RESUMO
Eleven 2'-N-acyl derivatives (5a-k) were prepared from ecteinascidin 770 (Et 770: 1b) via known 18,6'-O-bisallyl-protected compound (3) in three steps. Their in vitro cytotoxicities were determined by measuring IC50 values against human cell lines HCT116 and DU145. 5-Isoxazolecarboylamide derivative (5i) and 4-methoxybenzoylamide derivative (5k) were found to be promising leads for further optimization.
Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We report herein eleven 2'-N-acyl derivatives that were prepared from ecteinascidin 770 (Et 770: 1b) via 18,6'-O-bisallyl protected compound (4) in excellent yields. 2'-N-Acyl derivatives (6a-k) generally showed higher cytotoxicity than 1b. Among them, 3-quinolineacyl derivative (6g) and 4-fluorocinnamoyl derivative (6h) exhibited approximately 50- and 70-fold higher cytotoxicity to the HCT116 human colon carcinoma cell line, respectively, than 1b. Both compounds are potent inhibitors of the in vitro growth of several tumor cells and are therefore promising leads for further optimization. We also report the transformation of 1b into Et 788 (3), which is the first example of an ecteinascidin derivative having a primary amide at C-21 position.