Relationships between the structure of taxol analogues and their antimitotic activity.
A variety of synthetic analogues of taxol, a naturally occurring antitumor diterpene, were examined for their potency to inhibit microtubule disassembly. For some of the compounds, the in vitro cytotoxic properties showed a good correlation with the tubulin assay. This structure-activity relationship study shows that inhibition of microtubule disassembly is quite sensitive to the configuration at C-2' and C-3'. A correlation between the conformation of the side chain at C-13 and the activity is suggested. Of all the compounds examined, one of the most potent in inhibiting microtubule disassembly and in inhibiting murine P388 leukemic cells, N-debenzoyl-N-tert-(butoxycarbonyl)-10-deacetyltaxol, named taxotere, was selected for evaluation as a potential anticancer agent.
Guéritte-Voegelein
F
F
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France.
Guénard
D
D
Lavelle
F
F
Le Goff
M T
MT
Mangatal
L
L
Potier
P
P
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001921:Brain / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D017239:Paclitaxel; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D014404:Tubulin / Q000378:metabolism
D000470:Alkaloids; D000970:Antineoplastic Agents; D014404:Tubulin; D017239:Paclitaxel