Synthesis of Daunorubicin Analogues Containing Truncated Aromatic Cores and Unnatural Monosaccharide Residues Eric Fan, Wei Shi, and Todd L. Lowary* Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, UniVersity of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada tlowary@ualberta.ca ReceiVed December 12, 2006 The anthracycline antibiotics daunorubicin and doxorubicin have been used widely as anticancer drugs, but their cardiotoxicity limits their clinical use. We describe here the preparation of a small panel of daunorubicin analogues in which the anthraquinone core is replaced with simpler aromatic moieties that lack a quinone functionality. The targets consist of a functionalized 1,2,3,4-tetrahydro-naphthalene or 1,2,3,4-tetrahydro-anthracene core bound to one of three monosaccharides: daunosamine, acosamine, or 4-amino-2,3,6-trideoxy-L-threo-hexopyranose. Key steps in the synthesis included an enantioselective ring opening of benzo-fused norbornene derivatives for the preparation of the core structures and the use of silver hexafluorophosphate-promoted thioglycoside activation in the glycosylation of these cores. Evaluation of these compounds against the MCF-7 cancer cell line demonstrated that the identity of the carbohydrate moiety appeared to have little influence on the cytotoxicity. Moreover, the analogues with the 1,2,3,4- tetrahydro-naphthalene core showed no cytotoxicity, while those possessing the 1,2,3,4-tetrahydro- anthracene moiety were more active. The IC 50 values for the latter group of compounds were in the range of 94-134 µM, compared to 17 µM for doxorubicin and 5 µM for daunorubicin. Introduction The anthracycline antibiotics daunorubicin (1, Chart 1) and doxorubicin (2), first isolated in the 1960s from Streptomyces peucetius, 1 have found widespread clinical use as anticancer agents. 2 Synthetic analogues of these natural products, for example epirubicin (3) 3 and idarubicin (4), 4 have also entered the clinic, and a very large number of other analogues have been synthesized and their cytotoxicity has been evaluated (e.g., 5 and 6). 5 These compounds, all of which contain an an- thraquinone core attached to a carbohydrate moiety, are inhibi- tors of topoisomerases, enzymes that manage the topology of DNA. 6 More specifically, doxorubicin and its analogues function as topoisomerase poisons through stabilization of the “cleavable (1) (a) Cassinelli, F.; Orezzi, P. G. Microbiol. 1963, 11, 167-174. (b) Di Marco, A.; Gaetani, M.; Orezzi, P.; Scarpinato, B. M.; Silvestrini, R.; Soldati, M.; Dasdia, T.; Valentini, L. Nature 1964, 201, 706-707. (c) Di Marco, A.; Gaetani, M.; Dorigotti, L.; Soldati, M.; Bellini, O. Cancer Chemother. Rep. 1964, 38, 31-38. (2) (a) Weiss, R. B. Semin. Oncol. 1992, 19, 670-686. (b) Arcamone, F. M. Anthracyclines. In Anticancer Agents from Natural Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC Press: Boca Raton, FL, 2005; pp 299-320. (3) Robert, J. Drugs 1993, 45, 20-30. (4) Borchmann, P.; Huebel, K.; Schnell, R.; Engert, A. Int. J. Clin. Pharmacol. Ther. 1997, 35, 80-83. (5) Recent examples: (a) Guano, F.; Pourquier, P.; Tinelli, S.; Binaschi, M.; Bigioni, M.; Animati, F.; Manzani, S.; Zunino, F.; Kohlhagen, G.; Pommier, Y.; Capranico, G. Mol. Pharmacol. 1999, 56, 77-84. (b) Zunino, F.; Pratesi, G.; Perego, P. Biochem. Pharmacol. 2001, 61, 933-938. (c) Cipollone, A.; Berettoni, M.; Bigioni, M.; Binaschi, M.; Cermele, C.; Monteagudo, E.; Olivieri, L.; Palomba, D.; Animati, F.; Goso, C.; Maggi, C. A. Bioorg. Med. Chem. 2002, 10, 1459-1470. (d) Portugal, J.; Cashman, D. J.; Trent, J. O.; Ferrer-Miralles, N.; Przewloka, T.; Fokt, I.; Priebe, W.; Chaires, J. B. J. Med. Chem. 2005, 48, 8209-8219. (e) Zhang, G.; Fang, L.; Zhu, L.; Aimiuwu, J. E.; Shen, J.; Cheng, H.; Muller, M. T.; Lee, G. E.; Sun, D.; Wang, P. G. J. Med. Chem. 2005, 48, 5269-5278. (f) Fang, L.; Zhang, G.; Li, C.; Zheng, X.; Zhu, L.; Xiao, J. J.; Szakacs, G.; Nadas, J.; Chan, K. K.; Wang, P. G.; Sun, D. J. Med. Chem. 2006, 49, 932-941. (g) Zhang, G.; Fang, L.; Zhu, L.; Zhong, Y.; Wang, P. G.; Sun, D. J. Med. Chem. 2006, 49, 1792-1799. (h) Horton, D.; Khare, A. Carbohydr. Res. 2006, 341, 2631-2640. (6) Champoux, J. J. Annu. ReV. Biochem. 2001, 70, 369-413. 10.1021/jo062542q CCC: $37.00 © 2007 American Chemical Society J. Org. Chem. 2007, 72, 2917-2928 2917 Published on Web 03/21/2007