Synthesis and characterisation of platinum(II) complexes with the antiviral agents Ftorafur and Furavir

Abstract

Novel hybrid drugs, [Pt(NH 3) 2(Ftorafur–H) 2] ( 1) and [Pt(NH 3) 2(Furavir) 2](NO 3) 2 ( 2), have been prepared by reaction of Ftorafur (Ft) and Furavir (Fr) with cisplatin. Ftorafur, a prodrug of 5-fluorouracil containing a 2-tetrahydrofuranyl radical linked to N(1), is stable when coordinated to platinum through N(3) but the N(1)furanyl bond is hydrolysed by platinum substrates (such as [Pt(NH 3) 2(H 2O) 2] 2+ and [Pt(dien)(H 2O)] 2+) in the free state. In contrast, Furavir, a derivative of N(2)-acetyl-acyclovir carrying a 2-tetrahydrofuranyl radical linked to the terminal part of the (2-oxy)-ethoxymethyl chain bound to N(9), when coordinated to platinum through N(7), readily undergoes hydrolysis of the Ofuranyl bond releasing 2-hydroxytetrahydrofuran and leaving N(2)-acetyl-acyclovir coordinated to platinum. It is suggested that the hydrolysis of the Xfuranyl bond (X=N or O for Ftorafur and Furavir, respectively), which is catalysed by Lewis acids, is favoured in the latter case by the long and flexible (2-oxy)-ethoxymethyl chain which allows the metal centre to reach over the furanyl moiety. This is not possible in the case of the Ftorafur derivative. This investigation has demonstrated the possibility of controlling the hydrolysis of a coordinated substrate in a multifunctional platinum drug by a suitable choice of the position of the breakable bond with respect to the metal centre.