Kassab Refaie M, Ali Mohamed A M, Al-Hussain Sami A, Zaki Magdi E A, Muhammad Zeinab A, Abdel Halim Alyaa S
Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt.
Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia.
ChemMedChem. 2025 Jul 18;20(14):e202500045. doi: 10.1002/cmdc.202500045. Epub 2025 Jun 6.
Poly(ADP-ribose) polymerase 1 (PARP1) plays a pivotal role in DNA damage repair and represents a promising antineoplastic target. Novel bis-heterocyclic derivatives based on a bis-phenacyl bromide scaffold were synthesized and assessed for their antineoplastic potential against eight malignant cell lines, and PARP1 inhibitory activity. These derivatives exhibited selective cytotoxicity toward MCF7 and PC-3 cancer cell lines, while showing limited or no toxicity to other malignant cell lines. Derivatives 5a-e, 13, 18, 34, 35, and 36 (IC < 10 μM) were most effective against PC-3 cells. Derivatives 5a, 5d, 5e, 12, 25, 28a and 34 demonstrated remarkable potency against MCF7 cells (IC = 0.006-0.417 μM), surpassing the efficacy of doxorubicin. Mechanistic investigations indicated that their cytotoxicity involved programmed cell death induction, as evidenced by increased protein expression of caspase-7, cytochrome C, BAX, and p53, as well as reduced BCL-2 protein levels, along with sub-G1 cell cycle cessation via cyclin-dependent kinase genes expression downregulation. All derivatives showed PARP1 inhibitory activity, with 5a-e, 8a, 13, 34, and 36, outperforming olaparib with sub-nanomolar IC values. Molecular docking revealed that the derivatives docked well with PARP1, consistent with enzymatic inhibition data. Our findings support further optimization of these bis-heterocyclic scaffolds as next-generation anticancer agents and potent PARP1 inhibitors.
聚（ADP - 核糖）聚合酶1（PARP1）在DNA损伤修复中起关键作用，是一个很有前景的抗肿瘤靶点。合成了基于双苯甲酰溴支架的新型双杂环衍生物，并评估了它们对八种恶性细胞系的抗肿瘤潜力以及PARP1抑制活性。这些衍生物对MCF7和PC - 3癌细胞系表现出选择性细胞毒性，而对其他恶性细胞系的毒性有限或无毒性。衍生物5a - e、13、18、34、35和36（IC＜10 μM）对PC - 3细胞最有效。衍生物5a、5d、5e、12、25、28a和34对MCF7细胞显示出显著的效力（IC = 0.006 - 0.417 μM），超过了阿霉素的疗效。机制研究表明，它们的细胞毒性涉及程序性细胞死亡诱导，这表现为半胱天冬酶 - 7、细胞色素C、BAX和p53的蛋白表达增加，以及BCL - 2蛋白水平降低，同时通过细胞周期蛋白依赖性激酶基因表达下调导致亚G1期细胞周期停滞。所有衍生物均显示出PARP1抑制活性，其中5a - e、8a、13、34和36的表现优于奥拉帕尼，IC值为亚纳摩尔。分子对接显示这些衍生物与PARP1对接良好，与酶抑制数据一致。我们的研究结果支持进一步优化这些双杂环支架，使其成为下一代抗癌药物和有效的PARP1抑制剂。
