Temirak Ahmed, Soliman Ahmed A F, Shalaby Mohamed B, Eshak Mariam G, Khalil Wagdy K B, Shafiq Zahid, Boshta Nader M
Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre Dokki Giza 12622 Egypt
Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Center Giza 12622 Egypt.
RSC Adv. 2025 Jun 6;15(24):19204-19217. doi: 10.1039/d5ra02046h. eCollection 2025 Jun 4.
The search for new anticancer agents targeting apoptotic and autophagic pathways is crucial due to their roles in cellular homeostasis and cancer cell elimination. In this study, we synthesized and evaluated a series of 1,3,5-trisubstituted-1-pyrazole derivatives as potential inhibitors of Bcl-2, a key regulator of apoptosis and autophagy. Several compounds activated pro-apoptotic proteins Bax, p53, and Caspase-3. Structure-activity relationship (SAR) studies assessed the cytotoxic effects of the compounds on MCF-7, A549, and PC-3 cancer cell lines. Compounds 4, 5, 6b, 6c, 7, 8, 10b, 10c, and 12b showed significant cytotoxicity against MCF-7 cells (IC: 3.9-35.5 μM), with similar activity observed against A549 and PC-3 cell lines. Compounds 6c, 8, 10b, and 10c also induced DNA damage, as evidenced by increased comet tail length, suggesting they cause genotoxic stress through DNA strand breaks. SAR analysis highlighted the importance of chlorophenyl, thiazole, and sulfonamide groups in enhancing cytotoxicity. Molecular docking confirmed high binding affinity of compounds 10b and 10c to Bcl-2 through key hydrogen bonding interactions. These findings suggest that the 1,3,5-trisubstituted-1-pyrazole derivatives effectively target Bcl-2, activate apoptotic pathways, and induce DNA damage, making them promising candidates for further anticancer investigation.
由于凋亡和自噬途径在细胞稳态和癌细胞清除中发挥作用，寻找靶向这些途径的新型抗癌药物至关重要。在本研究中，我们合成并评估了一系列1,3,5-三取代-1-吡唑衍生物，作为凋亡和自噬的关键调节因子Bcl-2的潜在抑制剂。几种化合物激活了促凋亡蛋白Bax、p53和Caspase-3。构效关系（SAR）研究评估了这些化合物对MCF-7、A549和PC-3癌细胞系的细胞毒性作用。化合物4、5、6b、6c、7、8、10b、10c和12b对MCF-7细胞显示出显著的细胞毒性（IC：3.9-35.5 μM），对A549和PC-3细胞系也观察到类似的活性。化合物6c、8、10b和10c还诱导了DNA损伤，彗星尾长增加证明了这一点，表明它们通过DNA链断裂引起基因毒性应激。SAR分析强调了氯苯基、噻唑和磺酰胺基团在增强细胞毒性方面的重要性。分子对接证实化合物10b和10c通过关键的氢键相互作用与Bcl-2具有高结合亲和力。这些发现表明，1,3,5-三取代-1-吡唑衍生物有效地靶向Bcl-2，激活凋亡途径并诱导DNA损伤，使其成为进一步抗癌研究的有希望的候选物。
