C-7-炔基化和芳基化吡咯并三嗪C-核糖核苷的合成及其抗肿瘤活性
Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides.
作者信息
Li Qingfeng, Groaz Elisabetta, Persoons Leentje, Daelemans Dirk, Herdewijn Piet
机构信息
Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1041, 3000 Leuven, Belgium.
Laboratory of Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1043, 3000 Leuven, Belgium.
出版信息
ACS Med Chem Lett. 2020 Jul 9;11(8):1605-1610. doi: 10.1021/acsmedchemlett.0c00269. eCollection 2020 Aug 13.
Abstract
A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold with various alkynyl and aryl groups starting from a common 7-iodo-pyrrolotriazine C-ribonucleoside intermediate. Analogues bearing a 7-cyclopropyl-, 7-propyl-, and 7-butylacetylene moiety displayed potent cytotoxic activity, with the latest being the most selective of this series toward cancer cells. Further insights revealed that such C-nucleosides could exert their antiproliferative action by causing dose-dependent DNA damage.
摘要
许多具有生物活性的核苷类似物含有腺嘌呤等电子体4-氨基-吡咯并[2,1-][1,2,4]三嗪，它通过C-C异头键与各种糖部分相连。我们利用钯催化的交叉偶联化学，从常见的7-碘-吡咯并三嗪C-核糖核苷中间体开始，迅速用各种炔基和芳基对这种杂环骨架的7位进行官能化。带有7-环丙基、7-丙基和7-丁基乙炔部分的类似物表现出强大的细胞毒性活性，其中最后一种是该系列中对癌细胞最具选择性的。进一步的研究表明，此类C-核苷可通过引起剂量依赖性DNA损伤发挥其抗增殖作用。
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