Design, synthesis and biological evaluation of coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-12 DOI:10.1016/j.bmcl.2025.130240

Mengrong Lei , Hanxue Huang , Jiayi Li , Jinlin Zhang , Geng Yu , Xin Jin , Junyan Liu , Fenghua Kang , Zhaoqian Liu

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Abstract

A series of hybrids (8a-h and 11a-h) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound 8a was identified as the most active compound with IC₅₀ value of 0.28 μM in H1299 cells, superior to TAE226 (IC₅₀ = 2.28 μM). In addition, 8a was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, 8a exhibited potent kinase inhibitory activity of FAK (IC₅₀ = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, 8a was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, 8a may be a promising candidate for the treatment of NSCLC.

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含香豆素的2,4-二苯基嘧啶衍生物作为治疗非小细胞肺癌的新型黏附激酶抑制剂的设计、合成和生物学评价

设计并合成了一系列含有2,4-二苯基嘧啶支架和香豆素片段的杂交体（8a-h和11a-h），作为新型的局灶黏附激酶（FAK）抑制剂，用于干预非小细胞肺癌（NSCLC）。大多数化合物均能有效抑制NSCLC细胞的增殖，其中化合物8a在H1299细胞中活性最强，IC50值为0.28 μM，优于TAE226 （IC50 = 2.28 μM）。此外，8a还被发现抑制NSCLC细胞的侵袭和迁移。此外，8a对FAK具有明显的激酶抑制活性（IC50 = 4.968 nM），对多种激酶家族具有明显的选择性，从而导致H1299细胞周期阻滞、凋亡诱导以及MMP-2和MMP-9的表达呈剂量依赖性降低。此外，8a对小鼠是相对安全的，并且在小鼠中比TAE226更有效地抑制植入的NSCLC肿瘤的生长。因此，8a可能是治疗非小细胞肺癌的一个有希望的候选药物。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.