PMID: 7932561Sep 30, 1994Paper

The effect of the aromatic rings of taxol on biological activity and solution conformation: synthesis and evaluation of saturated taxol and taxotere analogues

Journal of Medicinal Chemistry
T C BogeG I Georg

Abstract

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 ...Continue Reading

Citations

Mar 16, 2002·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·M L Miller, I Ojima
May 29, 2002·Bioorganic & Medicinal Chemistry Letters·Wei-Shuo FangQi-Cheng Fang
Oct 26, 1999·Bioorganic & Medicinal Chemistry·E J RohS U Choi
Apr 20, 2001·Proceedings of the National Academy of Sciences of the United States of America·J P SnyderE Nogales
Oct 9, 2012·Drug Development and Industrial Pharmacy·Madhushree GokhaleFrank Rinaldi
Sep 1, 2008·Expert Opinion on Drug Discovery·Wei-Shuo Fang, Shao-Rong Wang
Oct 2, 2004·Journal of Pharmaceutical Sciences·M JumaaV J Stella
Aug 6, 2013·Current Opinion in Solid State & Materials Science·Rong TongJianjun Cheng

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