Mamindla Anjaneyulu, Murugan Dhanashree, Varadhan Manikandan, Ajaykamal Tamilarasan, Rangasamy Loganathan, Palaniandavar Mallayan, Rajendiran Venugopal
Department of Chemistry, School of Basic and Applied Sciences, Central University of Tamil Nadu Thiruvarur 610005 India
Drug Discovery Unit (DDU), Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT) Vellore 632014 Tamilnadu India.
RSC Adv. 2024 Oct 7;14(43):31704-31722. doi: 10.1039/d4ra04997g. eCollection 2024 Oct 1.
The promising biological applications of thiosemicarbazone derivatives have inspired the design, synthesis, and study of their Cu(ii) complexes for anticancer therapeutic applications. Herein, we have evaluated the DNA/protein binding, DNA cleaving, and cytotoxic properties of four mixed-ligand Cu(ii) complexes of the type Cu(L)(diimine) 1-4, where HL is 4-oxo-4-chromene-3-carbaldehyde-4()-phenylthiosemicarbazone and diimine is 2,2'-bipyridine (bpy, 1) 1,10-phenanthroline (phen, 2), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp, 3), or dipyrido-[3,2-:2',3'-]-quinoxaline (dpq, 4). Interestingly, complex 3 with higher lipophilicity shows stronger DNA binding and oxidative DNA cleavage, higher ROS production, and more reversible redox behaviour, resulting in its remarkable cytotoxicity (IC, 1.26 μM) against HeLa cervical cancer cells, and rendering it 5 times more potent than the widely used drug cisplatin. The same complex induces enhanced apoptotic cell death on HeLa cells but lower toxicity towards the non-cancerous PBMC cells. Molecular docking studies suggest that all the complexes bind in the minor groove of DNA and subdomain II of HSA, which is in close agreement with the experimental results. Also, 3 shows cytotoxicity higher than the analogous mixed ligand Cu(ii) complexes, reported already, emphasizing the importance of co-ligand in tuning the anticancer activity.
硫代氨基脲衍生物有前景的生物学应用激发了人们对其用于抗癌治疗的铜（II）配合物的设计、合成及研究。在此，我们评估了四种Cu(L)(二亚胺) 1 - 4型混合配体铜（II）配合物的DNA/蛋白质结合、DNA切割及细胞毒性性质，其中HL为4 - 氧代 - 4 - 色烯 - 3 - 甲醛 - 4 -（） - 苯基硫代氨基脲，二亚胺为2,2'-联吡啶（bpy，1）、1,10 - 菲咯啉（phen，2）、5,6 - 二甲基 - 1,10 - 菲咯啉（5,6 - dmp，3）或二吡啶并[3,2 - :2',3'-]喹喔啉（dpq，4）。有趣的是，具有较高亲脂性的配合物3表现出更强的DNA结合和氧化性DNA切割、更高的活性氧生成以及更可逆的氧化还原行为，导致其对HeLa宫颈癌细胞具有显著的细胞毒性（IC，1.26 μM），且使其比广泛使用的药物顺铂的效力高5倍。同一配合物在HeLa细胞上诱导增强的凋亡性细胞死亡，但对非癌性PBMC细胞的毒性较低。分子对接研究表明，所有配合物均结合于DNA的小沟和人血清白蛋白的亚结构域II，这与实验结果密切相符。此外，3表现出比已报道的类似混合配体铜（II）配合物更高的细胞毒性，强调了共配体在调节抗癌活性中的重要性。
