Platinum(II) aminophosphine anticancer complexes and their interactions with nucleotides

• Main Author: Watchman, Elaine Beth
• Published: University of Edinburgh 2002
• Subjects: 615
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663504

A series of platinum(II) aminophosphine complexes has been prepared and their interactions with nucleotides studied, such complexes are potential anticancer agents combining cytotoxic phosphines with features of platinum am(m)ine drugs. Ligands of the form Ph₂P(CH₂)₃NRR’ have been prepared, where R and R’ are alkyl groups of varying steric bulk. On complexation with platinum the ligands form six-membered chelate rings bound via P and N and the extent of chelation has been shown to be controlled by the bulk of the substituents. Chelate formation is also pH dependent with low pH favouring a ring-operated structure due to protonation of the amine group. All the complexes formed were fully characterised by the use of ³¹P NMR and X-ray crystallography. Nucleotides are ideal model compounds for studying the interactions of platinum complexes with DNA, the target for platinum drugs <i>in vivo</i>. The aminophosphine complexes prepared were reacted with four different nucleotides and their binding analysed by ¹H NMR. Binding was most prominent to the nucleotides guanosine and thymidine. The complexes can bind two guanosine per Pt to form monofunctional adducts but with the other nucleotides only monofunctional binding was observed. The formation of these bound adducts was confirmed by electrospray ionisation mass spectrometry. The pH dependence of thymidine binding was investigated since binding occurs through the endocyclic N3 site which has a high pK_a of ca. 10. Although the extent of binding of the complexes decreased at low pH, the thymidine remained fully bound over an usually wide pH range 4-12. For the less sterically hindered complexes binding also decreased at low pH due to competition from chelate ring-closing reactions. Competition reactions were carried out with the complexes and all four nucleotides together to determine the selectivity of binding by capillary electrophoresis. Surprisingly thymidine binding was as prevalent as guanosine, this is in contrast to Pt-am(m)ine anticancer complexes which have a much higher affinity for the purine bases than pyrimidines.