RESUMO
Putative dual action compounds (DACs 3a-d) based on azabicyclo[5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn2+-chelating 2,2'-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn2+ chelation on in vitro activity of DPA-substituted DACs 3a-d was sometimes perceivable, but did not lead to strong cellular synergistic effects. In particular, the linker connecting DPA with the ABD scaffold seems to influence cellular Zn2+-chelation, with longer lipophilic linkers/DAC 3c being the optimal choice.
Assuntos
Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Quelantes/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Mimetismo Molecular , Zinco/química , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Quelantes/química , HumanosRESUMO
Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn(2+)-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn(2+)) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn(2+) chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn(2+) chelation.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quelantes/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Mitocondriais/química , Mimetismo Molecular , Zinco/química , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Quelantes/química , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectrofotometria UltravioletaRESUMO
The concurrent employment of α-amino acid-derived chiral components such as aldehydes and α-isocyanoacetates, in a sequential Ugi reaction/cyclization two-step strategy, opens the door to the synthesis of three structurally distinct piperazine-based scaffolds, characterized by the presence of L-Ala and/or L-Phe-derived side chains and bearing appropriate functionalities to be easily applied in peptide chemistry. By means of computational studies, these scaffolds have been demonstrated to act as minimalist peptidomimetics, able to mimic a well defined range of peptide secondary structures and therefore potentially useful for the synthesis of small-molecule PPI modulators. Preliminary biological evaluation of two different resistant hepatocellular carcinoma cellular lines, for which differentiation versus resistance ability seem to be strongly correlated with well defined types of PPIs, has revealed a promising antiproliferative activity for selected compounds.