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

Novel hybrid drugs, [Pt(NH3)(2)(Ftorafur-H)(2)] (1) and [Pt(NH3)(2)(Furavir )(2)](NO3)(2) (2), have been prepared by reaction of Ftorafur (Ft) and Fura vir (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 s ubstrates (such as [Pt(NH3)(2)(H2O)(2)](2+) and [Pt(dien)(H2O)](2+)) in the free state. In contrast, Furavir, a derivative of N(2)-acetyl-acyclovir ca rrying 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-hydro xytetrahydrofuran 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 coordin ated substrate in a multifunctional platinum drug by a suitable choice of t he position of the breakable bond with respect to the metal centre. (C) 200 1 Published by Elsevier Science B.V.