabolismo , Espectrometría de Fluorescencia , Relación Estructura-ActividadRESUMEN
Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.
Asunto(s)
Antineoplásicos/farmacocinética , Cromanos/síntesis química , Cromonas/síntesis química , Inhibidores Enzimáticos/síntesis química , Sirtuina 2/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromanos/farmacocinética , Cromanos/farmacología , Cromonas/farmacocinética , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Tubulina (Proteína)/metabolismoRESUMEN
SIRT6 is a modulator of chromatin structure having an important role in healthy ageing, and there is a crucial need to find specific modulators for it. Therefore, the activity of SIRT6 should be studied using a variety of methods. We examined the capability of SIRT6 to deacetylate a set of five fluorogenic substrates based on p53 and histone H3 sequences. The substrate designed around H3K56 deacetylation site exhibited the best signal-to-background ratio and was chosen for further studies. Nicotinamide is a known inhibitor for sirtuins, and it was found to be less potent inhibitor for SIRT6 than it is for SIRT1. In addition, we studied 15 other small molecule sirtuin modulators using the H3K56 based substrate. EX-527, quercetin and three pseudopeptidic compounds were found to be the most potent SIRT6 inhibitors, exhibiting over 50% deacetylation inhibition. These findings describe the first modulators of SIRT6 activity at the physiologically important H3K56 deacetylation site.
Asunto(s)
Histonas/metabolismo , Sirtuinas/metabolismo , Acetilación/efectos de los fármacos , Carbazoles/química , Carbazoles/farmacología , Histonas/química , Humanos , Estructura Molecular , Niacinamida/química , Niacinamida/farmacología , Péptidos/química , Péptidos/farmacología , Quercetina/química , Quercetina/farmacología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/metabolismo , Sirtuinas/antagonistas & inhibidores , Sirtuinas/biosíntesis , Relación Estructura-ActividadRESUMEN
Sirtuin 1 (SIRT1) is the most studied human sirtuin and it catalyzes the deacetylation reaction of acetylated lysine residues of its target proteins, for example histones. It is a promising drug target in the treatment of age-related diseases, such as neurodegenerative diseases and cancer. In this study, a series of known substrate-based sirtuin inhibitors was analyzed with comparative molecular field analysis (CoMFA), which is a three-dimensional quantitative structure-activity relationships (3D-QSAR) technique. The CoMFA model was validated both internally and externally, producing the statistical values concordance correlation coefficient (CCC) of 0.88, the mean value r(2)m of 0.66 and Q(2)F3 of 0.89. Based on the CoMFA interaction contours, 13 new potential inhibitors with high predicted activity were designed, and the activities were verified by in vitro measurements. This work proposes an effective approach for the design and activity prediction of new potential substrate-based SIRT1 inhibitors.
Asunto(s)
Modelos Moleculares , Sirtuina 1/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Relación Estructura-Actividad CuantitativaRESUMEN
The modulation of protein deacetylase SIRT1 has a vast therapeutic potential in treatment of several aging-associated diseases. Active regulator of SIRT1 (AROS) is a small endogenous protein which was originally reported to activate SIRT1 through a direct interaction in cancer cells. We show that the interaction between the two proteins is weak and does not alter the activity of SIRT1 in non-cancerous human cells. The results of different in vitro SIRT1 activity assays disclosed AROS as an inhibitor of SIRT1. The functional relationship between AROS and SIRT1 proved to be dependent on the biological context and experimental setting.
Asunto(s)
Proteínas Nucleares/metabolismo , Sirtuina 1/metabolismo , Factores de Transcripción/metabolismo , Acetilación , Células Epiteliales/enzimología , Células HEK293 , Histonas/química , Humanos , NAD/química , Proteínas Nucleares/química , Unión Proteica , Procesamiento Proteico-Postraduccional , Epitelio Pigmentado de la Retina/citología , Sirtuina 1/química , Factores de Transcripción/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results.
