# Substitution Kinetics, DNA/BSA Interactions, Cytotoxicity Evaluation and Computational Analysis of [bis‐(azaaryl)amine)Pt(II)/Pd(II)Cl] Complexes, Azaaryl = Quinoline or Phenanthridine

## TL;DR

This study explores new platinum and palladium complexes as potential anticancer drugs, showing promising interactions with DNA and proteins, and better efficacy than cisplatin in some cancer cell lines.

## Contribution

The paper introduces novel bis(azaaryl)amine Pt(II)/Pd(II)Cl complexes with improved DNA/BSA interactions and cytotoxicity profiles.

## Key findings

- Pt/Pd complexes showed strong DNA and BSA binding with potential as groove binders and partial intercalators.
- PtL1Cl demonstrated superior efficacy against breast and pancreatic cancer cells compared to cisplatin.
- Molecular docking predicted strong binding affinity to protease-inhibiting proteins linked to cancer progression.

## Abstract

The search for metal‐based anticancer agents with improved efficacy and reduced side effects is ongoing. The activities of these anticancer drugs depend on their aqueous stability, substitutional reactivity at target sites (cytotoxicity) and nontarget sites (toxicity), as well as their transportation and cell bioavailability. In this study, six square‐planar Pt(II) and Pd(II) complexes (Pt/PdL1Cl‐3), all bearing the bis(azaaryl)amine (azaaryl = quinoline or phenanthridine) chelating ligands, were synthesised and characterised by various spectroscopic methods. Their biochemical interactions with bovine serum albumin (BSA)/deoxyribonucleic acid (DNA) and rates of ligand exchange with biological nucleophiles (guanine and thiourea) were probed spectrophotometrically. DFT‐optimised molecular structures in Gaussian 9 were computed. Molecular docking simulations of the optimised structures at the receptors of CT‐DNA, BSA and relevant enzymes that upregulate cancer progression were conducted. The metal complexes showed moderate to strong interactions (K

b
ca.104) with calf thymus DNA (CT‐DNA) and BSA. On BSA, the metal complexes were predominantly bound in Subdomain IIIA. Ethidium bromide’s (EtBr) competitive binding titrations and docking simulations suggested that these complexes are bimodal DNA binders, functioning both as groove binders and partial intercalators. The rates of chloride substitutions decreased in the order: PdL1Cl > PdL2Cl > PdL3Cl and PtL1Cl > PtL2Cl > PtL3Cl. Molecular docking of PtL1Cl predicted stronger binding affinity towards proteins associated with the inhibition of proteases for cervical (PDB: 5VBN), breast (4DRH) and prostate cancers (PDB: XPO1). The in vitro cytotoxic effects of uncoordinated ligands (L1-L3) and their respective Pt/PdL1Cl-3 metal complexes were tested at a single dose of 10 μM in the human breast (MCF‐7, T47D and MDA‐MB‐231), cervical (HeLa and CaSki) and pancreatic (PANC‐1 and CFPAC‐1) cancer cell lines, as well in a noncancerous human dermal fibroblasts (FG‐0) cell line. The Pt/PdL1Cl complexes showed promise as lead inhibitory compounds against breast (T47D, MDA‐MB‐231) and pancreatic (PANC‐1) cancer cells. The efficacy of PtL1Cl against the T47D cell line was superior to that of the anticancer drug cisplatin.