RESUMO
In order to probe the S1 and S1' mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with Ki values in the nanomolar range.
Assuntos
Aminobenzoatos/síntese química , Benzocicloeptenos/síntese química , Antígenos CD13/antagonistas & inibidores , Inibidores de Proteases/síntese química , Aminobenzoatos/química , Animais , Benzocicloeptenos/química , Antígenos CD13/química , Antígenos CD13/isolamento & purificação , Rim/química , Rim/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteases/química , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , TermodinâmicaRESUMO
A new class of low molecular weight, highly potent and selective non peptidic inhibitors of aminopeptidase N (APN/CD13) is described. We report the synthesis and in vitro evaluation of racemic substituted analogues of 7-amino-benzocyclohepten-6-one 1a. We investigated various substitutions on the aromatic ring with phenyl and halogen groups. In vitro kinetic studies revealed that these compounds are among the most effective APN/CD13 inhibitors found so far. Hydrophobic substituents placed at position 1 or 4 on the cycloheptenone 1a led to the potent compounds 1c-h,b'-c',f',h' with K(i) in the nanomolar range. The key finding of the present work was the observed additive effect of 1,4-disubstitutions which led to the discovery of the picomolar inhibitor 1d' (K(i)=60 pM). The designed inhibitors retain the selectivity of our lead structure 1a towards selected members of the aminopeptidase family, combined with an impressive increase in inhibitory potency and a conserved stability.
Assuntos
Anisóis/farmacologia , Antígenos CD13/antagonistas & inibidores , Cicloeptanos/farmacologia , Aeromonas/enzimologia , Animais , Anisóis/síntese química , Anisóis/química , Cicloeptanos/síntese química , Cicloeptanos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Rim/enzimologia , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , SuínosRESUMO
We report the efficient synthesis and biological evaluation of new benzodioxinoindolocarbazoles heterocycles (BDCZs) designed as potential anticancer agents. Indolic substitution and maleimide variations were performed to design a new library of BDCZs and their cytotoxicity were evaluated on two representative cancer cell lines. Several derivatives have shown a marked cytotoxicity with IC(50) values in the nanomolar range. Results are reported in this Letter.
Assuntos
Antineoplásicos/síntese química , Carbazóis/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carbazóis/síntese química , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia/tratamento farmacológico , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológicoRESUMO
A quantitative structure-retention and retention-activity relationships investigations were performed on the lipophilicities of some 1,3-oxazolidine systems as estimated by RP-HPTLC retention parameters. The classical R(Mo) values were compared with the factors scores obtained by principal component analysis based also onto the TLC retention data. The lipophilicities (R(Mo) and factor scores) were correlated with the theoretical molecular descriptors of 1,3-oxazolidine derivatives providing by the ALCHEMY 2000 software package. The reliability of the factor scores values as lipophilic indices are shown by their significant correlation with the classical R(Mo) values and other molecular descriptors. In addition, the "lipophilicity chart" described by the first two components, and/or the "lipophilicity space" described by the first three components have the effect of separating compounds from each other most effectively from the congeneric (similarity) aspect point of view. Finally, these findings support the idea that the chromatographic process of the investigated compounds in this paper and consequently their partitioning over a bio-membrane are controlled mainly by lipophilicity.