Synthesis and structural characterization of platinum(II)-acyclovir complexes

Abstract

The hybrid drug [Pt(en)(acv)2]2+ (en = 1,2-diaminoethane) has been prepared by direct reaction between acyclovir [9-(2-hydroxyethoxymethyl)guanine (acv), a nucleoside analog with potent antiviral activity] and the platinum complex [PtCl(dmso)(en)]Cl (dmso = dimethyl sulfoxide). Multinuclear NMR spectroscopy data indicated a bifunctional complex with two acv molecules N(7)-co-ordinated to the platinum atom and involved in fast conformational equilibrium with no preferred conformational state along the N(7)–Pt or N(9)–CH2 bonds. Comparison between the crystal structure of [Pt(en)(acv)2]2+ and the closely related cis-[Pt(NH3)2(acv)2]2+ indicates that the guanine planes can assume very different orientations with respect to the co-ordination plane; slant by ca. 50° in the former case, nearly perpendicular in the latter case. A O(6)· · ·H–N–Pt hydrogen bond interaction is responsible for deviation from the upright position in the compound. On the basis of the observed correlation between strength of the hydrogen bond and deviation from orthogonality, the bond must be considered rather weak. Such a hydrogen bond was not formed in the closely related [Pt(NH3)2(acv)2]2+ complex having the nucleobases nearly perpendicular to the co-ordination plane. However in the latter case the observed trends in Pt–N(7)–C(5) and Pt–N(7)–C(8) angles are in accord with an attractive interaction between the O(6) and platinum atoms. Therefore the arrangements of the nucleobases in [Pt(en)(acv)2]2+ and [Pt(NH3)2(acv)2]2+ represent two conformational energy minima with involvement of O(6) in either hydrogen bonding (former case) or a platinum attractive interaction (latter case).