Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells.
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.
Hutt
Oliver E
OE
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
Reddy
Bollu S
BS
Nair
Sajiv K
SK
Reiff
Emily A
EA
Henri
John T
JT
Greiner
Jack F
JF
Chiu
Ting-Lan
TL
Vandervelde
David G
DG
Amin
Elizabeth A
EA
Himes
Richard H
RH
Georg
Gunda I
GI
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*
D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin; D050257:Tubulin Modulators; C426624:epothilone C