Submitted to: Biotechnology and Bioengineering
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/31/2008
Publication Date: 4/15/2008
Citation: Cotterill, I.C., Rich, J.O., Scholten, M.W., Mozhaeva, L., Michels, P.C. 2008. Reversible derivatization to enhance enzymatic synthesis: Chemoenzymatic synthesis of Doxorubicin-14-O-Esters. Biotechnology and Bioengineering. 101(3):435-440. Interpretive Summary: Doxorubicin has found widespread use in the treatment of a variety of cancers, including cancers of the breast, ovary and lung, despite the known therapeutic drawbacks. Since the discovery of doxorubicin, thousands of the analogs have been developed in the largely unsuccessful search for an improved pharmaceutical. In this report, we describe a novel synthesis of an important class of doxorubicin-based derivatives. This enzyme-catalyzed system has distinct advantages over the accepted chemical route, including productivity, selectivity, and improved downstream handling. These types of compounds will continue to be critical in the treatment of many cancers, and robust synthetic approaches like those described herein are necessary for drug development and production.
Technical Abstract: An efficient three-step, chemoenzymatic synthesis of unprotected doxorubicin-14-O-esters from doxorubicin hydrochloride salt is described. The key step is a lipase-catalyzed regioselective transesterification/esterification using commercially-available acyl donors and doxorubicin reversibly derivatized with N-alloc to improve substrate loadings. The overall yield is ca. 60% and chromatographic purification is not required, thereby making the process more amenable to scale-up.