Synthetic analog of anticancer drug daunorubicin from daunorubicinone using one-pot enzymatic UDP-recycling glycosylation

• An in vitro UDP-recycling system was developed for efficient glycosylation of natural products.
• Recycling of UDP, a byproduct of glycosylation reaction enhanced the catalysis activity of glycosyltransferase.
• Two novel daunorubicinone glucosides were produced and structurally characterized.
• New synthetic analogs were accessed for their altered physical and biological properties.

Doxorubicin and daunorubicin are two widely used anticancer drugs containing deoxyaminosugar unit in their structure. Altering the sugar moiety could generate novel drugs, which could have different biological potency than daunorubicin and doxorubicin. In this study, daunorubicinone was used as a substrate for the production of two different novel glucoside derivatives via enzymatic glycosylation, and their physical and biological activities were assessed and compared with standard compounds. A one-pot enzymatic glycosylation system was designed in vitro to maintain continuous generation of UDP-α-d-glucose, which is used as the donor substrate by the glycosyltransferase enzyme, YjiC, for the glycosylation of acceptor molecule, daunorubicinone, aglycone of daunorubicin. The result indicates an increased conversion (∼74.8%) of daunorubicinone 7-O-α-d-glucoside and ∼22.2% of daunorubicinone-7,9-di-O-α-d-glucoside in one-pot UDP-α-d-glucose recycling system in comparison to regular reaction at 90 min incubation period. Both the glucosylated daunorubicinone exhibited improved water solubility, and stability over a wide range of pH (4.5–8.5) and high temperatures. However, anticancer activity assay against four different cancer cell lines showed complete loss of anticancer property upon glucosylation of daunorubicinone.

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