It is estimated that about 10% of the drugs approved worldwide can be classified as prodrugs. Prodrugs, which have no or poor biological activity, are chemically modified versions of a pharmacologically active agent, which must undergo transformation in vivo to release the active drug. They are designed in order to improve the physicochemical, biopharmaceutical and/or pharmacokinetic properties of pharmacologically potent compounds. This article describes the basic functional groups that are amenable to prodrug design, and highlights the major applications of the prodrug strategy, including the ability to improve oral absorption and aqueous solubility, increase lipophilicity, enhance active transport, as well as achieve site-selective delivery. Special emphasis is given to the role of the prodrug concept in the design of new anticancer therapies, including antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT).

Nucleosides, nucleotides, and oligonucleotides site-specifically modified with metal complexes are of interest for analytical applications (hybridization probes, electrochemical sensors) [1,2] and therapeutic uses (anticancer agents and radiopharmaceuticals), [3,4] as novel materials for the assembly of nanostructures, [5,6] for structural and mechanistic studies (DNA-mediated electron and energy transfer), [7] and for the construction of artificial chemical nucleases. [8,9] Metal-containing nucleosides, the precursors of the corresponding metal-derivatized nucleic acids, have been predominantly constructed by the synthesis of nucleosidechelator conjugates followed by metal complexation (chelator-type metallanucleosides).[10] Another kind of metal-containing nucleoside is obtained by coupling the nucleoside moiety with a metallocene such as ferrocene (the p complex type of metallanucleoside). [11,12] Herein we describe a new type of metal-bearing nucleoside obtained by conjugation of the nucleoside with a metallacarborane moiety.Metallacarboranes are a vast family of metallocene-type complexes consisting of at least one carborane cage ligand and one or more metal atoms. Carborane (borane) clusters are versatile and efficient ligands for metals like Al, Au, Co, Cr, Cu, Fe, Ir, Mn, Ni, Pt, and many others, [13,14] and potentially allow incorporation of an array of metals with different properties into a nucleic acid or its components. For

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A general approach to the synthesis of nucleoside conjugates between derivatives of thymidine (T), 2′‐O‐deoxycytidine (dC), 2′‐O‐deoxyadenosine (dA), and 2′‐O‐deoxyguanosine (dG), and metallacarborane complexes is described. Metallacarborane–nucleoside derivatives are prepared by reaction of the dioxane–metallacarborane adduct with a base‐activated 3′,5′‐protected nucleoside. In the case of T and dG a mixture of regioisomers, which is easily separable by chromatographic methods, is obtained, thus yielding a series of modifications containing metallacarborane groups at the 2‐O, 3‐N, 4‐O and 1‐N, 2‐N, 6‐O locations, respectively; dC and dA are alkylated at the exo‐amino function. The proposed methodology provides a route for the synthesis and study of nucleic acids modified with metallacarboranes at designated locations and a versatile approach to the incorporation of metals into DNA.