Synthesis and Preliminary Biological Evaluation of Arimetamycin A Disaccharide Decorated Anthracyclines
Huseman, Eric Douglas
The arimetamycins A-C are recently discovered anthracycline natural products that feature a conserved steffimycin aglycone adorned with various carbohydrates. Cytotoxicity evaluation against a panel of four cancel cell lines revealed that AMA had nanomolar activity (IC50) while arimetamycins B and C demonstrated micromolar activity. Furthermore, AMA proved more cytotoxic than established anthracycline chemotherapeutics daunorubicin and doxorubicin and maintained its nanomolar activity against the multidrug resistant (MDR) lung cancer cell line H69AR. As the arimetamycins vary only in the composition of their carbohydrates, these data indicate that the AMA glycan is critical for the molecule’s cytotoxicity. To further study this disaccharide composed of the rare, branched deoxy-N,N-dimethylamino monosaccharides L-brasiliose and L-lemonose, a protected AMA disaccharide was synthesized on gram scale. Transformation of this intermediate into a novel lipophilic, acyl glycosyl donor and subsequent glycosidation with the aglycone of daunorubicin (DNR) afforded a DNR-AMA hybrid anthracycline. This hybrid demonstrated sub-micromolar activity (TC50) against a panel of three cancer cell lines and maintained its potency against the MDR H69AR lung cancer cell line. Mechanistic studies showed that the DNR-AMA hybrid inhibits the ability of human topoisomerase II alpha to relax positively and negatively supercoiled DNA. Additionally, changes in electrophoretic mobility indicate that DNR-AMA hybrid is likely a DNA intercalator.