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.
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。
