Journal
ACS CENTRAL SCIENCE
Volume 7, Issue 8, Pages 1327-1337Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.1c00040
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Funding
- National Institutes of Health [1R35GM133602, R01GM126363]
- American Chemical Society Petroleum Research Fund
- Dean's Faculty Fellowship from the College of Arts & Science at Vanderbilt University
- Vanderbilt Chemical Biology of Infectious Diseases (CBID) [T32 AI112541]
- Camille Dreyfus TeacherScholar
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This study investigated the cytotoxicity of arimetamycin A glycan on compound IC50. By synthesizing a modified acyl donor and glycosylating it with three anthracycline aglycones, arimetamycin A and two novel hybrid anthracyclines were successfully synthesized, showing enhanced cytotoxicity compared to parent anthracyclines. Mechanistic evaluation indicated that one of the hybrid compounds inhibited the ability of human topoisomerase II alpha to relax DNA supercoils.
The arimetamycin A glycan governs the compound's cytotoxicity (IC50). To study this branched, deoxy-amino disaccharide, we designed and synthesized a modified acyl donor that underwent glycosylation with three anthracycline aglycones: steffimycinone, daunorubicinone, and doxorubicinone. The result of the approach was a synthesis of arimetamycin A and two novel hybrid anthracyclines. Each molecule exhibited enhanced cytotoxicity in comparison to the parent anthracyclines, steffimycin B, daunorubicin, and doxorubicin. An orienting mechanistic evaluation revealed that the daunorubicin hybrid inhibits the ability of human topoisomerase II alpha to relax negatively and positively supercoiled DNA.
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