Asunto(s)
ADN-Topoisomerasas de Tipo I/química , Quinazolinas/química , Sirtuinas/antagonistas & inhibidores , Inhibidores de Topoisomerasa I/química , Alcaloides/química , Sitios de Unión , Carbolinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Activación Enzimática/efectos de los fármacos , Células Hep G2 , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Quinazolinas/síntesis química , Quinazolinas/farmacología , Sirtuinas/metabolismo , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/farmacologíaRESUMEN
In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G1 phase.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Péptidos/farmacología , Sirtuinas/antagonistas & inhibidores , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Sirtuinas/química , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
SIRT3 is a member of the sirtuin family of histone deacetylases. It is a mitochondrial protein, which has an important role in metabolic homeostasis but it may also act as a tumor suppressor or promoter. Increased SIRT3 transcription has been associated with node-positive breast cancer and oral squamous cell carcinoma. To identify novel SIRT3 inhibitors we have established a virtual screening workflow by using shape-based filtering and flexible docking protocol. The Chembridge database was screened and 40 molecules were selected and tested in an in vitro assay. Two novel scaffolds were identified among the tested hits. The 5-amino-2-phenyl-benzoxazole scaffold was selected for further structure-activity studies and a series of its analogs was tested. The SIRT3 inhibition for this series ranged between 13% and 71%.
Asunto(s)
Benzoxazoles/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Sirtuina 3/antagonistas & inhibidores , Animales , Benzoxazoles/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Sirtuina 3/metabolismo , Relación Estructura-ActividadRESUMEN
A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 µM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.
Asunto(s)
Cromanos/síntesis química , Cromonas/síntesis química , Sirtuina 2/antagonistas & inhibidores , Cromanos/química , Cromonas/química , Dicroismo Circular , Pruebas de Enzimas , Conformación Molecular , Sirtuina 2/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
SIRT6 belongs to the family of histone deacetylases (class III), but it also has mono-ADP-ribosyltransferase activity. SIRT6 is a nuclear sirtuin that has been associated with aging, cellular protection, and sugar metabolism. Despite these important roles for SIRT6, thus far, there are only a few weak SIRT6 inhibitors available, and no structure-activity relationship (SAR) studies have been published. This is the first study concerning peptides and pseudopeptides as SIRT6 deacetylation inhibitors and the first SAR data concerning SIRT6. We also investigated the molecular interactions using a homology model. We report three compounds exhibiting 62-91% SIRT6 inhibition at 200 µM concentration. These compounds can serve as starting points for systematic SAR studies and SIRT6 inhibitor design.
RESUMEN
The lack of substrate-bound crystal structures of SIRT1 and SIRT2 complicates the drug design for these targets. In this work, we aim to study whether SIRT3 could serve as a target structure in the design of substrate based pseudopeptidic inhibitors of SIRT1 and SIRT2. We created a binding hypothesis for pseudopeptidic inhibitors, synthesized a series of inhibitors, and studied how well the fulfillment of the binding criteria proposed by the hypothesis correlated with the in vitro inhibitory activities. The chosen approach was further validated by studying docking results between 12 different SIRT3, Sir2Tm, SIRT1 and SIRT2 X-ray structures and homology models in different conformational forms. It was concluded that the created binding hypothesis can be used in the design of the substrate based inhibitors of SIRT1 and SIRT2 although there are some reservations, and it is better to use the substrate-bound structure of SIRT3 instead of the available apo-SIRT2 as the target structure.
