Synthesis and biological activity of C-6 and C-7 modified paclitaxels

Structure modification of paclitaxel at the C-6 and C-7 positions has been achieved using the readily available intermediate 6 alpha-hydroxy-7-epipacl itaxel (2). While a single diastereomer of the cyclic sulfite of 2 was prep ared at lower temperature, both diastereomers were obtained at room tempera ture. The cyclic sulfate was found to be inert toward nucleophilic attack, which confirms the great steric hindrance of the beta-face of the C-6 and C -7 region of paclitaxel. Derivatization at the 6 beta-position with a nitro gen-containing function was accomplished using the alternate substrate 6 al pha-trifluoromethanesulfonate (9), with the 7-epi hydroxyl group protected to avoid the formation of C-ring rearranged product. Hydrogenation of the 6 beta-azide was difficult but could be achieved in moderate yield under hig h pressure. Similar to other C-6 and C-7 modified analogs reported earlier, these new compounds displayed comparable in vitro cytotoxicity to paclitax el against the HCT116 human colon cancer cell line and the A2780 human brea st cancer cell line. (C) 2000 Elsevier Science Ltd. All rights reserved.