Design, synthesis and biological evaluation of bridged epothilone D analogues.
Six epothilone D analogues with a bridge between the C4-methyl and the C12-methyl carbons were prepared in an attempt to constrain epothilone D to its proposed tubulin-binding conformation. Ring-closing metathesis (RCM) was employed as the key step to build the C4-C26 bridge. In antiproliferative assays in the human ovarian cancer (A2780) and prostate cancer (PC3) cell lines, and also in tubulin assembly assay, all these compounds proved to be less active than epothilone D.
Chen
Qiao-Hong
QH
Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. qchen06@vt.edu
Ganesh
Thota
T
Brodie
Peggy
P
Slebodnick
Carla
C
Jiang
Yi
Y
Banerjee
Abhijit
A
Bane
Susan
S
Snyder
James P
JP
Kingston
David G I
DG
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin; C114026:desoxyepothilone B