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4275
glucuronide conjugates as prodrugs. Currently, we are
working on the next step towards clinically interesting
platinum prodrugs through developing b-glucuronyl-
platinum conjugates based on highly potent platinum
drugs in combination with traceless linkers.
Acknowledgements
We thank Dr. Daan Noort (TNO, The Netherlands) for
valuable suggestions and Ing. Hans van den Elst for
technical assistance. This work was supported by the
Netherlands Council for Chemical Research with finan-
cial aid from the Netherlands Organisation for Scientific
Research (NWO). We also thank Johnson & Matthey
(Reading, UK) for their generous loan of K2PtCl4. This
work has been performed under the auspices of the joint
BIOMAC Research Graduate School of Leiden Uni-
versity and Delft University of Technology.
Scheme 2. Reagents and conditions: Deuterated phosphate buffer
(pD 7.2), b-glucuronidase, 37 ꢁC.
References and notes
1. Reedijk, J. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 3611.
2. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99,
2451.
3. Rosenberg, B.; Van Camp, L.; Trosko, J. F.; Mansour, V.
H. Nature 1969, 222, 385.
4. Kelland, L. R.; Sharp, S. Y.; O’Neill, C. F.; Raynaud, F.
I.; Beale, P. J.; Judson, I. R. J. Inorg. Biochem. 1999, 77,
111.
5. Reedijk, J. Chem. Commun. 1996, 801.
7. Tietze, L. F.; Feuerstein, T. Curr. Pharm. Des. 2003, 9,
2155.
8. Xu, G.; McLeod, H. L. Clin. Cancer Res. 2001, 7, 3314.
9. Syrigos, K. N.; Epenetos, A. A. Anticancer Res. 1999, 19,
605.
10. Dubowchik, G. M.; Walker, M. A. Pharmacol. Ther. 1999,
83, 67.
11. Hanessian, S.; Wang, J. Can. J. Chem. 1993, 71, 896.
12. For a review on b-glucuronide-mediated drug release: de
Graaf, M.; Boven, E.; Scheeren, H. W.; Haisma, H. J.;
Pinedo, H. M. Curr. Pharm. Des. 2002, 8, 1391.
13. Bosslet, K.; Straub, R.; Blumrich, M.; Czech, J.; Gerken,
M.; Sperker, B.; Kroemer, H. K.; Gesson, J. P.; M, K.;
Monneret, C. Cancer Res. 1998, 58, 1195.
14. Appleton, T. G.; Hall, J. R.; Neale, D. W.; Thompson, C.
S. M. Inorg. Chem. 1990, 29, 3985.
15. Gibson, D.; Rosenfeld, A.; Apfelbaum, H.; Blum, J. Inorg.
Chem. 1990, 29, 5125.
16. Kelsen, D. P.; Scher, H.; Alcock, N.; Leyland-Jones, B.;
Donner, A.; Williams, L.; Greene, G.; Burchenal, J. H.;
Tan, G.; Philips, F. S.; Young, C. W. Cancer Res. 1982,
42, 4831.
Figure 1. 1H NMR spectra at 37 ꢁC and pD 7.2 depicting (A) b-glu-
curonyl-platinum conjugate 12 in the absence of b-glucuronidase, (B)
b-glucuronidase-mediated release of platinum compound 13 with re-
17. de Groot, F. M.; Damen, E. W.; Scheeren, H. W. Curr.
Med. Chem. 2001, 8, 1093.
18. Dushin, R. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1992,
114, 3471.
19. Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 6661.
lease of glucuronic acid ( ) and (C) glucuronic acid.
ꢀ
20. Adam, W.; Bialas, L.; Hadjiarapoglou, L. Chem. Ber.
1991, 124, 2377.
21. Davis, N. J.; Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181.
22. de Nooy, A. E. J.; Besemer, A. C.; Van Bekkum, H. Recl.
Trav. Chim. Pays-Bas 1994, 113, 165.
In conclusion, we have demonstrated for the first time,
that the b-glucuronidase-based prodrug therapy is fea-
sible for platinum complexes. The virtually instanta-
neous cleavage of the synthesised conjugate (12) by
b-glucuronidase demonstrates the potential of platinum-
23. de Nooy, A. E. J.; Besemer, A. C. Tetrahedron 1995, 51, 8023.