Asunto(s)
Péptidos/química , Sirtuina 1/antagonistas & inhibidores , Sirtuina 2/antagonistas & inhibidores , Acetilación , Apoproteínas/antagonistas & inhibidores , Células Cultivadas , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Modelos Moleculares , Imitación Molecular , Péptidos/síntesis química , Péptidos/farmacología , Unión Proteica , Técnicas de Síntesis en Fase Sólida , Estereoisomerismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P(app) ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed. Then, the in vivo brain/blood ratio was determined for the total brain and plasma concentrations and also for the unbound extracellular drug concentrations after a single dose (50 µmol/kg i.p.). KYP-2047 had a significantly higher P(app) than JTP-4819. In vivo, KYP-2047 had higher total and unbound brain/blood ratios. KYP-2047 was equally distributed between the cortex, hippocampus and striatum. In the case of JTP-4819, the unbound brain extracellular concentrations could not be readily predicted from the unbound blood levels, probably because of its poor membrane penetration properties. KYP-2047 displayed a better ability to reach the intracellularly located brain PREP, and it inhibited this enzyme more effectively than JTP-4819 after an equimolar single dose. In conclusion, KYP-2047 showed better brain penetration characteristics than JTP-4819 both in vitro and in vivo. KYP-2047 is a brain-penetrating, potent and long-acting PREP inhibitor; thus, it represents a convenient pharmacological tool for assessing the potential of PREP as a drug target.
Asunto(s)
Encéfalo/metabolismo , Prolina/análogos & derivados , Pirrolidinas/farmacocinética , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/enzimología , Barrera Hematoencefálica/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/enzimología , Permeabilidad Capilar , Cromatografía Liquida , Evaluación Preclínica de Medicamentos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Endotelio Vascular/metabolismo , Masculino , Espectrometría de Masas , Microdiálisis , Microvasos/citología , Estructura Molecular , Prolina/sangre , Prolina/farmacocinética , Prolil Oligopeptidasas , Pirrolidinas/sangre , Ratas , Ratas Wistar , Inhibidores de Serina Proteinasa/sangre , Distribución TisularRESUMEN
Sirtuins catalyze the NAD(+) dependent deacetylation of N(epsilon)-acetyl lysine residues to nicotinamide, O'-acetyl-ADP-ribose (OAADPR) and N(epsilon)-deacetylated lysine. Here, an easy-to-synthesize Ac-Ala-Lys-Ala sequence has been used as a probe for the screening of novel N(epsilon)-modified lysine containing inhibitors against SIRT1 and SIRT2. N(epsilon)-Selenoacetyl and N(epsilon)-isothiovaleryl were the most potent moieties found in this study, comparable to the widely studied N(epsilon)-thioacetyl group. The N(epsilon)-3,3-dimethylacryl and N(epsilon)-isovaleryl moieties gave significant inhibition in comparison to the N(epsilon)-acetyl group present in the substrates. In addition, the studied N(epsilon)-alkanoyl, N(epsilon)-alpha,beta-unsaturated carbonyl and N(epsilon)-aroyl moieties showed that the acetyl binding pocket can accept rather large groups, but is sensitive to even small changes in electronic and steric properties of the N(epsilon)-modification. These results are applicable for further screening of N(epsilon)-acetyl analogues.
Asunto(s)
Inhibidores de Histona Desacetilasas/química , Lisina/análogos & derivados , Péptidos/química , Sirtuina 1/antagonistas & inhibidores , Sirtuina 2/antagonistas & inhibidores , Secuencia de Aminoácidos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Lisina/síntesis química , Lisina/farmacología , Péptidos/síntesis química , Péptidos/farmacología , Sirtuina 1/metabolismo , Sirtuina 2/metabolismo , Relación Estructura-ActividadRESUMEN
N()-Thioacetyl-lysine-containing tri-, tetra-, and pentapeptides, based on the alpha-tubulin and p53 protein sequences, were studied as SIRT1 and SIRT2 inhibitors. The potency of the pentapeptides depended on the selection of the side chains. The removal of N- and C-terminal residues of the pentapeptides yielded tripeptides with retained SIRT1 inhibitory activity but decreased SIRT2 inhibitory activity. The most potent SIRT1 inhibitors were equipotent with the reference compound (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) with the IC(50) values of 180-330 nM.