RESUMO
In the search for a new class of histone deacetylase inhibitors, we prepared a series of very simple benzofused hydroxamic acids to find an anchoring fragment of minimal molecular weight: they showed very good ligand efficiencies. Following these findings, classical fragment growing work was performed to increase binding energy and selective cytotoxicity. In the second phase of the work, information from the SARs of the benzothiophene series and data available in literature, we explored the in vitro pharmacological properties of the 6-substituted-7-fluoro-benzothiophene hydroxamates and the 5-susbtituted-benzofuran hydroxamates.
Assuntos
Benzofuranos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Tiofenos/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Células HCT116 , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
In the search for a new class of histone deacetylase inhibitors, we prepared a series of simple benzofused hydroxamic acids to find an anchoring fragment of minimal molecular weight. These initial hits, all belonging to the benzothiophene class, showed very good ligand efficiencies. Following these findings, a classical fragment growing approach was performed to increase binding affinity and cytotoxicity.
Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Tiofenos/química , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/toxicidade , Ligação ProteicaRESUMO
We report here the strategy used in our research group to find a new class of histone deacetylase (HDAC) inhibitors. A series of 5,11-dihydrodibenzo[b,e]azepine-6-ones alkylated on the amide nitrogen with an alkyl chain bearing an hydroxamic acids moiety at the end, has been designed (based upon the general motif for HDAC inhibitors), synthesized and tested. This allowed us to identify a new series of submicromolar HDAC inhibitors, which showed antiproliferative activity on HCT-116 colon carcinoma cells.
Assuntos
Azepinas/química , Azepinas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Relação Estrutura-AtividadeRESUMO
A series of α,α-cycloalkylglycine sulfonamide compounds of general formula 1 has previously been identified by our group as selective human B(2)(hB(2)) receptor antagonists. Here we report the in vitro and in vivo BK antagonist activity of a further evolution of the series, consisting in compounds of the general formula 2, containing either an alkyl piperazine or a 4-alkyl piperidine ring bearing various positively charged groups (R'). These studies unexpectedly revealed quite a flat nanomolar/subnanomolar SAR for the binding affinity, while differences were seen in the in vitro functional activities. We propose that variations in the residence time may explain these results.
Assuntos
Antagonistas de Receptor B2 da Bradicinina , Glicina/análogos & derivados , Glicina/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Bradicinina/metabolismo , Broncoconstrição/efeitos dos fármacos , Células CHO , Cricetinae , Glicina/síntese química , Cobaias , Humanos , Hipotensão/tratamento farmacológico , Receptor B2 da Bradicinina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A series of N-substituted 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of histone deacetylase (HDAC) inhibitors (zinc binding moiety-linker-capping group) has been previously reported by our group. Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells. We report here the second part of the strategy used in our research group to find a new class of HDAC inhibitors, namely the SAR study for the compounds bearing a sulfonyl group on the piperidine nitrogen. In the present work, we have considered both sulfonamides and sulfonyl ureas.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Piperidinas/química , Piperidinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Humanos , Sulfonas/química , Sulfonas/farmacologiaRESUMO
We report here the strategy used in our research group to find a new class of histone deacetylase (HDAC) inhibitors. A series of N-substituted 4-alkylpiperazine and 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of HDAC inhibitors (zinc binding moiety-linker-capping group) has been designed, prepared, and tested for HDAC inhibition. Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells.
Assuntos
Antineoplásicos/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Piperazinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Piperazina , Relação Estrutura-AtividadeRESUMO
Starting from in-house capped tripeptide libraries, we have developed two series of compounds as potent antagonists of the hNK(2) receptor with a reduced peptide character. These two series maintained a crucial amide bond, which could not be methylated or substituted with classical isostere without a dramatic loss in binding affinity, very likely due conformational changes. We report here the planning, synthesis and evaluation of molecules belonging to the selected chemical series, which contain a strategically placed hydrogen bond acceptor. The aim of the work was to improve membrane permeability via the formation of an intramolecular hydrogen bonding, and at the same time to maintain the structural characteristics geometry and polarity of the amide linkage so as to retain a relevant binding affinity for the biological target.
Assuntos
Receptores da Neurocinina-2/antagonistas & inibidores , Permeabilidade da Membrana Celular , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Oligopeptídeos/farmacologia , SolubilidadeRESUMO
As part of a project aimed at the identification of a series of small, orally available antagonists for the hNK(2) receptor, starting from one of our capped dipeptide libraries, we succeeded in the chemical optimization of the first identified leads, finally producing a class of molecules with significant activity in our animal model after iv administration. We herein report the results of further chemical modifications made to reduce the overall peptide character of this series and the consequent improvement of their in vivo antagonist activity. The present work identified 6-methylbenzo[b]thiophene-2-carboxylic acid (1-[(S)-1-benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl]cyclopentyl)amide (10i), endowed with subnanomolar potency in all the in vitro tests and being highly potent and of long duration upon in vivo testing after both iv and id dosing.