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

Abstract

The multinuclear ( 1H, 15N, 31P and 195Pt) 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(NH 3) 2(Am)Cl] NO 3 (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(NH 3) 2(Am)Cl] + with 5′-GMP suggested that the reactions proceed via direct nucleophilic attack and no loss of ammonia. cis-[Pt(NH 3) 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(NH 3) 2(4-mepy)(H 2O)](NO 3) 2 (5.63) has been determined at 298 K by the use of distortionless enhancement by polarization transfer (DEPT) 15N NMR spectroscopy and compared to the pK a value of cis-[PtCl(H 2O)(NH 3) 2] +. © 2004 Elsevier B.V. All rights reserved.