RING-OPENING REACTIONS OF THE ANTICANCER DRUG CARBOPLATIN - NMR CHARACTERIZATION OF CIS-[PT(NH3)2(CBDCA-O)(5'-GMP-N7)] IN SOLUTION

We have studied reactions of the anticancer drug [Pt(NH3)2(CBDCA-O,O')] (carboplatin, ''Paraplatin'', where H2CBDCA is cyclobutane-1,1-dicarboxylic acid) with nitrate, phosphate, chloride, and 5'-guanosine monophosphate (5'-GMP)in aqueous solution at 310 K using H-1, N-15, [H-1, N-15], and P-31 NMR spectroscopy. In each case (except nitrate) a ring-opened species containing monodentate CBDCA was detected during the course of the reaction. A structure for cis-[Pt(NH3)2(CBDCA-O)(5'-GMP)] is proposed which accounts for the inequivalence of all six cyclobutane ring protons in this complex. There is a close hydrophobic contact between the cyclobutane ring of monodentate CBDCA and the purine ring of coordinated 5'-GMP. The reaction of carboplatin with 5'-GMP (k(obs1) 4.1 x 10(-6) s-1) was faster than that with phosphate (k(obs) 4.3 x 10(-7) s-1), phosphate and chloride (k(obs) 1.2 x 10(-6) s-1), or water alone (<5 x 10(-9) s-1), suggesting that direct attack of nucleotides on carboplatin may be of importance in the mechanism of action for this drug.