鉴定新型吡咯并[2,3-d]嘧啶类化合物作为Src 酪氨酸激酶抑制剂，在体外对神经胶质瘤具有活性。
Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma.
机构信息
Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
出版信息
Eur J Med Chem. 2017 Feb 15;127:369-378. doi: 10.1016/j.ejmech.2016.12.036. Epub 2016 Dec 19.
In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC value of 7.1 μM.
在过去的几年中，已有几种吡咯并[2,3-d]嘧啶衍生物获得美国 FDA 和其他国家的批准，用于治疗各种疾病，或目前处于 I/II 期临床试验阶段。本文介绍了一系列新型吡咯并[2,3-d]嘧啶的合成和表征，包括化合物 8a-j，并对其针对多形性胶质母细胞瘤（GBM）的活性进行了研究。对接研究和 MM-GBSA 分析表明，这些化合物能够有效地与Src 的 ATP 结合位点相互作用。对一个小型激酶（Src、Fyn、EGFR、Kit、Flt3、Abl、AblT315I）的进行了酶促分析，结果显示我们的吡咯并[2,3-d]嘧啶对 Src 具有出人意料的选择性。最后，对衍生物在 U87 GBM 细胞系上的抗增殖活性进行了测试。化合物 8h 对 U87 细胞系表现出相当大的细胞毒性作用，IC 值为 7.1 μM。
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