Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin.
The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the beta-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1-C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
Oliver E
OE
Hutt
Jun
J
Inagaki
Bollu S
BS
Reddy
Sajiv K
SK
Nair
Emily A
EA
Reiff
John T
JT
Henri
Jack F
JF
Greiner
David G
DG
VanderVelde
Ting-Lan
TL
Chiu
Elizabeth A
EA
Amin
Richard H
RH
Himes
Gunda I
GI
Georg
D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D015335:Molecular Probes / Q000138:chemical synthesis; D019920:Photoaffinity Labels / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators
D034261:Epothilones; D015335:Molecular Probes; D019920:Photoaffinity Labels; D014404:Tubulin; D050257:Tubulin Modulators; C426624:epothilone C