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1.
J Med Chem ; 55(18): 8193-7, 2012 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-22931526

RESUMO

Inhibition of sirtuins has recently been proposed as a promising anticancer strategy. Some of the new benzodeazaoxaflavins (2a, 2b, and 2d) here reported as SIRT1/2 inhibitors were endowed with pro-apoptotic properties in human U937 leukemia cells and, most importantly, together with the prototype MC2141 (1) displayed antiproliferative effects in cancer stem cells from patients with colorectal carcinoma and glioblastoma multiforme, known to be highly tumorigenic, resistant to conventional cancer chemotherapy, and responsible, at least in part, for cancer relapse or recurrence.


Assuntos
Flavinas/química , Flavinas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Sirtuínas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Flavinas/síntese química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos
2.
J Med Chem ; 54(10): 3492-9, 2011 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-21528845

RESUMO

We report the design and concise synthesis, in two steps from commercially available material, of novel, bioactive derivatives of the enzyme cofactor nicotinamide adenine dinucleotide (NAD). The new synthetic dinucleotides act as sirtuin (SIRT) inhibitors and show isoform selectivity for SIRT2 over SIRT1. An NMR-based conformational analysis suggests that the conformational preferences of individual analogues may contribute to their isoform selectivity.


Assuntos
NAD/química , Sirtuína 1/química , Sirtuína 2/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Modelos Químicos , Oxirredução , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas , Proteínas Recombinantes de Fusão/química , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores
3.
Bioorg Med Chem ; 19(12): 3669-77, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21315612

RESUMO

Small molecules interfering with posttranslational modification of histones are of interest as tools to study epigenetic regulation of gene transcription. Specifically, drugs that interfere with histone deacetylation could be useful to induce differentiation, growth arrest as well as apoptotic cell death in tumor cells. One class of histone deacetylases is known as sirtuins some of which (Saccharomyces cerevisiae Sir2) are for example inhibited by the lactone splitomicin leading to telomeric silencing in yeast. However, splitomicin is only a micromolar inhibitor of yeast Sir2 and does not inhibit human subtypes and the lactone is prone to hydrolytic ring opening. In preliminary SAR-studies, splitomicin analogs lacking this hydrolytically labile ring were described as inactive while the naphthalene moiety could successfully be replaced by smaller aromatic rings in a fragment-like dihydrocoumarin. Here we report the synthesis and biological activity of a series of hydrolytically stable analogs with activity against human SIRT1 and 2. These comparatively small compounds characterized by high ligand efficiency are used as a starting point toward the development of specific inhibitors of histone deacetylases from the class of sirtuins.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Pironas/síntese química , Pironas/farmacologia , Sirtuínas/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , NAD/química , Naftalenos/química , Pironas/química
4.
Biochim Biophys Acta ; 1799(10-12): 726-39, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20601279

RESUMO

Histone deacetylases (HDACs) are enzymes that cleave acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Unlike the other three of the four classes of HDACs that have been identified in humans, which are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD(+)) for their catalytic activity. The seven members of the class III HDACs are also named sirtuins for their homology to Sir2p, a yeast histone deacetylase. Sirtuin inhibitors have been critical for the linkage of sirtuin activity to many physiological and pathological processes, and sirtuin activity has been associated with the pathogenesis of cancer, HIV, and metabolic and neurological diseases. Presented here is an overview of the many sirtuin inhibitors that have provided insight into the biological role of sirtuins.


Assuntos
Inibidores de Histona Desacetilases , NAD , Sirtuínas , Animais , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/enzimologia , NAD/química , NAD/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/enzimologia , Sirtuínas/química , Sirtuínas/metabolismo
6.
J Nat Prod ; 73(4): 709-11, 2010 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-20158242

RESUMO

Fractionation of the extract of the marine cyanobacterium Lyngbya majuscula collected from Panama led to the isolation of malyngolide dimer (1). The planar structure of 1 was determined using 1D and 2D NMR spectroscopy and HRESI-TOFMS. The absolute configuration was established by chemical degradation followed by chiral GC-MS analyses and comparisons with an authentic sample of malyngolide seco-acid (4). Compound 1 showed moderate in vitro antimalarial activity against chloroquine-resistant Plasmodium falciparum (W2) (IC(50) = 19 microM) but roughly equivalent toxicity against H-460 human lung cell lines. Furthermore, because the closely related cyanobacterial natural product tanikolide dimer (5) was a potent SIRT2 inhibitor, compound 1 was evaluated in this assay but found to be essentially inactive.


