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 for the Attack of Nucleophiles on Cisplatin and BNP3029 and their Monoaquated Derivatives

Pavankumar Pnv

doi:10.4172/2161-0398.1000163

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.

Highlights

Cisplatin has been an important anticancer agent and has demonstrated a broad spectrum of anti-cancer activity against a variety of tumors including germ cell tumors, ovarian and bladder carcinomas, squamous cell tumors of the head and neck, esophageal cancers, and non-small cell lung tumors either as a single agent or in combination with other chemotherapy drugs (Figure 1) [1,2,3]
We employed the newest basis set and potential from Stoll’s group for platinum along with the recommended cc-pVDZ basis set on the ligand atoms within the density functional formalism for the geometry optimizations of cisplatin, oxaliplatin and BNP3029 to assess the performance of the new basis set and potential for platinum
Using the gas-phase optimized geometries, we performed solution-phase optimizations of cisplatin, oxaliplatin and BNP3029 using the same basis sets and the potentials employed in the gas-phase optimizations and compared the gas-phase and solution-phase geometries to the experiment, where available

Summary

Introduction

Cisplatin has been an important anticancer agent and has demonstrated a broad spectrum of anti-cancer activity against a variety of tumors including germ cell tumors, ovarian and bladder carcinomas, squamous cell tumors of the head and neck, esophageal cancers, and non-small cell lung tumors either as a single agent or in combination with other chemotherapy drugs (Figure 1) [1,2,3]. Since the discovery of cisplatin’s anti-tumor properties, hundreds of platinum analogues have been synthesized and tested for their anti-tumor properties and only very few have been approved for use in patients [3,5]. Newer analogues such as Picoplatin and Satraplatin [6] {a Pt (IV) analogue and the first oral platinum agent} are currently in clinical trials (Figure 1)

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Discussion

Conclusion