Synthesis and structural characterization of platinum(II)-acyclovir complexes

Abstract

The hybrid drug [Pt(en)(acv)₂]²⁺ (en = 1,2-diaminoethane) has been prepared by direct reaction between acyclovir [9-(2-hydroxyethoxymethyl)guanine (acv), a nucleoside analog with potent antiviral activity] and the platinum complex [PtCl(dmso)(en)]Cl (dmso = dimethyl sulfoxide). Multinuclear NMR spectroscopy data indicated a bifunctional complex with two acv molecules N(7)-co-ordinated to the platinum atom and involved in fast conformational equilibrium with no preferred conformational state along the N(7)–Pt or N(9)–CH₂ bonds. Comparison between the crystal structure of [Pt(en)(acv)₂]²⁺ and the closely related cis-[Pt(NH₃)₂(acv)₂]²⁺ indicates that the guanine planes can assume very different orientations with respect to the co-ordination plane; slant by ca. 50° in the former case, nearly perpendicular in the latter case. A O(6)  · · ·  H–N–Pt hydrogen bond interaction is responsible for deviation from the upright position in the compound. On the basis of the observed correlation between strength of the hydrogen bond and deviation from orthogonality, the bond must be considered rather weak. Such a hydrogen bond was not formed in the closely related [Pt(NH₃)₂(acv)₂]²⁺ complex having the nucleobases nearly perpendicular to the co-ordination plane. However in the latter case the observed trends in Pt–N(7)–C(5) and Pt–N(7)–C(8) angles are in accord with an attractive interaction between the O(6) and platinum atoms. Therefore the arrangements of the nucleobases in [Pt(en)(acv)₂]²⁺ and [Pt(NH₃)₂(acv)₂]²⁺ represent two conformational energy minima with involvement of O(6) in either hydrogen bonding (former case) or a platinum attractive interaction (latter case).

References

1. G. B. Elion, Angew. Chem., 1989, 101, 893.
2. G. Hänggi, H. Schmalle and E. Dubler, Inorg. Chem., 1988, 27, 3131.
3. E. Dubler, G. Hangi and H. Schmalle, Inorg. Chem., 1990, 29, 2518.
4. E. Dubler, G. Hangi and H. Schmalle, Inorg. Chem., 1992, 31, 3728.
5. G. Hangi, H. Schmalle and E. Dubler, Inorg. Chem., 1993, 32, 6095.
6. N. P. Johnson, J. L. Butour, G. Villani, F. L. Wimmer, M. Defais, V. Pierson and V. Brabec, Progress in Clinical Biochemistry and Medicine, Springer, Berlin, 1989, vol. 10, pp. 1–24.
7. S. E. Sherman and S. J. Lippard, Chem. Rev., 1987, 87, 1153.
8. M. B. Snyder, L. D. Saravolatz, N. Markowitz, D. Pohlod, R. C. Taylor and S. G. Ward, J. Antimicrob. Chemother., 1987, 19, 815; E. Dubler, M. Grüter-Heini, G. Hänggi, M. Knoepfel and H. Schmalle, EUROBIC II, Florence, 30 August–3rd September, 1994, abstr. 110.
9. L. Cavallo, R. Cini, J. Kobe, L. G. Marzilli and G. Natile, J. Chem. Soc., Dalton Trans., 1991, 1867.
10. M. Coluccia, A. Boccarelli, C. Cermelli, M. Portolani and G. Natile, Metal Based Drugs, 1995, 2, 249.
11. A. Sinur and S. Grabner, Acta Crystallogr., Sect. C, 1995, 51, 1769.
12. R. Romeo, D. Minniti and S. Lanza, Inorg. Chim. Acta, 1997, 22, 87.
13. G. M. Sheldrick, SHELXL 93, Program for Refinement of Crystal Structures, University of Göttingen, 1993.
14. G. M. Sheldrick, SHELXS 86, Program for Crystal Structure Determination, University of Göttingen, 1986.
15. M. Nardelli, PARST 95, A System of Computer Routines for Calculating Molecular Parameters from Results of Crystal Structure Analysis, University of Parma, 1995.
16. L. Zsolnai, ZORTEP, An Interactive ORTEP Program. University of Heidelberg, 1994.
17. H. A. Tajmir-Riahi and T. Theophanides, Can. J. Chem., 1983, 61, 1813.
18. R. R. Holmes, J. Chem. Phys., 1967, 46, 3718.
19. A. T. M. Marcelis, H.-J. Korte, B. Krebs and J. Reedijk, Inorg. Chem., 1982, 21, 4059; R. E. Cramer and P. L. Dahlstrom, Inorg. Chem., 1985, 24, 3420; J. Am. Chem. Soc. 19791013679; Y. Xu, G. Natile, F. P. Intini and L. G. Marzilli, J. Am. Chem. Soc., 1990, 112, 8177.
20. N. C. Gonnella and J. D. Roberts, J. Am. Chem. Soc., 1982, 104, 3162.
21. M. Witanowski, L. Stefaniak and G. A. Webb, Annu. Rep. NMR Spectrosc., 1981, 11B, 366.
22. G. M. Arvanitis, D. Gibson, T. J. Emge and H. M. Berman, Acta Crystallogr., Sect. C, 1994, 50, 1217.
23. R. W. Gellert and R. Bau, J. Am. Chem. Soc., 1975, 97, 7379.
24. J. D. Orbell, K. Wilkowski, B. De Castro, L. G. Marzilli and T. J. Kistenmacher, Inorg. Chem., 1982, 21, 813.
25. J. D. Orbell, M. R. Taylor, S. L. Birch, S. E. Lawton, L. M. Vilkins and L. J. Keefe, Inorg. Chim. Acta, 1988, 152, 125.
26. R. Taylor and O. Kennard, J. Am. Chem. Soc., 1982, 104, 3209.
27. G. I. Birnbaum, M. Cygler and D. Shugar, Can. J. Chem., 1984, 62, 2646.
28. I. Turel, N. Bukovec, M. Goodgame and D. J. Williams, Polyhedron, 1997, 16, 1701.
29. B. Lippert, G. Raudaschl, C. J. L. Lock and P. Pilon, Inorg. Chim. Acta, 1984, 93, 43.
30. B. L. Heyl, K. Shinozuka, S. K. Miller, D. G. VanDerveer and L. G. Marzilli, Inorg. Chem., 1985, 24, 661.
31. L. Sindellari, H. Schöllhorh, U. Thewalt, G. Raudaschl-Sieber, G. Müller and B. Lippert, Inorg. Chim. Acta, 1990, 168, 27.
32. A. Erxleben, I. Mutikainen and B. Lippert, J. Chem. Soc., Dalton Trans., 1994, 3667.
33. L. Maresca, G. Natile, F. P. Intini, F. Gasparrini, A. Tiripicchio and M. Tiripicchio-Camellini, J. Am. Chem. Soc., 1986, 108, 1180.
34. F. P. Intini, M. Lanfranchi, G. Natile, C. Pacifico and A. Tiripicchio, Inorg. Chem., 1996, 35, 1715.
35. A. Bondi, J. Phys. Chem., 1964, 68, 441.
36. R. Cini, F. P. Fanizzi, F. P. Intini, L. Maresca and G. Natile, J. Am. Chem. Soc., 1993, 115, 5123.