Evaluation of Newly Synthesized Schiff Base Pd(II) Complexes for Prostate Cancer Treatment Through In Vitro Cytotoxicity and Molecular Mechanistic Studies

Background/Objectives: Palladium(II) complexes are promising anticancer agents with potential advantages over platinum drugs. This study aimed to synthesize and characterize three novel Pd(II) complexes (2a–c) with Schiff base ligands derived from salicylic acid and amine scaffolds, and to evaluate their antitumor activity against prostate cancer cells. Methods: The Pd(II) complexes were synthesized and structurally characterized. Cytotoxicity was tested on two human prostate cancer cell lines (PC-3, DU-145) and healthy fibroblasts (MRC-5). Apoptosis induction was assessed by flow cytometry focusing on Bcl-2 and caspase proteins. Molecular docking examined binding to androgen receptor (AR) and apoptotic regulators (CASP3, BCL2, BAX). DNA and human serum albumin (HSA) binding were also investigated. Results: All complexes showed significant cytotoxicity, with complex 2c outperforming cisplatin (IC50: 7.1 µM in DU-145; 8.6 µM in PC-3). Apoptosis was confirmed as the main cytotoxic mechanism involving Bcl-2 and caspase activation. Docking studies revealed complex 2c had the strongest binding affinity to AR and apoptotic proteins via hydrogen bonds, π–π stacking, and hydrophobic interactions. DNA and HSA binding supported their biological relevance. Conclusions: Complex 2c exhibits potent anticancer activity through apoptosis induction and dual targeting of AR and apoptotic pathways, making it a promising candidate for further anticancer drug development.