Malik Manzoor Ahmad, Raza Md Kausar, Mohammed Arif, Wani Mohmmad Younus, Al-Bogami Abdullah Saad, Hashmi Athar Adil
Bioinorganic Lab., Department of Chemistry, Jamia Millia Islamia New Delhi 110025 India
Department of Chemistry, University of Kashmir Srinagar Jammu and Kashmir India.
RSC Adv. 2021 Dec 10;11(62):39349-39361. doi: 10.1039/d1ra06227a. eCollection 2021 Dec 6.
Coordination compounds from simple transition metals are robust substitutes for platinum-based complexes due to their remarkable anticancer properties. In a quest to find new metal complexes that could substitute or augment the platinum based chemotherapy we synthesized three transition metal complexes C1-C3 with Cu(ii), Ni(ii), and Co(ii) as the central metal ions, respectively, and evaluated them for their anticancer activity against the human keratinocyte (HaCaT) cell line and human cervical cancer (HeLa) cell lines. These complexes showed different activity profiles with the square planar copper complex C1 being the most active with IC values lower than those of the widely used anticancer drug cisplatin. Assessment of the morphological changes by DAPI staining and ROS generation by DCFH-DA assay exposed that the cell death occurred by caspase-3 mediated apoptosis. C1 displayed interesting interactions with Ct-DNA, evidenced by absorption spectroscopy and validated by docking studies. Together, our results suggest that binding of the ligand to the DNA-binding domain of the p53 tumor suppressor (p53DBD) protein and the induction of the apoptotic hallmark protein, caspase-3, upon treatment with the metal complex could be positively attributed to a higher level of ROS and the subsequent DNA damage (oxidation), generated by the complex C1, that could well explain the interesting anticancer activity observed for this complex.
由于具有显著的抗癌特性，简单过渡金属的配位化合物是铂基配合物的有力替代品。为了寻找能够替代或增强铂基化疗的新型金属配合物，我们合成了三种过渡金属配合物C1 - C3，它们分别以Cu(ii)、Ni(ii)和Co(ii)作为中心金属离子，并评估了它们对人角质形成细胞（HaCaT）细胞系和人宫颈癌（HeLa）细胞系的抗癌活性。这些配合物表现出不同的活性谱，其中平面正方形铜配合物C1活性最高，其半数抑制浓度（IC）值低于广泛使用的抗癌药物顺铂。通过DAPI染色评估形态变化以及通过DCFH - DA测定法评估活性氧生成，结果表明细胞死亡是由caspase - 3介导的凋亡所致。C1与Ct - DNA表现出有趣的相互作用，吸收光谱证实了这一点，对接研究也验证了这一点。总之，我们的结果表明，配体与p53肿瘤抑制蛋白（p53DBD）的DNA结合域结合，以及在用金属配合物处理后诱导凋亡标志性蛋白caspase - 3，可能正向归因于C1配合物产生的较高水平的活性氧以及随后的DNA损伤（氧化），这可以很好地解释该配合物所观察到的有趣抗癌活性。
