Guided by the molecular hybridization principle, a novel series of 4-chloropyridazinoxyphenyl conjugates (3a–h, 4a–e, and 5) was designed and synthesized as proposed apoptotic inducers and PARP-1 inhibitors. The growth inhibition % of the designed hybrids was investigated in eleven cancer cell lines, where the anticancer activities were found to be in the following order: 4-chloropyridazinoxyphenyl-aromatic ketones hybrids (3a–h) > 4-chloropyridazinoxyphenyl-benzyloxyphenylethan-1-one hybrids (4a–e) > 4-chloropyridazinoxyphenyl-thiazolidine-2,4-dione hybrid (5). Further, the most sensitive three cancer cell lines (HNO97, FaDu, and MDA-MB-468) were selected to measure the IC₅₀ values of the new hybrids. Moreover, the frontier three members (3c, 3e, and 4b) were selected for the measurements of apoptotic protein markers (p53, BAX, caspase 3, caspase 6, BCL-2, and CK 18). Besides, the impact of compounds 3a–e and 4b on the activity of PARP-1 was investigated, where 3c, 3d, and 3e demonstrated comparable efficiencies to olaparib. Furthermore, γ-H2Ax, a well-established marker for double-strand DNA breaks, was examined and the occurrence of DNA damage was observed. In addition, a significant inhibition of cell proliferation and a remarkable 15 to 50-fold reduction in the number of colonies compared to the control group were recorded. Finally, the PARP-1 inhibitory potential of the novel hybrids was compared to the co-crystal of the target receptor (PDB ID: 6NTU) using molecular docking.

中文翻译：

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设计和合成新型氯哒嗪杂合体作为有前景的抗癌药物，通过分子杂交策略诱导细胞凋亡和抑制 PARP-1

在分子杂交原理的指导下，设计并合成了一系列新型4-氯哒嗪氧基苯基缀合物（3a-h、4a-e和5 ）作为细胞凋亡诱导剂和PARP-1抑制剂。在 11 种癌细胞系中研究了设计的杂合体的生长抑制百分比，发现其抗癌活性按以下顺序排列： 4-氯哒嗪氧基苯基-芳香酮杂合体 ( 3a–h ) > 4-氯哒嗪氧基苯基-苄氧基苯基乙烷-1-一种杂化物 ( 4a–e ) > 4-氯哒嗪氧基苯基-噻唑烷-2,4-二酮杂化物 ( 5 )。此外，选择最敏感的三种癌细胞系（HNO97、FaDu和MDA-MB-468）来测量新杂交体的IC _50值。此外，选择前沿三个成员（3c、3e和4b）来测量凋亡蛋白标记物（p53、BAX、caspase 3、caspase 6、BCL-2和CK 18）。此外，还研究了化合物3a-e和4b对 PARP-1 活性的影响，其中3c、3d和3e表现出与奥拉帕尼相当的效率。此外，还检查了 γ-H2Ax（一种成熟的双链 DNA 断裂标记）并观察了 DNA 损伤的发生。此外，与对照组相比，细胞增殖受到显着抑制，集落数量显着减少 15 至 50 倍。最后，使用分子对接将新型杂交体的 PARP-1 抑制潜力与目标受体的共晶 (PDB ID：6NTU) 进行比较。