Platinum(II) triammine antitumour complexes:: structure-activity relationship with guanosine 5′-monophosphate (5′-GMP)

The multinuclear (H-1, N-15, P-31 and Pt-195) NMR spectroscopies. ES-MS and HPLC have been employed to investigate the structure-activity relationship for the reactions between guanosine 5'-monophosphate (5'-GMP) and the platinum(II)-triamine complexes of the general formulation cis-[Pt(NH3)(2)(Am)Cl]NO3 (where Am represents a substituted pyridine). The order of reaction rate of the reactions was found to be: 3-phpy > 4-phpy > py > 4-mepy > 3-mepy > 2-mepy. The two basic factors, steric and electronic, were attributed to the order of the binding rate constants. A possible mechanism of the reaction of cis-[Pt(NH3)(2)(Am)Cl](+) with 5'-GMP suggested that the reactions proceed via direct nucleophilic attack and no loss of ammonia. cis-[Pt(NH3)(2)(Am)Cl](+) binds to the N7 nitrogen of the guanine residue of 5'-GMP to form a coordinate bond with the Pt metal centre. This mechanism is apparently different from that of cisplatin. The pK(a) value of cis-[Pt(NH3)(2)(4-mepy)(H2O)](NO3)(2) (5.63) has been determined at 298 K by the use of distortionless enhancement by polarization transfer (DEPT) N-15 NMR spectroscopy and compared to the pK(a) value of cis-[PtCl(H2O)(NH3)(2)](+). (C) 2004 Elsevier B.V. All rights reserved.