RESUMO
Various analogues of the marine alkaloids, discorhabdins, have been synthesized. The strategy contains spirocyclization with phenyliodine(III) bis(trifluoroacetate) (PIFA), oxidative fragmentation of the ß-amino alcohols with the hypervalent iodine reagent C(6)F(5)I(OCOCF(3))(2), the detosylation and dehydrogenation reaction of the pyrroloiminoquinone unit in the presence of a catalytic amount of NaN(3) and the bridged ether synthesis with HBr-AcOH as the key reactions. All the synthesized compounds were evaluated by in vitro MTT assay for cytotoxic activity against the human colon cancer cell line HCT-116. Furthermore, the discorhabdin A oxa analogues were also evaluated against four kinds of tumor model cells, a human colon cancer cell line (WiDr), a human prostate cancer cell line (DU-145) and murine leukemia cell lines (P388 and L1210). For the identification of the target, discorhabdin A and the discorhabdin A oxa analogue were evaluated by an HCC panel assay. In the test, discorhabdins could have a novel mode of action with the tumor cells.
Assuntos
Quinonas/síntese química , Tiazepinas/síntese química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias/tratamento farmacológico , Quinonas/farmacologia , Quinonas/uso terapêutico , Relação Estrutura-Atividade , Tiazepinas/farmacologia , Tiazepinas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Discorhabdin A (1) exhibits a strong cytotoxic activity in vitro, but it is difficult to synthesize and handle due to the instability of its highly strained N,S-acetal structure. We then designed the analogues of discorhabdin A which also have strong cytotoxic activity and stability. The synthesis and examination of the biological activity of various types of stable discorhabdin A oxa analogues (2) were achieved.
Assuntos
Alcaloides/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Biologia Marinha , Ocitocina/análogos & derivados , Quinonas/síntese química , Compostos de Espiro/síntese química , Tiazepinas/síntese química , Acetais , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ocitocina/síntese química , Ocitocina/química , Quinonas/química , Quinonas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Tiazepinas/química , Tiazepinas/farmacologiaRESUMO
The first stereoselective total synthesis of a potent antitumor alkaloid, discorhabdin A (1), which is a unique sulfur-containing pyrroloiminoquinone alkaloid, is described. The key step in the stereocontrolled total synthesis of 1 involves both a diastereoselective oxidative spirocyclization using a hypervalent iodine(III) reagent and an efficient construction of the labile and highly strained N,S-acetal skeleton. These methodologies provide a breakthrough in the total syntheses of these promising new antitumor agents, discorhabdins and their analogues, which should serve as valuable probes for structure-activity studies.