Molecular Structure and Bonding in Platinum-Picoline Anticancer Complex: Density Functional Study

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Abstract
Density functional study has been performed for a new anticancer agent, cis-[PtCl2(NH3)(2-picoline)] (1), AMD473, now clinically tested. The molecular structure, natural charges, orbital occupancies, vibrational frequencies and metal-ligand stretching force constants were calculated using the modified Perdew-Wang functional (mPW1PW) with the combined D95V(d,p) and LANL2DZ basis set. For comparison, analogous calculations were performed for: cis-[PtCl2(NH3)(3-picoline)] (2), cis-[PtCl2(NH3)(pyridine)] (3) and cisplatin. The interesting structural feature of 1 is almost perpendicular orientation of the 2-picoline ligand with respect to the molecular plane. In the remaining complexes, 2 and 3, the tilt of the pyridine ring is smaller. The position of the methyl group in 1 introduces steric hindrance to an axial approach of the Pt metal. The natural bond analysis (NBO) has provided detailed insight into the electronic donor-acceptor interactions within the platinum coordination sphere. The results clearly indicate that the Pt-N(py) bond is stronger than Pt-NH3 bond, and the Pt-Cl bond trans to 2-picoline is weaker than the cis Pt-Cl bond. Thus, both the trans effect of the 2-picoline ligand and a steric hindrance of Pt in 1 can be of key importance in the different mode of binding of this drug to DNA, in comparison with cisplatin.