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Methyl scanning: total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s)
Authors:Pirrung Michael C  Liu Yufa  Deng Liu  Halstead Diana K  Li Zhitao  May John F  Wedel Michael  Austin Darrell A  Webster Nicholas J G
Institution:Department of Chemistry, Levine Science Research Center, Box 90317, Duke University, Durham, NC 27708-0317, USA. michael.pirrung@ucr.edu
Abstract:The principle of methyl scanning is proposed for determination of the sites of interaction between biologically active small molecules and their macromolecular target(s). It involves the systematic preparation of a family of methylated derivatives of a compound and their biological testing. As a functional assay, the method can identify the regions of a molecule that are important (and unimportant) for biological activity against even unknown targets, and thus provides an excellent complement to structural biology. Methyl scanning was applied to demethylasterriquinone B1, a small-molecule mimetic of insulin. A new, optimal total synthesis of this natural product was developed that enables the family of methyl scan derivatives to be concisely prepared for evaluation in a cellular assay. The results of this experiment were used to design a biotin-demethylasterriquinone conjugate for use as an affinity reagent. This compound was prepared in tens of milligram quantities in a four-step synthesis.
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