STEREOSPECIFIC AND KINETIC CONTROL OVER THE HYDROLYSIS OF A STERICALLY HINDERED PLATINUM PICOLINE ANTICANCER COMPLEX

cis-[PtCl2(NH2)(2-picoline)] (1) (AMD473) is a recently reported activ e anticancer complex. Hydrolysis may be an important step in its intra cellular activation and interaction with DNA. In this paper we employe d [H-1, N-15] 2D NMR spectroscopy to determine the hydrolysis rates fo r each chloride ligand of this complex and its 3-picoline analogue 2. We also report the pK(a) values of the aqua and diaqua ligands as well as the X-ray crystal structures of 1 and 2. For the 3-picoline comple x 2 the rate of hydrolysis of the Cl- trans to NH3 (k(1b) = 1.0 x 10(- 4) s(-1), I = 0.1 M, 310 K) is Similar to that of cisplatin, but slowe r for the Cl- trans to 3-picoline (k(1a) = 4.5 x 10(-5) s(-1)). Both o f the first hydrolysis rates for the 2-picoline complex 1 are slower t han those of 2, but in contrast to 2, the hydrolysis of the Cl- trans to NH3 (cis to 2-picoline) is slower (k(1b) = 2.2 x 10(-5) s(-1)) than for the Cl- trans to 2-picoline (k(1a) = 3.2 x 10(-5) s(-1)). The cry stal structure of 2 revealed that the pyridine ring is tilted by 49 de grees with respect to the Pt square plane, whereas in 1 the ring is al most perpendicular (103 degrees). This introduces steric hindrance by the CH3 group towards an axial approach to Pt from above, leading to a destabilisation of the expected trigonal-bipyramidal transition state , an effect well-known in substitution reactions of Pt-II complexes. T he pK(a) values for the monoaqua adducts of 1 (6.13 and 6.49) and 2 (5 .98 and 6.26 for H2O trans to picoline and NH3, respectively) and for the diaqua adducts (5.22, 7.16 for 1 and 5.07, 6.94 for 2) are >0.3 un its lower than for cisplatin. The slowness of the hydrolysis, combined with the dominance of (inert) hydroxo species, is expected to contrib ute to a greatly reduced reactivity of the sterically-hindered 2-picol ine complex under intracellular conditions.