Assuntos
Cianobactérias/química , Éteres Cíclicos/isolamento & purificação , Éteres Cíclicos/farmacologia , Toxinas de Lyngbya/química , Toxinas de Lyngbya/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Éteres Cíclicos/química , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Toxinas de Lyngbya/farmacologia , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Panamá , Testes de Sensibilidade Parasitária , Pironas/química , Pironas/isolamento & purificação , Pironas/farmacologia , Relação Estrutura-Atividade
7.
Med Res Rev ; 30(6): 861-89, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19824050

RESUMO

Histone deacetylases (HDACs) are enzymes that cleave off acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Four different classes of HDACs have been identified in humans so far. Although classes I, II, and IV are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD(+)) for their catalytic activity. According to their homology to Sir2p, a yeast histone deacetylase, the class III is also termed sirtuins. Seven members have been described in humans so far. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with the pathogenesis of cancer, HIV, metabolic, or neurological diseases. Herein, we present an overview over sirtuins including their biology, targets, inhibitors, and activators and their potential as new therapeutic agents.


Assuntos
NAD/química , Sirtuínas/química , Animais , Epigênese Genética , Infecções por HIV/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Químicos , Neoplasias/metabolismo , Niacinamida/química , Ligação Proteica , Resveratrol , Transdução de Sinais , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo , Sirtuína 2/química , Sirtuína 2/metabolismo , Estilbenos/farmacologia
8.
J Med Chem ; 53(3): 1383-6, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-20030343

RESUMO

Class III histone deacetylases (sirtuins) play pivotal roles in many cellular processes. They are linked to extended lifespan and to the pathogenesis of cancer and neuronal disorders. We present novel sirtuin inhibitors based on a 6,7-dichloro-2-oxindole scaffold with low micromolar activity. In vitro activity was rationalized by docking studies, and hyperacetylation of sirtuin targets could be demonstrated in cell culture.


Assuntos
Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Indóis/farmacologia , Sirtuínas/antagonistas & inibidores , Acetilação , Western Blotting , Ensaio de Imunoadsorção Enzimática , Inibidores de Histona Desacetilases/síntese química , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , NAD/metabolismo , Sirtuínas/metabolismo , Relação Estrutura-Atividade
9.
J Org Chem ; 74(15): 5267-75, 2009 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-19572575

RESUMO

Tanikolide seco-acid 2 and tanikolide dimer 3, the latter a novel and selective SIRT2 inhibitor, were isolated from the Madagascar marine cyanobacterium Lyngbya majuscula. The structure of 2, isolated as the pure R enantiomer, was elucidated by X-ray experiment in conjunction with NMR and optical rotation data, whereas the depside molecular structure of 3 was initially thought to be a meso compound as established by NMR, MS, and chiral HPLC analyses. Subsequent total synthesis of the three tanikolide dimer stereoisomers 4, 5, and ent-5, followed by chiral GC-MS comparisons with the natural product, showed it to be exclusively the R,R-isomer 5. Tanikolide dimer 3 (= 5) inhibited SIRT2 with an IC(50) = 176 nM in one assay format and 2.4 microM in another. Stereochemical determination of symmetrical dimers such as compound 3 pose intriguing and subtle questions in structure elucidation and, as shown in the current work, are perhaps best answered in conjunction with total synthesis.


Assuntos
Cianobactérias/química , Inibidores Enzimáticos/química , Lactonas/química , Dimerização , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Lactonas/isolamento & purificação , Lactonas/farmacologia , Madagáscar , Conformação Molecular , Estrutura Molecular , Sirtuína 2/antagonistas & inibidores , Estereoisomerismo
10.
Cancer Lett ; 280(2): 222-32, 2009 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-19268440

RESUMO

Epigenetics is defined as heritable changes in gene expression that occur without changes in DNA sequence. Major mechanisms of epigenetics are post-translational histone modifications such as reversible acetylation. Histone deacetylases (HDACs) maintain the acetylation level of histones but also act on non-histone substrates that are involved in signal transduction or cellular transport processes. One important non-histone substrate is tubulin. The isotypes responsible for tubulin deacetylation are HDAC6 and the NAD(+)-dependent histone deacetylase (sirtuin) Sirt2. Here we review the action of those enzymes on tubulin and present an overview over existing inhibitors with a focus on their structural interaction with the targets.


Assuntos
Inibidores de Histona Desacetilases , Modelos Moleculares , Sirtuínas/antagonistas & inibidores , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Acetilação , Sítios de Ligação , Epigênese Genética , Desacetilase 6 de Histona , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Ligação Proteica , Pironas/química , Pironas/farmacologia , Sirtuína 2 , Sirtuínas/metabolismo , Triazóis/química , Triazóis/farmacologia , Moduladores de Tubulina/química
11.
ChemMedChem ; 3(12): 1965-76, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18985648

RESUMO

NAD+-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors.


Assuntos
Inibidores Enzimáticos/química , Sirtuínas/antagonistas & inibidores , Tiobarbitúricos/química , Algoritmos , Sítios de Ligação , Simulação por Computador , Bases de Dados Factuais , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Sirtuínas/farmacologia , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Termodinâmica , Tiobarbitúricos/síntese química , Tiobarbitúricos/farmacologia
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