Synthesis and structure–activity relationships of taxuyunnanine C derivatives as multidrug resistance modulator in MDR cancer cells

New taxoids bearing a bulky acyloxy group at C-2, C-5, C-7, C-9, C-10, and C-14 were obtained by chemical and bio- transformations of taxuyunnanine C and its analogs. In them, compounds 3, 5, 6, 8, and 9a have significant effects of the accumulation of calcein in MDR 2780AD. Since compounds 6 and 8 have no cytotoxic activity, they are desirable compounds as MDR cancer reversal agent. Since compounds 3, 5, and 9a have moderate cytotoxic activity, they are expected to be lead compounds of new-type anticancer agents. A series of new generation taxoids bearing a bulky group on different positions such as C-2, C-5, C-7, C-9, C-10 or C-14 were obtained by chemical modifications and biotransformation of taxuyunnanine C ( 1) and its analogs, 4, 5, and 10. Compounds 3, 5, 6, 8, and 9a showed significant activity toward calcein accumulation in MDR 2780AD cells. The most effective compound 9a with a cinnamoyloxy group at C-14 and a hydroxyl group at C-10 was actually efficient for the cellular accumulation of the anticancer agent, vincristine, in MDR 2780AD cells. The enhancing effects of 6 and 9a for taxol, adriamycin, and vincristine were at the same levels as those of verapamil toward MDR 2780AD cells. Thus, compounds 6 and 9a can modulate the multidrug resistance of cancer cells. The cytotoxicity (IC 50) of the compounds was examined against human normal cell line, WI-38, and cancer model cell lines, VA-13 and HepG2. Since compounds 6 and 8 had no cytotoxicity, they were expected to be lead compounds of MDR cancer reversal agents. On the contrary, compounds 3, 5, and 9a showed cell growth inhibitory activity toward VA-13 and/or HepG2 as well as accumulation activity of calcein and/or vincristine in MDR 2780AD and they were expected to be lead compounds of new-type anticancer agents.