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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Doxsaliform: A Novel N-Mannich Base Prodrug of a Doxorubicin Formaldehyde Conjugate

Author(s): P. S. Cogan, C. R. Fowler, G. C. Post and T. H. Koch

Volume 1, Issue 3, 2004

Page: [247 - 255] Pages: 9

DOI: 10.2174/1570180043399000

Price: $65


Development of a water-soluble prodrug of doxorubicin-formaldehyde conjugate, a labile, active metabolite of doxorubicin, is described. The lead compound is the doxorubicin-salicylamide N-Mannich base, N-(2-hydroxybenzamidomethyl)-doxorubicin (doxsaliform), prepared in 72% yield from reaction of salicylamide with doxorubicin in the presence of formaldehyde. Doxsaliform releases doxorubicin-formaldehyde conjugate under physiological conditions with a half-life of 57 min. The stability of the prodrug is augmented both by salt formation in acidic media and by covalent modification of the 2-hydroxyl of the salicylamide moiety. Doxsaliform is 4 fold more active than doxorubicin against MCF-7 breast and PC-3 prostate cancer cell lines and 10 fold more active against the doxorubicin resistant MCF-7 / ADR cell line.

Keywords: doxorubicin, formaldehyde, prodrug, salicylamide, trigger

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