Skip to main content

ORIGINAL RESEARCH article

Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 12 - 2024 | doi: 10.3389/fchem.2024.1447831

Design, synthesis, and bioevaluation of diarylpyrimidine derivatives as novel microtubule destabilizers

Provisionally accepted
Yutao Xiu Yutao Xiu 1,2Yujing Zhang Yujing Zhang 2Shanbo Yang Shanbo Yang 1,2Lingyu Shi Lingyu Shi 1,2Dongming Xing Dongming Xing 1,2,3Chao Wang Chao Wang 1,2*
  • 1 The Affiliated Hospital of Qingdao University, Qingdao, China
  • 2 Qingdao University, Qingdao, Shandong Province, China
  • 3 Tsinghua University, Beijing, Beijing, China

The final, formatted version of the article will be published soon.

    In this work, a series of new diarylpyrimidine derivatives as microtubule destabilizers were designed, synthesized, and evaluated for anticancer activities. Based on restriction configuration strategy, we introduced the pyrimidine moiety containing the hydrogenbond acceptors as cis-olefin bond of CA-4 analogs to improve structural stability.Compounds 11a-t exerted antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and MCF-7), due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HSF cells, as evidenced by MTT assays. In mechanistic investigations, compound 11s remarkably inhibited tubulin polymerization and disorganized microtubule in SGC-7901 cells by binding to tubulin. Moreover, 11s caused G2/M phase cell cycle arrest in SGC-7901 cells in a concentration-dependent manner. Furthermore, molecular modeling analysis revealed that 11s interacts with tubulin through binding to the colchicine site. In addition, the prediction of physicochemical properties disclosed that 11s conformed well to the Lipinski's rule of five. This work offered a fresh viewpoint for the discovery of new tubulin-targeting anticancer drugs.

    Keywords: microtubule destabilizer, Combretastatin A-4, Antiproliferative activity, Pyrimidine, molecular docking

    Received: 12 Jun 2024; Accepted: 10 Jul 2024.

    Copyright: © 2024 Xiu, Zhang, Yang, Shi, Xing and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Chao Wang, The Affiliated Hospital of Qingdao University, Qingdao, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.