Комбретастатины А-4 и А-1 и их производные: обзор

В обзоре литературы рассмотрены результаты исследований различных ингибиторов тубулина (основного компонента микротрубочек), преимущественно колхициноподобных соединений – комбретастатинов А-4 и А-1 (СА-4 и СА-1). Представлены данные исследований SAR (structure activity relation), механизмов действия, оцененных в системах in vitro (на культурах опухолевых клеток) и in vivo (у животных с привитыми опухолями мышей и ксенографтами опухолей человека различного гистогенеза), охарактеризовано фосфатное производное комбретастатина А-4 как vascular disrupting agent (VDAs), описаны подходы к получению аналогов СА-4, стабильных в cis-конфигурации, и способы повышения гидрофильности перспективных производных при сохранении их высокой цитотоксичности. Приведены данные о результатах клинических испытаний СА-4Р и СА-1Р, назначаемых индивидуально или в комбинации с химиопрепаратами. На основании анализа имеющихся результатов исследований производных комбретастатинов А-4 и А-1 сделан вывод об отсутствии среди них в  настоящее время идеального водорастворимого вещества со стабильной cis-конфигурацией молекулы и высокой цитотоксической активностью, на основе которого можно создать активное противоопухолевое лекарственное средство. Целью обзора является систематизация данных о противоопухолевой активности, путях модификации и возможностях терапевтического использования соединений на основе комбретастатинов (СА-4 и СА-1) и их производных.

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