title: Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues.
abstract: The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand-target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides.
authors.affiliation: Department of Chemistry and Biochemistry, the Harper Cancer Research Institute, and the Warren Family Research Center for Drug Discovery & Development, University of Notre Dame, Notre Dame, IN 46556, USA. lwoods4@nd.edu.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Woods
authors.affiliation: Department of Chemistry and Biochemistry, the Harper Cancer Research Institute, and the Warren Family Research Center for Drug Discovery & Development, University of Notre Dame, Notre Dame, IN 46556, USA. jarico81@gmail.com.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Arico
authors.affiliation: Department of Chemistry and Biochemistry, the Harper Cancer Research Institute, and the Warren Family Research Center for Drug Discovery & Development, University of Notre Dame, Notre Dame, IN 46556, USA. jdfrein@gmail.com.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Frein
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. sackettd@mail.nih.gov.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Sackett
authors.affiliation: Department of Chemistry and Biochemistry, the Harper Cancer Research Institute, and the Warren Family Research Center for Drug Discovery & Development, University of Notre Dame, Notre Dame, IN 46556, USA. taylor.61@nd.edu.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Taylor
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D034261:Epothilones / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin; C114026:desoxyepothilone B
keywords: binding site; cancer; conformation; epothilone