Studies of paclitaxel analogs modified in ring C
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The structurally novel diterpenoid paclitaxel (Taxol®), originally isolated from Taxus brevifolia, is one of the most promising new anticancer drugs. Its structural complexity and unique biological activity have provided the impetus for a number of structure-activity relationship (SAR) studies for the last twenty years, with the aim of developing analogs with improved bioactivity. Because of the absence of information on the structure-activity relationship of the C-6 position and the ring C skeleton of paclitaxel, it was goal of this research to synthesize paclitaxel analogs modified in ring C in order to evaluate the effects of these modifications on biological activity and to reveal the chemistry of paclitaxel. The inactivity of the C-6 methylene group towards chemical modifications has been overcome by the formation of a double bond at the C- 6 and C-7 positions. Modification of the C-6 position has been achieved for the first time and over 20 new paclitaxel analogs modified at both the C-6 and C-7 positions have been synthesized. Biological evaluation of these compounds reveal that the C-6 and C-7 positions do not play significant roles in the biological activity of paclitaxel, although the two deoxygenated paclitaxel analogs, 7-deoxy-6Î±-hydroxypaclitaxel and 7,lO-dideoxy-6ahydroxypaclitaxel, were found to be more active than paclitaxel. Modification of the ring C skeleton has been accomplished for the first time, and several new C-nor-paclitaxel analogs have been synthesized. Biological evaluation showed that these C-nor-paclitaxel analogs were less active than paclitaxel, indicating that the ring C skeleton plays a crucial role in the biological activity of paclitaxel. Biological evaluation also showed that all oxetane ring-opened paditaxel analogs were essentially inactive. These results indicate that changes in the size and conformation of ring C and the attached oxetane ring make a significant contribution to the activity of paclitaxel.
- Doctoral Dissertations