Sawiris Michael M, Khalil Omneya M, Halim Peter A, Hassan Marwa S A
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Gesr El Suez St., PO 11786, Cairo, Egypt.
Bioorg Chem. 2025 Oct;165:109075. doi: 10.1016/j.bioorg.2025.109075. Epub 2025 Oct 7.
Three series of pyrazoline compounds (3a-f, 4a-f and 5a-f) were designed and synthesized as antiproliferative agents and potential dual EGFR/VEGFR-2 inhibitors for targeted cancer therapy. All the synthesized compounds were screened by National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines. Compounds 2f, 3b, 3c, 3e, 3f, 4b and 4e were selected for further antiproliferative activity investigation via MTT assay. Compounds 2f, 3e and 3f demonstrated better IC results than doxorubicin in breast T47D and MCF7 cancer cells. Compound 3e was the most potent against EGFR and VEGFR2 with IC values of 0.142 and 0.071 μM compared to erlotinib and axitinib with IC values of 0.064 and 0.050 μM, respectively. Moreover, it reduced VEGFR2 phosphorylation and total VEGFR2 concentration in T47D cells by approximately 3.8 and 2.9-fold, respectively. Compound 3e also caused cell cycle arrest at G0/G1 phase and demonstrated significant increase in early and late apoptosis. Additionally, it upregulated pro-apoptotic genes (caspase-3, p53 and Bax) and downregulated anti-apoptotic gene (BCL-2). Boyden chamber and wound healing assays demonstrated that compound 3e could impair cell migration and invasion in T47D cells. The selectivity indices of compound 3e towards T47D or MCF7 breast cancer cells over the normal breast cell line MCF10A were approximately 46 and 25, respectively. In-silico studies revealed that compound 3e has a bioavailability score of 0.55 and did not violate Lipiniski's rule. Also, the molecular docking studies and molecular dynamics simulations confirmed that compound 3e could interact with EGFR (PDB: 1M17) and VEGFR2 (PDB: 4AG8) analogously to erlotinib and axitinib, respectively.
设计并合成了三类吡唑啉化合物（3a - f、4a - f和5a - f），作为抗增殖剂以及用于靶向癌症治疗的潜在双效表皮生长因子受体/血管内皮生长因子受体-2（EGFR/VEGFR-2）抑制剂。美国国立癌症研究所（NCI），贝塞斯达，对所有合成化合物针对60种人类癌细胞系的抗癌活性进行了筛选。通过MTT法选择化合物2f、3b、3c、3e、3f、4b和4e进行进一步的抗增殖活性研究。在乳腺癌T47D和MCF7癌细胞中，化合物2f、3e和3f的半数抑制浓度（IC）结果优于阿霉素。与厄洛替尼和阿西替尼的IC值分别为0.064和0.050 μM相比，化合物3e对EGFR和VEGFR2的抑制作用最强，IC值分别为0.142和0.071 μM。此外，它使T47D细胞中VEGFR2的磷酸化水平和总VEGFR2浓度分别降低了约3.8倍和2.9倍。化合物3e还导致细胞周期停滞在G0/G1期，并使早期和晚期凋亡显著增加。此外，它上调促凋亡基因（半胱天冬酶-3、p53和Bax）并下调抗凋亡基因（BCL-2）。Boyden小室实验和伤口愈合实验表明，化合物3e可抑制T47D细胞的迁移和侵袭。化合物3e对T47D或MCF7乳腺癌细胞相对于正常乳腺细胞系MCF10A的选择性指数分别约为46和25。计算机模拟研究表明，化合物3e的生物利用度评分为0.55，未违反Lipinski规则。此外，分子对接研究和分子动力学模拟证实，化合物3e可分别与EGFR（PDB：1M17）和VEGFR2（PDB：4AG8）相互作用，类似于厄洛替尼和阿西替尼。
