RESUMO
The first Z-stereoselective method for the synthesis of the natural marine alkynol lembehyne C, containing a 1Z,5Z,9Z-triene moiety, in 41% yield was developed using the new Ti-catalyzed cross-coupling of oxygenated and aliphatic 1,2-dienes as the key step. It was found for the first time that lembehyne C exhibits moderate cytotoxicity against Jurkat, K562, U937, and HL60 cancer cells and also efficiently induces apoptosis in Jurkat cells, with the cell death mechanism being activated by the mitochondrial pathway. The lembehyne C inhibition of the cell cycle follows the mitotic catastrophe mechanism.
Assuntos
Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , EstereoisomerismoRESUMO
The communication reports a new stereoselective method for the synthesis of a natural acetylenic alcohol, lembehyne B. The key stage of the process uses new cross-cyclomagnesiation reaction of aliphatic and oxygenated 1,2-dienes with Grignard reagents in the presence of a catalytic amount of Cp2TiCl2. A study of the cytotoxic properties of lembehyne B on tumor cell lines using flow cytometry demonstrated that this is a selective inducer of early apoptosis of the Jurkat, HL-60 and K562 cell cultures and hypodiploid (sub-G1) sub-population inducer in cell cycle studies for all cell lines used.
Assuntos
Álcoois/farmacologia , Alcinos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Álcoois Graxos/farmacologia , Álcoois/síntese química , Álcoois/química , Alcinos/síntese química , Alcinos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Álcoois Graxos/síntese química , Álcoois Graxos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
An original method has been developed for the synthesis of 1,3-dyine derivatives of natural lembehyne B in high yields (50-67%) and with high selectivity (>98%). The key stage of the synthesis is new Ti-catalyzed cross-cyclomagnesiation of oxygenated and aliphatic 1,2-dienes induced by Grignard reagents. For studying the effect of the structure on the antitumor and neuritogenic activities, a series of lembehyne B analogues with different distances between the terminal hydroxy group and the 1,3-diyne moiety was prepared and tested for neuritogenic activity on mouse neuroblastoma Neuro 2A cells and for cytotoxicity, induction of apoptosis, and effects on the cell cycle using Jurkat, U937, K562, HeLa, and Hek293 tumor cell lines.