Comprehensive Comparative Study Using Ab Initio Computational Approaches on the Structures of Cisplatin, Oxaliplatin and BNP3029 (A Novel Substituted Cyano Ligand-based Platinum Analogue) and Activation Energy Barriers f

Pavankumar PNV, Ayala PY, P

Abstract

Cisplatin is an important anti-cancer agent widely used in the clinic; however, it has several notable limitations. To develop novel platinum analogues, key characteristics were considered that may result in more effective platinum analogues. Herein results based on ab initio geometry optimizations (gas- and solution-phase) on cisplatin (1), oxaliplatin_1R_2R (2) and BNP3029 (3, a novel substituted cyano ligand-based platinum analogue, PtCl2[N≡C(CH2)3(C6H5)]2) using the recently published potentials and basis sets for platinum are presented. Optimized quantum mechanical derived geometries of the 3 platinum agents were in good agreement with available experimental geometries. The reactivity of BNP3029 was compared to cisplatin by computing the activation free energy barriers for the attack of various nucleophiles on both 1 and 3 and their monoaquated derivatives. Based on the activation energy barriers, it was determined that: (i) the reaction rate may be similar for the attack of water on cisplatin and BNP3029; (ii) the reaction rate for the attack of DNA bases was slower for monoaquated BNP3029 compared to monoaquated cisplatin; and (iii) the reaction rates for a thiol/thiolate attack on monoaquated cisplatin or monoaquated BN3029 were similar. BNP3029 demonstrated potent cytotoxic activity in a variety of human cancer cell lines in comparison to cisplatin and oxaliplatin and also had potent cytotoxic activity in several platinum resistant cell lines.