title: Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells.
abstract: The total synthesis of C25-benzyloxy epothilone C is described. A sequential Suzuki-Aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C8-C12 fragment. The C25-benzyloxy analog exhibited significantly reduced biological activity in microtubule assembly and cytotoxicity assays. Molecular modeling simulations indicated that excessive steric bulk in the C25 position may reduce activity by disrupting key hydrogen bonds that are crucial for epothilone binding to beta-tubulin.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Hutt
authors.forename: Bollu S
authors.initials: BS
authors.lastname: Reddy
authors.forename: Sajiv K
authors.initials: SK
authors.lastname: Nair
authors.forename: Emily A
authors.initials: EA
authors.lastname: Reiff
authors.forename: John T
authors.initials: JT
authors.lastname: Henri
authors.forename: Jack F
authors.initials: JF
authors.lastname: Greiner
authors.forename: Ting-Lan
authors.initials: TL
authors.lastname: Chiu
authors.forename: David G
authors.initials: DG
authors.lastname: Vandervelde
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Amin
authors.forename: Richard H
authors.initials: RH
authors.lastname: Himes
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D014404:Tubulin / Q000096:biosynthesis* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin; D050257:Tubulin Modulators; C426624:epothilone C