3h-吡咯并[3,2-f]-喹啉-9-酮衍生物的合成及体外评价，这些衍生物表现出很强的抗白血病活性和选择性。
Synthesis and in vitro evaluation of 3h-pyrrolo[3,2-f]-quinolin-9-one derivatives that show potent and selective anti-leukemic activity.
机构信息
Department of Pharmaceutical Sciences, University of Padova, Italy.
出版信息
ChemMedChem. 2010 Aug 2;5(8):1373-85. doi: 10.1002/cmdc.201000180.
Abstract
A series of new substituted 7-phenyl-3H-pyrrolo[3,2-f]quinolin-9-ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI(50) values in the nanomolar range. The active compounds strongly blocked tubulin assembly and colchicine binding to tubulin. Their activities were equal to or greater than that of the reference compound combretastatin A-4. Flow cytometry studies showed that the two most active compounds arrested Jurkat cells in the G(2)/M cell-cycle phase in a concentration-dependent manner. This effect was associated with apoptosis, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and cleavage of the enzyme poly(ADP-ribose) polymerase.
摘要
一系列新型取代的 7-苯基-3H-吡咯并[3,2-f]喹啉-9-酮被合成并评估其抗增殖活性。最具活性的衍生物对人白血病细胞系表现出高选择性，并能强力抑制其生长，半数抑制浓度（GI50）值在纳摩尔范围内。活性化合物强烈抑制微管蛋白聚合和秋水仙素与微管蛋白的结合。它们的活性与参考化合物 combretastatin A-4 相当或更强。流式细胞术研究表明，两种最活跃的化合物以浓度依赖的方式将 Jurkat 细胞阻滞在 G2/M 细胞周期阶段。这种作用与细胞凋亡、线粒体去极化、活性氧的产生、半胱天冬酶-3 的激活以及多聚（ADP-核糖）聚合酶的切割有关。
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