RESUMO
Andrographolide 1, the cytotoxic agent of the plant Andrographis paniculata was subjected to semi-synthetic studies leading to the preparation of a number of potent and novel analogues. Of the analogues synthesized, while 8,17-epoxy andrographolide 6 retained the cytotoxic activity of 1, ester derivatives of 6 exhibited considerable improvement in activity. Lower activity was observed when the epoxy moiety in the triacetate 9, derived from 6 was modified. Synthesis and structure-activity relationships are discussed.
Assuntos
Antineoplásicos/farmacologia , Diterpenos/farmacologia , Andrographis , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Diterpenos/administração & dosagem , Diterpenos/síntese química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
An acyclic tripeptide based on a heterochiral D-pro-L-pro template shows a propensity to exist as a 3(10) helical conformation and can be cyclized, via ring-closing metathesis, to the corresponding cyclic tetrapeptides without disrupting the helical conformations in CDCl(3) as well as in DMSO-d(6) solutions. The detailed conformational studies were carried out by using NMR spectroscopy, X-ray crystallography, molecular dynamic simulations, and circular dichroism spectroscopy.
