title: Synthesis of daunorubicin analogues containing truncated aromatic cores and unnatural monosaccharide residues.
abstract: 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 IC50 values for the latter group of compounds were in the range of 94-134 microM, compared to 17 microM for doxorubicin and 5 microM for daunorubicin.
authors: Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2, Canada.
authors: Eric
authors: E
authors: Fan
authors: Wei
authors: W
authors: Shi
authors: Todd L
authors: TL
authors: Lowary
mesh_terms: D018943:Anthracyclines / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009005:Monosaccharides / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009005:Monosaccharides; D003630:Daunorubicin