2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives as potent antitumor agents

Design, synthesis and biological evaluation of novel 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives as potent antitumor agents

  • Eur J Med Chem. 2025 Apr 22:293:117671. doi: 10.1016/j.ejmech.2025.117671.
Ju Liu 1,  Junfeng Gao 1,  Rui Jing 1,  Siyu Lin 1,  Yunpeng Zhou 1,  Zhicheng Zhang 1,  Enhui Han 1,  Fanqi Jin 1,  Yunlei Hou 2,  Chunyan Li 3,  Ye Chen 4,  Jiwei Shen 5,  Shi Ding 6
Affiliations

Affiliations

  • 1 College of Pharmacy of Liaoning University, API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 3 Shenyang Xingqi Pharmaceutical Co., Ltd., 68 Sishui street, Hunnan District, Shenyang, 110163, PR China.
  • 4 College of Pharmacy of Liaoning University, API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China. Electronic address: sy-chenye@163.com.
  • 5 College of Pharmacy of Liaoning University, API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China. Electronic address: shenjiwei1213@163.com.
  • 6 College of Pharmacy of Liaoning University, API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China. Electronic address: dingshi_destiny@163.com.
PMID: 40347792 DOI: 10.1016/j.ejmech.2025.117671
Abstract

A series of 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against PI3Kα and antiproliferative activities against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 Cancer cell lines. Inhibitory activities against PI3Kα evaluation indicated that some compounds showed excellent PI3Kα activity in vitro, and IC50 values of eight compounds (17c, 17e, 17f, 17h, 17l, 17m, 17o, 17p) were less than 100 nM. The most promising compound 17f (PI3Kα: IC50 = 0.039 μM) showed remarkable antiproliferative against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cell lines with IC50 values of 3.48 μM, 1.06 μM, 2.21 μM and 0.93 μM, respectively. Furthermore, 17f effectively reduced p-PI3K protein expression and inhibited the activation of downstream signaling Akt and mTOR proteins in MDA-MB-453 cells. In addition, 17f induced cell Apoptosis by down-regulating the expression levels of anti-apoptotic proteins Bcl-xL and Bcl-2 and up-regulating the expression of anti-apoptotic protein Bax, and in MDA-MB-453 cells. All these results indicated the potential of compound 17f to develop as potent Anticancer agent.

Keywords

Antitumor activity; PI3K inhibitors; Synthesis; Thieno[3,2-d]pyrimidine derivatives.

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