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.
Hutt
Oliver E
OE
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
Inagaki
Jun
J
Reddy
Bollu S
BS
Nair
Sajiv K
SK
Reiff
Emily A
EA
Henri
John T
JT
Greiner
Jack F
JF
VanderVelde
David G
DG
Chiu
Ting-Lan
TL
Amin
Elizabeth A
EA
Himes
Richard H
RH
Georg
Gunda I
GI
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