Synthesis and characterization of functionalized thymidine as a potential carrier for cisplatin-like drugs q Carlo Nervi a , Marco A. Vigna a , Giorgio Cavigiolio b,1 , Mauro Ravera b , Domenico Osella b, * a Dipartimento di Chimica IFM, Universita ` di Torino, Via P. Giuria 7, 10125 Torino, Italy b Dipartimento di Scienze dellÕAmbiente e della Vita, Universita ` del Piemonte Orientale ‘‘Amedeo Avogadro’’, Spalto Marengo 33, 15100 Alessandria, Italy Received 13 January 2005; accepted 9 February 2005 Available online 12 April 2005 Abstract Pursuing the idea of using a biological nanovector to drive the non-specific cytotoxic activity of Pt(II) complexes toward biolog- ical targets, we have singled out thymidine (T) as a potential biological carrier for delivery of cisplatin-like drugs to DNA. Thymi- dine was functionalized by first reacting it with solid sodium hydride and 1,3-diiodopropane, producing high yields of N3-iodopropylthymidine. Further reaction with ethylenediamine gave the bio-ligand N3-(3-ethylenediamine)propylthymidine which reacts in turn with K 2 PtCl 4 , resulting in a cisplatin-like nucleoside. This derivative (or more soluble analogues) can be phosphorylated by the cellular enzyme pool and incorporated into the grow- ing DNA chain, thus making them suitable candidates as potential antiproliferative agents, exploiting both alkylating and antime- tabolite mechanisms. Ó 2005 Elsevier B.V. All rights reserved. Keywords: Cisplatin; Thymidine; Antimetabolite; Multinuclear NMR spectroscopy 1. Introduction Cisplatin, cis-PtCl 2 (NH 3 ) 2 , is the most successfully employed metal-based drug in the treatment of a num- ber of cancers [1]. Cisplatin and its second-generation congeners act by means of direct (electrophilic) interac- tion with DNA, most frequently binding at the N7 atoms of adjacent guanines (G). This intrastrand adduct is thought to be the lesion responsible for DNA distor- tion and cell death [2,3]. Attempts to specifically inhibit selected pathways thought to be required in cancer cell metabolism fall within the so-called ‘‘drug targeting and delivery’’ ap- proach. Antimetabolites represent an interesting class of antitumor drugs that share the ability to inhibit the biosynthesis or function of nucleic acids [4]. The best- characterized agent is probably 5-fluorouracil (5-FU) (1)(Fig. 1). This pyrimidine analogue requires intercel- lular enzymatic conversion to the corresponding nucleo- tide through ribosylation and phosphorylation in order to exert its cytotoxic activity, which consists in thymi- dylate synthase inhibition. Another nucleotide ana- logue, 3 0 -azido-3 0 -deoxythymidine (AZT) (2)(Fig. 1), exerts antiviral activity against HIV. The drug is initially phosphorylated by thymidine kinase and then inhibits reverse trascriptase, due to the presence of the 3 0 -azido 0020-1693/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2005.02.015 q Presented at the local meeting of the American Chemical Society, 13 April 2002, Butte, MT, USA. * Corresponding author. Tel.: +39131287429; fax: +39131287416. E-mail address: domenico.osella@mfn.unipmn.it (D. Osella). 1 Current address: ChildrenÕs Hospital Oakland Research Institute (CHORI), Martin Luther King Jr. Way, Oakland, CA 94609, USA. www.elsevier.com/locate/ica Inorganica Chimica Acta 358 (2005) 2799–2803