Contrasting chemistry of cis- and trans-platinum(II) diamine anticancer compounds: hydrolysis studies of picoline complexes.
cis-[PtCl2(NH3)(2-picoline)] (AMD473) is currently on clinical trials as an anticancer drug. The trans isomer, AMD443 (1), is also cytotoxic in a variety of cancer cell lines. The X-ray crystal structure of the trans isomer (1) shows that the pyridine ring is tilted by 69 degrees with respect to the platinum square-plane in contrast to the cis isomer in which it is almost perpendicular (103 degrees ). In the 3-picoline (2) and 4-picoline (3) trans isomers, the ring is tilted by 58 degrees /60 degrees (2 molecules/unit cell) and by 56 degrees , respectively. Hydrolysis may be an important step in the intracellular activation and anticancer mechanism of action of these complexes. The first hydrolysis step is relatively fast even at 277 K, with rate constants (determined by 1H,15N NMR) of k1 = 2.6 x 10(-5) s(-1), 12.7 x 10(-5) s(-1), and 5.2 x 10(-5) s(-1) (I = 0.1 M) for formation of the monoaqua complexes of 1-3, respectively. Although the hydrolysis of 3 is slower than 2, it is hydrolyzed to a greater extent. No formation of the diaqua complex was observed for any of the three complexes at 277 K, and it accounts for <3% of the platinum species at 310 K. In general the extent of hydrolysis of the trans complexes is much less than for their cis analogues. The pK(a) values for the monoaqua adducts of 1-3 were determined to be 5.55, 5.35, and 5.39, respectively, suggesting that they would exist largely as the monohydroxo complex at physiological pH. The pKa values for the diaqua adducts were determined to be 4.03 and 7.01 for 1, 3.97 and 6.78 for 2, and 3.94 and 6.88 for 3, the first pK(a) being >1 unit lower than for related cis complexes.
McGowan
Geraldine
G
School of Chemistry, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JJ, UK.
Parsons
Simon
S
Sadler
Peter J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents; D006868:Hydrolysis; D007939:Leukemia L1210; D051379:Mice; D010847:Picolines / Q000737:chemistry*
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D010847:Picolines; C034697:transplatin; D002945:Cisplatin