Chelate-ring-opened adducts of [Pt(en)(Me-Mal-O,O′)] (en = ethane-1,2-diamine, Me-Mal = 2-methylmalonate) with methionine derivatives: relevance to the biological activity of platinum anticancer agents

Abstract

The anticancer drug carboplatin [Pt(cbdca-O,O′)(NH₃)₂] which contains the chelated dicarboxylate ligand cbdca, cyclobutane-1,1-dicarboxylate, may be activated in vivo by reaction with sulfur ligands. The reactions between the analogue [Pt(en)(Me-Mal-O,O′)] 1 (en = ethane-1,2-diamine, Me-Mal = 2-methylmalonate) and the methionine derivatives N-acetyl-L-methionine (Ac-Met), glycyl-L-methionine (Gly-Met) and L-methionylglycine (Met-Gly) have been studied at pH 7 and 4, 310 K, using ¹H and two-dimensional [¹H, ¹⁵N] heteronuclear single quantum coherence NMR spectroscopy and HPLC. The ring-opened species [Pt(en)(Me-Mal-O)(L-S)] (L = Ac-Met, Gly-Met or Met-Gly) containing monodentate malonate and S-bound monodentate methionine ligands were predominant in solution after 2 h. The second-order rate constant for the ring-opening reaction of 1 with Ac-Met at pH 6.56 was determined to be (1.48 ± 0.03) × 10^{- 1} s^-1 M^-1, and was similar for reactions with Gly-Met. Methylmalonate α-CH deuteriation rates were determined to be free Me-Met > ring-opened complex ⪢ 1. Molecular-mechanics modelling suggested that hydrogen bonding between the free carboxylate group of monodentate Me-Mal and the co-ordinated amine groups, and between the two ring-opened ligands may contribute to the stability of the mixed-ligand adducts. However, in the case of Met-Gly, the ring-opening rate [(5.26 ± 0.10) × 10 ^-2 s^-1 M^-1] was nearly three times slower than that for the reaction of 1 with Ac-Met. In contrast, the ring-closure rate of [Pt(en)(Me-Mal-O)(Met-Gly-S)] [k₁ = (1.37 ± 0.03) × 10^-4 s^-1] to give the S,N-chelated adduct was faster than that of [Pt(en)(Me-Mal-O)(Ac-Met-S)]^-2 [(2.27 ± 0.04) × 10 ^-5 s^-1]. The S,N-chelated adducts [Pt(en)(Ac-MetH_-1-S,N)] 3, [Pt(en)(Gly-MetH_-1-S,N)]⁺ and [Pt(en)(Met-GlyH_-1-S,N)]⁺ became the predominant products of the reactions after about 24 h. Ring-opened adducts of chelated dicarboxylate platinum anticancer complexes with methionine derivatives could play a significant role in their mechanism of action.

