Kravchenko Dmitri V, Kysil Volodymyr M, Tkachenko Sergey E, Maliarchouk Sergey, Okun Ilya M, Ivachtchenko Alexandre V
Department of Organic Chemistry, Chemical Diversity Research Institute, Khimki, Moscow Region, Russia.
Farmaco. 2005 Oct;60(10):804-9. doi: 10.1016/j.farmac.2005.08.001. Epub 2005 Sep 21.
A convenient synthesis of novel 8-sulfonyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines is described. As key steps to assemble the target molecular scaffold, our method features (a) Pfitzinger reaction of isatin-5-sulfonate 1 with methyl 3-oxo-3-phenylpropanoate, (b) formation of 1-(1H-pyrazol-4-yl)-1H-pyrrole-2,5-dione intermediate 5, and (c) reaction of sulfinic acid 9 with acrylate or methylacrylate leading to the corresponding sulfonyl propionates. Two compounds, ester 11 and morpholide 13, have been identified as potent inhibitors of caspase-3 with IC50 = 6 nM. Our primary data suggest noncompetitive and reversible character of caspase-3 inhibition.
本文描述了一种新型8-磺酰基-1,3-二氧代-4-甲基-2,3-二氢-1H-吡咯并[3,4-c]喹啉的简便合成方法。作为组装目标分子骨架的关键步骤，我们的方法具有以下特点：(a) 异吲哚啉-5-磺酸盐1与3-氧代-3-苯基丙酸甲酯的费茨inger反应；(b) 1-(1H-吡唑-4-基)-1H-吡咯-2,5-二酮中间体5的形成；(c) 亚磺酸9与丙烯酸酯或甲基丙烯酸酯反应生成相应的磺酰丙酸酯。两种化合物，酯11和吗啉代物13，已被鉴定为半胱天冬酶-3的有效抑制剂，IC50 = 6 nM。我们的初步数据表明半胱天冬酶-3抑制具有非竞争性和可逆性。
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