The effect of the aromatic rings of taxol on biological activity and solution conformation: synthesis and evaluation of saturated taxol and taxotere analogues.
The synthesis and biological evaluation of novel cyclohexyl analogues of taxol and taxotere are detailed. 2-(Cyclohexylcarbonyl)-2-debenzoylbaccatin III (6) was prepared from baccatin III by hydrogenation. Subsequent coupling of 6 with N-t-BOC-3-[(tert-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone (7), followed by removal of the protecting groups, afforded 2-(cyclohexylcarbonyl)-2-debenzoyltaxotere (9). In a similar synthetic sequence, 3'-cyclohexyl-3'-dephenyltaxol (14) was prepared from N-benzoyl-3-[(tert-butyldimethylsilyl)oxy]-4-cyclohexyl-2-azetidinone (12) and (triethylsilyl)baccatin III. The taxol analogue 15, in which all three taxol phenyl groups are substituted by a cyclohexyl moiety, was synthesized in one step from taxol via hydrogenation. All three analogues (9, 14, and 15) exhibited strong activity in the microtubule assembly assay and cytotoxicity comparable to taxol against B16 melanoma cells. It was also shown that 9, like taxol and taxotere, has an extended side chain in chloroform, but in DMSO/water mixtures preferentially adopts a different conformation in which the 2-(cyclohexylcarbonyl), 3'-phenyl, and 4-acetyl groups cluster. However, this behavior does not appear to occur for 3'-cyclohexyl analogues 14 and 15, in which the side chain conformation remains extended independent of solvent. These results suggest the aromaticity of the 3'-phenyl ring significantly stabilizes the clustered conformation.
Boge
T C
TC
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
Himes
R H
RH
Vander Velde
D G
DG
Georg
G I
GI
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002725:Chloroform; D004121:Dimethyl Sulfoxide; D000077143:Docetaxel; D008546:Melanoma, Experimental / Q000473:pathology / Q000648:ultrastructure; D008870:Microtubules / Q000187:drug effects; D008968:Molecular Conformation; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship; D043823:Taxoids
C089716:10-O-acetyl-2-O-(cyclohexylcarbonyl)-2-debenzoyltaxotere; C089718:2-O-(cyclohexylcarbonyl)-2-debenzoylbaccatin III 13-O-(N-(cyclohexylcarbonyl)-3-cyclohexylisoserinate); D000970:Antineoplastic Agents; D012996:Solutions; D043823:Taxoids; C089717:baccatin III 13-O-(N-benzoyl-3-cyclohexylisoserinate); D000077143:Docetaxel; D002725:Chloroform; D017239:Paclitaxel; D004121:Dimethyl Sulfoxide