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基于吡啶并[3',2':5,6]硫代吡喃并[4,3 - ]嘧啶的抗增殖多激酶抑制剂的发现

Discovery of Pyrido[3',2':5,6]thiopyrano[4,3-]pyrimidine-Based Antiproliferative Multikinase Inhibitors.

作者信息

Salerno Silvia, Barresi Elisabetta, García-Argáez Aída Nelly, Taliani Sabrina, Simorini Francesca, Amendola Giorgio, Tomassi Stefano, Cosconati Sandro, Novellino Ettore, Da Settimo Federico, Marini Anna Maria, Dalla Via Lisa

机构信息

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.

Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.

出版信息

ACS Med Chem Lett. 2019 Jan 17;10(4):457-462. doi: 10.1021/acsmedchemlett.8b00499. eCollection 2019 Apr 11.

DOI:10.1021/acsmedchemlett.8b00499
PMID:30996779
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6466516/
Abstract

Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (-) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds , , and revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.

摘要

蛋白激酶失调在癌细胞中极为常见，开发能够同时靶向参与血管生成和肿瘤生长的多种激酶途径的新型药物可能在癌症治疗中具有诸多优势。在此，我们报告了新型吡啶并硫代吡喃并嘧啶衍生物（-）的发现，该衍生物在抑制VEGFR-2 KDR方面具有高效力，并且对一组人类肿瘤细胞系具有抗增殖作用。对代表性的2-苯胺基取代化合物、和的选择性概况研究揭示了多种激酶靶点，这应可解释这些吡啶并硫代吡喃并嘧啶衍生物产生的强效抗增殖作用。

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