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Title: Application of combinatorial biocatalysis for a unique ring expansion of dihydroxymethylzearalenone

item Rich, Joseph
item Budde, Cheryl
item Mcconeghey, Luke
item Cotterill, Ian
item Mozhaev, Vadim
item Singh, Sheo
item Goetz, Michael
item Zhao, Annie
item Michels, Peter
item Khmelnitsky, Yuri

Submitted to: Bioorganic and Medicinal Chemistry Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/3/2009
Publication Date: 4/9/2009
Citation: Rich, J.O., Budde, C.L., Mcconeghey, L.D., Cotterill, I.C., Mozhaev, V.V., Singh, S.B., Goetz, M.A., Zhao, A., Michels, P.C., Khmelnitsky, Y.L. 2009. Application of combinatorial biocatalysis for a unique ring expansion of dihydroxymethylzearalenone. Bioorganic and Medicinal Chemistry Letters. 19:3059-3062.

Interpretive Summary: In this research, a new library of drug candidates was created using a unique process that can aid researchers in the search for new anti-cancer drugs. Although significant improvements have been made in the fight against cancer, considerable progress is still needed. We developed a unique enzyme-catalyzed ring expansion that involves two steps, the first to open the ring and the second to reclose the ring using a variety of test substances. This will help researchers in their search for new anti-cancer drugs by creating novel chemical structures for testing against various cancers.

Technical Abstract: Combinatorial biocatalysis was applied to generate a diverse set of dihydroxymethylzearalenone derivatives with modified ring structure. In one chemoenzymatic reaction sequence, dihydroxymethylzearalenone was first subjected to a unique enzyme-catalyzed oxidative ring opening reaction that creates two new carboxylic groups on the molecule. These groups served as reaction sites for further derivatization involving biocatalytic ring closure reactions with structurally diverse bifunctional reagents, including different diols and diamines. As a result, a library of cyclic bislactones and bislactams was created, with modified ring structures covering chemical space and structure activity relationships unattainable by conventional synthetic means.