Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): Synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex
Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): Synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex
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DOI：
10.1021/jm700940h
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发表时间：
2008-02-28
影响因子：
7.3
通讯作者：
Meijer, Laurent
中科院分区：
文献类型：
--
作者：
Echalier, Aude;Bettayeb, Karima;Meijer, Laurent
本文报道了3-（嘧啶-4-基）-7-叠氮doles （meriolins）的合成和生物学特性，它是天然产物meridianins和variolins之间的化学杂种，来源于海洋生物。Meriolins对细胞周期蛋白依赖性激酶（CDKs）和其他激酶（GSK-3, DYRK1A）表现出强大的抑制活性。1e （meriolin 5）和variolin B （Bettayeb， K.; Tirado， O. M.; Marionneau-Lambert， S.; Ferandin， Y.; Lozach， O.; Morris， J.; Mateo-Lozano， S.; Druckes， P.; Schachtele， C.; Kubbutat， M.; Liger， F.; Marquet， B.; Joseph， B.; Echalier， A.; Endicott， J.; Notario， V.; Meijer， L.）与CDK2/cyclin A复合物的晶体结构揭示了这两种抑制剂在激酶的atp结合囊内以非常不同的方式定位。结构-活性关系为进一步了解该激酶抑制剂家族的分子作用机制提供了帮助。在培养成单层或球形的细胞中，梅里亚林也是有效的抗增殖和促凋亡剂。美利亚蛋白的促凋亡作用与其CDK2和CDK9抑制活性密切相关。因此，Meriolins是一类很有前途的药理药物，可以进一步评估其对包括癌症、神经退行性疾病和多囊肾病在内的多种人类疾病的治疗作用，这些疾病暗示CDKs的异常调节。
We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between the natural products meridianins and variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to a lesser extent, other kinases (GSK-3, DYRK1A). The crystal structures of 1e (meriolin 5) and variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano, S.; Druckes, P.; Schachtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325-8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure-activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease.