Formylation of functionalized P-H bonds - A novel approach to the design of synthons for use in biomedicine

Formylation of phosphorus-hydrogen bonds has become a versatile strategy to producing compounds with phosphorus-carbon bonds. However, the utility of such reactions on functionalized phosphines is a recent development. Our la boratory has developed new approaches to the synthesis of phosphorus(III) h ydrides functionalized with main group backbones (e.g. thioether; (P2S2), a lkyl amino (P2N2)). The formylation of P2S2 and P2N2 functionalized phospho rus(III) hydrides, using formaldehyde, produced hydroxymethyl-substituted ( P(CH2OH)(n))(n) compounds. Recent results suggest that formylation of P-H b onds occur under mild conditions in aqueous media without the aid of transi tion metal catalysts. The hydroxymethyl (HMP) functionalized P2S2 and P2N2 phosphines are highly soluble in water and display oxidative-stability in a queous media. The HMP functionalized phosphines react with the early (e.g. Re(V)) and late transition metals (e.g. Rh(I), Pd(II), Pt(II), Ag(I) and Au (I)), under biphasic (aqueous-organic) solvent media to produce a new gener ation of water-soluble transition metal compounds. The electronic character istics of HMP groups dictate high kinetic inertness and thermal stability i n aqueous media and therefore provide a novel access to stabilize specific oxidation states of transition metals in aqueous media. Our laboratory has also concentrated its efforts on the application of HMP-based ligands in th e design of site-directed and tumor-specific radiopharmaceuticals. This int erest stems from the fact that the development of in vivo-stable (186/188)r henium (and Tc-99m) and (199)gold compounds and their conjugation to specif ic biomolecular vectors (e.g. peptides or proteins) will provide new avenue s in the discovery of cancer diagnostic, and more importantly, therapeutic pharmaceuticals. Our studies have demonstrated that the HMP ligands upon co mplexation with technetium-99m and gold-198, produce complexes that are hig hly stable under in vivo conditions as evidenced through studies in experim ental animal models. Details on ligand design and transition metal/organome tallic chemistry as they relate to the development of aqueous-soluble trans ition metal/radio-metal compounds with potential applications in nuclear me dicine will be discussed.