References

1. Platinum and Other Metal Complexes in Cancer Chemotherapy, ed. M. Nicolini, Martinus Nijhoff, Boston, 1988.
2. Platinum and Other Metal Complexes in Cancer Chemotherapy, ed. S. B. Howell, Plenum Press, New York, 1991.
3. M. A. Allsopp, G. J. Sewell, C. G. Rowland, C. M. Riley and R. L. Schowen, Int. J. Pharm., 1991, 69, 197.
4. L. Canovese, L. Cattalini, G. Chess and M. L. Tobe, J. Chem. Soc., Dalton Trans., 1988, 2135.
5. U. Frey, J. D. Ranford and P. J. Sadler, Inorg. Chem., 1993, 32, 1333.
6. P. J. Sadler, Adv. Inorg. Chem., 1991, 36, 1.
7. E. L. M. Lempers and J. Reedijk, Adv. Inorg. Chem., 1991, 37, 175.
8. K. J. Barnham, M. I. Djuran, P. S. del Murdoch and P. J. Sadler, J. Chem. Soc., Chem. Commun., 1994, 721.
9. S. S. G. E. van Boom and J. Reedijk, J. Chem. Soc., Chem. Commun., 1993, 1397.
10. C. M. Riley, L. A. Sternson, A. J. Repta and S. A. Slyter, Anal. Biochem., 1983, 130, 203.
11. P. S. del Murdoch, J. D. Ranford, P. J. Sadler and S. J. Berners-Price, Inorg. Chem., 1993, 32, 2249.
12. K. J. Barnham, U. Frey, P. del S. Murdoch, J. D. Ranford, P. J. Sadler and D. R. Newell, J. Am. Chem. Soc., 1994, 116, 11175.
13. P. M. Deegan, I. S. Pratt and M. P. Ryan, Toxicology, 1994, 89, 1.
14. K. J. Barnham, Z. Guo and P. J. Sadler, J. Chem. Soc., Dalton Trans., 1996, 2867.
15. K. J. Barnham, M. I. Djuran, P. del S. Murdoch, J. D. Ranford and P. J. Sadler, Inorg. Chem., 1996, 35, 1065.
16. M. J. Cleare, The Proceedings of the Third International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy, Leland Fikes Foundation Press, Dallas, 1977, 1; J. M. Hill, E. Loeb, A. S. Pardue, A. Khan, N. O. Hill, J. J. King and R. W. Hill, The Proceedings of the Third International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy, Leland Fikes Foundation Press, Dallas, 1977, 681.
17. J. Stonehouse, G. L. Shaw, J. Keeler and E. D. Laue, J. Magn. Reson., Ser. A, 1994, 107, 178.
18. S. J. Berners-Price and P. J. Sadler, Coord. Chem. Rev., 1996, 151, 1.
19. S. J. Berners-Price, U. Frey, J. D. Ranford and P. J. Sadler, J. Am. Chem. Soc., 1993, 115, 8649.
20. S. J. S. Kerrison and P. J. Sadler, J. Chem. Soc., Chem. Commun., 1977, 861.
21. A. Pasini and C. Caldirola, Inorg. Chim. Acta, 1988, 151, 19.
22. C. J. Boreham, J. A. Broomhead and D. P. Fairlie, Aust. J. Chem., 1981, 34, 659.
23. D. P. Fairlie and M. W. Whitehouse, Biochem. Pharmacol., 1982, 31, 933.
24. VNMR 4.3, Varian Nuclear Magnetic Resonance Instruments, Palo Alto, CA.
25. S. J. Berners-Price, T. A. Frenkiel, U. Frey, J. D. Ranford and P. J. Sadler, J. Chem. Soc., Dalton Trans., 1992, 2137.
26. E. L. M. Lempers, M. J. Bloemink and J. Reedijk, Inorg. Chem., 1991, 30, 201.
27. KALEIDAGRAPH, Synergy Software, Reading, PA, 1994.
28. HYPERCHEM, release 4.5, Hypercube Inc., Ontario.
29. P. Comba, T. W. Hambley and N. Okon, MOMEC, A Strain Energy Minimization Package adapted to HYPERCHEM, Altenhoff and Schmitz, Dortmund, 1995.
30. T. W. Hambley, Inorg. Chem., 1988, 30, 1073.
31. T. W. Hambley, Inorg. Chem., 1991, 30, 937.
32. E. C. L. Ling, G. W. Allen and T. W. Hambley, J. Chem. Soc., Dalton Trans., 1993, 3705.
33. S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, S. Profeta, jun. and P. Weiner, J. Am. Chem. Soc., 1984, 106, 765.
34. T. G. Appleton, P. D. Prenzler and R. A. Webb, 3th International Symposium on Applied Bioinorganic Chemistry, Fremantle, 1994, Abstract, p. A 11; 7th International Symposium on Platinum and other Metal Coordination Compounds in Cancer Chemotherapy, Amsterdam, 1995, Abstract, p. 105.
35. E. W. Abel, M. Booth and K. G. Orrell, J. Chem. Soc., Dalton Trans., 1980, 1582.
36. J. C. Barnes, G. Hunter and M. W. Lown, J. Chem. Soc., Dalton Trans., 1976, 1227.
37. E. W. Hansen and P. Ruoff, J. Phys. Chem., 1988, 92, 2641.
38. E. W. Hansen and P. Ruoff, J. Phys. Chem., 1989, 93, 2696.