title: Methyl scanning: total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s).
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.
authors.affiliation: Department of Chemistry, Levine Science Research Center, Box 90317, Duke University, Durham, NC 27708-0317, USA. michael.pirrung@ucr.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Pirrung
authors.forename: Yufa
authors.initials: Y
authors.lastname: Liu
authors.forename: Liu
authors.initials: L
authors.lastname: Deng
authors.forename: Diana K
authors.initials: DK
authors.lastname: Halstead
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Li
authors.forename: John F
authors.initials: JF
authors.lastname: May
authors.forename: Michael
authors.initials: M
authors.lastname: Wedel
authors.forename: Darrell A
authors.initials: DA
authors.lastname: Austin
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D011955:Receptors, Drug / Q000737:chemistry* / Q000302:isolation & purification; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; C119066:L 783281; D011955:Receptors, Drug; D011972:Receptor, Insulin