A detailed quantum chemical study of the interactions of [Pt(dien)Cl] + with a series of S-donor ligands: A computational approach Snehasis Banerjee a,b,⇑ , Asok K. Mukherjee b a Department of Chemistry, Government College of Engineering and Leather Technology, Salt Lake, Kolkata 700 098, India b Department of Chemistry, The University of Burdwan, Golapbag, Burdwan 713 104, India article info Article history: Received 8 December 2011 Received in revised form 6 April 2012 Accepted 6 April 2012 Available online 14 April 2012 Keywords: Platinum Sulfur DFT Diethylenetriamine Kinetic parameters Anticancer drug abstract The mechanism of substitution reaction of [Pt(dien)Cl] + (dien = diethylenetriamine) with a series of endogenous and exogenous S-containing ligands such as H 2 S, sodium methanethiolate (NaSMe), dimeth- ylsulfane (Me 2 S), diethylsulfane (Et 2 S), thiourea (TU), 1,3-dimethylthiourea (DMTU), 1,3-diethylthiourea (DMTU), sodium-2-mercaptoethanesulfonate (mesna), sodium diethyldithiocarbamate (Naddtc), L-methionine (Met) and L-cysteine (Cys) were studied by computational methods. Within the framework of transition state theory, DFT-based calculations were performed in gas phase using the B3LYP exchange–correlation functionals as implemented in the Gaussian 09 program. Pentacoordinated square pyramidal (SP) and trigonal–bipyramidal (TBP)-like structure transition states (TS) along with other sta- tionary points on potential energy surface were optimized and characterized. Results led us to conclude that for platination of S-ligands as protecting agents Naddtc, mesna and TU are more suitable than thiol and thioether ligands. Natural bond orbital (NBO) analysis method was performed for the investigation of major stabilizing orbital interactions. To obtain accurate energies for the reaction surfaces, single-point energies were calculated by conductor-like polarisable calculation model (CPCM) using larger basis sets at MP2 and B3LYP levels of theory. The sequence of rate constants found in our study in aqueous phase is: Naddtc > mesna > TU > Met > Cys > Me 2 S > Et 2 S  MeSH > H 2 S  DETU > NaSMe > DMTU. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction Since the discovery of its anticancer activity, cisplatin (cis- [PtCl 2 (NH 3 ) 2 ]) (alternatively called cis-DDP) has become one of the most important clinical anticancer drugs [1] but side effects and resistance seriously limit its clinical usage [2]. It is now gener- ally accepted that the interaction of cisplatin with DNA are respon- sible for cisplatin’s antitumor activity [3]. In blood, however, DNA is not the only cellular component capable of reaction with Pt(II) compounds. A number of reactive S-donor biomolecules such as cysteine (Cys), methionine (Met), glutathione (GSH), metallothio- nein (MT) and albumin are available for both kinetic and thermo- dynamic competition owing to their high affinity for platination [4,5]. However, the role of sulfur containing compounds has been controversial. On one hand, endogenous S-compounds are reported to have negative side effects such as nephro-, gastrointestinal, oto-, and neurotoxicity; these together with the acquired resistance of tumor cells limit the therapeutic efficacy [3,6,7]. Reactions with amino acids (Cys, Met), peptides (GSH) and proteins (enzymes) containing thioether or thiol groups are considered to trap and deactivate the drug before it reaches its cellular DNA target. Com- petitive binding of Pt(II) complexes to DNA constituents (mainly N7 atom of guanine or adenine) and protein-bound sulfur is critical to the metabolism and stability of the cytotoxic lesions of the drugs. On the other hand, platinum–sulfur interactions have been associated with positive effects such as delivery of active species to cells and/or serving as a drug reservoir for ultimate platination of DNA. To overcome or reduce the platinum binding by the bio- logic endogenous S-containing ligand, several exogenous congen- ers (‘‘rescue’’ or ‘‘protecting’’ agents) have been introduced which may even revert the Pt-protein binding and hence reduce the toxic side-effects. Regarding the mechanism of action of the Pt(II) complexes with biologically relevant molecules and S-containing nucleophiles, experimental and theoretical investigations [8–26] constitute a topic of current interest. A kinetic study of cisplatin bonding to S- donor atoms of cysteine and methionine has recently been pub- lished [8]. Kinetic preference of Pt(II) for bio-relevant thiols over 5 0 -Guanosine monophosphate (GMP) at physiological condition has been established [9]. Reedijk and co-workers [10] reported that in acidic solution coordination of GMP to aqua Pt complex is pre- ferred over GSH or S-methylglutathione and they have carried out a series of studies on the reaction of Glutathione, S-methyl glutathi- one, methionine etc., with monofunctional platinum substrate 2210-271X/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.comptc.2012.04.006 ⇑ Corresponding author at: Department of Chemistry, Government College of Engineering and Leather Technology, Salt Lake, Kolkata 700 098, India. E-mail address: sbanchem@gmail.com (S. Banerjee). Computational and Theoretical Chemistry 991 (2012) 116–123 Contents lists available at SciVerse ScienceDirect Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc