RESUMEN
The first total synthesis of vineomycin A1 (1) has been accomplished. Structure-activity relationship studies for cytotoxicity against human breast cancer MCF-7 cells using several synthetic vineomycin A1 analogues differing in the number and position of glycon moieties revealed that the cytotoxicity increased as the number of glycon moieties increased. The position of the glycon moiety was one of the key factors for the cytotoxicity of 1. Moreover, in vitro analysis of the cytotoxicity of 1 against MCF-7 cells indicated for the first time that 1 effectively induced cancer cell death by apoptosis, not by acting as a DNA intercalating agent.
Asunto(s)
Antraquinonas/farmacología , Antineoplásicos/farmacología , Antraquinonas/síntesis química , Antraquinonas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
An efficient and practical total synthesis of aquayamycin has been accomplished. The highly oxidized and stereochemically complex tetracyclic ring system was constructed using three key reactions: 1)â highly diastereoselective 1,2-addition of C-glycosyl naphthyllithium to a cyclic ketone, 2)â indium-mediated site-selective allylation-rearrangement sequence of naphthoquinone, and 3)â diastereoselective intramolecular pinacol coupling. This synthetic strategy offers a novel and efficient pathway to prepare aquayamycin-type angucycline antibiotics.