Synthesis of rotenoid derivatives with cancer and topoisomerase II inhibitory activities

Abstract

To investigate the structure-activity relationship of rotenoid compounds on cytotoxicity and topoisomerase II inhibition. It has been reported that 6-deoxyclitoriacetal, a rotenoid substance extracted from the dried root of Stemona collinse Craib., showed strong cytotoxic activity against various human cell lines and better than that of doxorubicin as a commercial anticancer drug. In this work, 6-deoxyclitoriacetal was converted to epoxide derivative by reacting with epichlorohydrin. The epoxide derivative was ring-opened with nucleophiles, morpholine and benzylamine compounds. All derivatives were tested for their cytotoxicity against KB, MCF-7, and NCI-H187 cell lines. In addition, the topisomerase II inhibitory assay were evaluated using doxorubicin and etoposide as references. It has been found that the epoxide derivetives (2) showed strong cytotoxicity against all three cell lines with IC50 of 2.87, 7.33, and 3.21 μg/ml for KB, MCF-7, and NCI-H187, respectively. Diethanolamine containing 6-deoxyclitoriacetal (10) was inactive for all three cell lines. The morpholine derivatives of 8 and 9 showed strong activity against NCI-H187 with IC50 of 2.93 and 4.70 μg/ml, respectively. In order to enhance bioavailability of the synthesized compounds, an acid addition salt of 8 was prepared by adding strong hydrochloric acid. The salt of morpholine containing 6-deoxyclitoriacetal hydrocholide showed stronger cytotoxicity against KB and NCI-H187 with IC50 of 0.68 and 0.63 IC50 μg/ml, respectively, than that of its free base (IC50 = 13.28 and 3.12 μg/ml, respectively. Its salt also has a stronger cytotoxity against KB than that of doxorubicin (IC50 = 2.01 μg/ml). From results of topoisomerase II assay revealed that most of 6-deoxyclitoriacetal inhibited topoisomerase II with %inhibition rate over 50%, except for 5 and 9 cannot be complete inhibited the activity of topoisomerase II activity. The morpholine derivative 8 at 100 μg exerted the most potent topoisomerase II enzyme with 93.5%inhibition