The pK, values of ~i s -[ P t C l ( H ~o ) ( N H ~) ~l + (6.41) and C ~S -[ P ~( H ~O ) ~( N H ~) ~] ~+ (5.37 and 7.21) have been determined at 300 K via the use of I5N-edited 1H NMR spectroscopy and [IH, 15N] heteronuclear multiple quantum coherence spectroscopy; this allows rapid measurements at low (millimolar) concentrations, and so avoids some of the problems associated with other methods. Cisplatin, ~i s -[ P t C l ~( N H ~) ~l1, is a widely used anticancer drug. Its mechanism of action is thought to involve activation via hydrolysis inside cells where the C1-concentration is much lower (ca. 4 mmol dm-3) than outside cells (ca. 104 mmol dm-3) .273 Platinum(~~)-OH~ bonds are more reactive towards DNA (e.g. guanine N7) than either Pt-CI or Pt-OH b0nds~4.5 and it is important therefore to determine the pK, values of the coordinated water molecules in the cisplatin hydrolysis products cis-[ PtC1( H20)(NH3)2] + 2 and cis-[ Pt( H20)2-(NH3)2]2+ 3. This is difficult to do because reactions of these species with base are complicated by the further hydrolysis of 2, and by the slow formation of hydroxo-bridged polymers. These complicate the interpretation of potentiometric titration curves.5-7 The pK, values of species in mixtures can be determined by NMR spectroscopy provided they have suitable resonances which can be monitored as a function of pH. 2b r 2a /I @ \ \ Cis -[ P t C I (0 H 2 ) (N H3) 21' cis -[ P t (0 H2)2 (N H

We have studied reactions of the anticancer drug [Pt(NH3)2(CBDCA-O,O')] (carboplatin, "Paraplatin", where H2CBDCA is cyclobutane-1,l-dicarboxylic acid) with nitrate, phosphate, chloride, and 5'-guanosine monophosphate (5'-GMP) in aqueous solution at 310 K using 'H, I5N, [IH, I5N], and 3iP 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 (koal 4.1 X 10" s-I) was faster than that with phosphate (kobs 4.3 X lk7 SKI), phosphate and chloride (kobs 1.2 X 1W s-I), or water alone (<5 X l k 9 s-I), suggesting that direct attack of nucleotides on carboplatin may be of importance in the mechanism of action for this drug.

Reactions of the anticancer drug carboplatin ("Paraplatin") with a variety of sulfur-containing amino acids have been investigated by (1)H and (15)N NMR spectroscopy and by HPLC. Thiols react very slowly and sulfur-bridged species containing four-membered Pt(2)S(2) rings are the predominant products. In contrast, reactions with thioether ligands are much more rapid, and kinetics for the initial stages of the reaction with L-methionine have been determined (k = 2.7 x 10(-)(3) M(-)(1) s(-)(1)). Surprisingly, very stable ring-opened species are formed such as cis-[Pt(CBDCA-O)(NH(3))(2)(L-HMet-S)] which has a half-life for Met-S,N ring-closure of 28 h at 310 K. A study of the formation of the analogous product for N-acetyl-L-methionine and its subsequent ring closure is reported. Reactions such as these may play a role in the biological activity of carboplatin.

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