RESUMO
FTase inhibitors constitute a new class of potential cancer therapeutics, especially in colorectal cancer where K-ras-selective mutations exist and have a role in tumorigenesis. The synthesis and biological evaluation of two nonpeptidic molecules (13 and 16) designed on the basis of a zinc chelator imidazole linked to two aromatic fragments able to fit in the "exit groove" and in the "A2 binding site" of FTase are described. These molecules are characterized respectively by a flexible phenylmethyl chain and a more constrained scaffold so as to evaluate their respective influences on site recognition. They have been evaluated in vitro and in vivo against human colon cancer cell lines and 13 not only inhibited tumor growth but also showed no toxic effects at the dose used.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/métodos , Neoplasias do Colo/tratamento farmacológico , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/antagonistas & inibidores , Animais , Células HT29 , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de NeoplasiasRESUMO
A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced cellular evaluation of the more potent farnesyltransferase inhibitors was explored and revealed a disorganization of tubulin in PC3 cells.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Azepinas/síntese química , Farnesiltranstransferase/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Moduladores de Tubulina/síntese química , Azepinas/farmacocinética , Azepinas/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/ultraestrutura , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/farmacologiaRESUMO
A new series of FTase inhibitors containing a tricyclic moiety--dioxodibenzothiazepine or dibenzocycloheptane--has been designed and synthesized. Among them, dioxodibenzothiazepine 18d displayed significant inhibitory FTase activity (IC(50)=17.3 nM) and antiproliferative properties.