Half-Lantern Cyclometalated Platinum(II) Complexes as Anticancer Agents: MolecularDocking, Apoptosis, Cell Cycle Analysis, and Cytotoxic Activity Evaluations

Background and Objective: In the design of modern metal-based anticancer drugs, platinum-based complexeshave gained growing interest. In this study, the anticancer activity of half-lantern cyclometalated Pt(II)‒Pt(II)complexes was evaluated using MTT, apoptosis, cell cycle analysis, and DNA binding studies. Materials and Methods: The cytotoxicity of Pt(II)‒Pt(II) complexes were evaluated against different cancer cell lines,such as human lung (A549), breast (MCF-7, and MDA-MB-231), ovarian (SKOV-3), and colon (HT-29) as well asnormal breast (MCF-10A), and human lung fibroblast (MRC-5) cells using MTT assay. BioLegend's PE Annexin, VApoptosis Detection Kit with 7AAD, was applied to assess the apoptotic effects of 1A and 1B compound againstMCF-7 and A549 cell lines. Cell cycle analysis was determined using the flow cytometry method. The interaction ofcompounds with four different DNA structures with PDB codes (1BNA, 1LU5, 3CO3, and 198D) has been investigatedby molecular docking. To achieve binding to DNA experimentally, the electrophoresis mobility shift assay andcomet assay were applied. Results: In the evaluation of cytotoxic effects, 1A showed the highest cytotoxicity among the studied compounds, andit showed higher potency with more selectivity against normal cell lines than cisplatin. This compound had IC50 of7.24, 2.21, 1.18, 2.71, 10.65, 18.32, and 49.21 μM against A549, SKOV3, HT29, MCF-7, MDA-MB-231, MRC-5, andMCF-10A, respectively, whereas cisplatin had IC50 of 9.75, 19.02, 107.23, 15.20, 18.09, 14.36, and 24.21 μm, respectively,on the same cell lines. In order to check the DNA binding activity of 1A, and 1B, electrophoretic mobility wasalso conducted, which indicated that the binding of these compounds led to a slight change in electrophoretic mobilityto DNA. The migration of chromosomal DNA from the nucleus in the form of a tail or comet was executed in thecomet assay of 1A on MCF-7. Examination of apoptosis of 1A and 1B on the MCF-7 cancer cell line showed that itcould increase induction of apoptosis in this cancerous cell in a concentration-dependent manner. Investigating theeffect of 1A using cell cycle analysis on MCF-7 cancer cell line showed that this complex affects stage G1 and S of thecell cycle. Conclusion: 1A has the potential to play a significant role in future biopharmaceutical studies.