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Synthesis of Daunorubicin Analogues Containing Truncated Aromatic Cores and Unnatural Monosaccharide Residues

Synthesis of Daunorubicin Analogues Containing Truncated Aromatic Cores and Unnatural Monosaccharide Residues

Eric Fan, Wei Shi, Todd L Lowary

J Org Chem. 2007 Apr 13;72(8):2917-28.

PMID: 17373847

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP26042637	Silver hexafluorophosphate		26042-63-7	Price

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