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

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-04-22 DOI:10.1016/j.ejmech.2025.117671

Ju Liu, Junfeng Gao, Rui Jing, Siyu Lin, Yunpeng Zhou, Zhicheng Zhang, Enhui Han, Fanqi Jin, Yunlei Hou, Chunyan Li, Ye Chen, Jiwei Shen, Shi Ding

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引用次数: 0

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, 2.21μM 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.

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新型4-（噻吩[3,2-d]嘧啶-4-基）啉衍生物的设计、合成和生物学评价

设计、合成了一系列4-（噻吩[3,2-d]嘧啶-4-基）啉衍生物，并测定了其对PI3Kα的体外抑制活性和对PC-3、22RV1、MDA-MB-231和MDA-MB-453癌细胞的体外抑制活性。体外抑PI3Kα活性评价表明，部分化合物具有较好的PI3Kα活性，其中8个化合物（17c、17e、17f、17h、17l、17m、17o、17p）的IC50值均小于100 nM。最有希望的化合物17f （PI3Kα: IC50 = 0.039 μM）对PC-3、22RV1、MDA-MB-231和MDA-MB-453细胞株的IC50值分别为3.48 μM、1.06 μM、2.21μM和0.93 μM。此外，17f有效地降低了MDA-MB-453细胞中p-PI3K蛋白的表达，抑制了下游信号AKT和mTOR蛋白的激活。此外，在MDA-MB-453细胞中，17f通过下调抗凋亡蛋白Bcl-XL和Bcl-2的表达水平，上调抗凋亡蛋白BAX的表达，诱导细胞凋亡。这些结果表明化合物17f作为一种有效的抗癌药物具有发展潜力。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.