Synthesis and Antitumor Activity of Fluorouracil - Oleanolic acid/Ursolic acid/Glycyrrhetinic acid Conjugates

As the obvious adverse effects of 5-FU limit its clinical usefulness, and the biodiversity activities of pentacyclic triterpenes, twelve pentacyclic triterpene-5-FU conjugates were synthesized and evaluated their antitumor activity. The results outlined that all the single substitution targeted hybrids (7a-12a) possessed much better antiproliferative activities than the double substitution targeted hybrids (7b-12b). Hybrid 12a exhibited good antiproliferative activities against all the tested MDR cell lines. Furthermore, it was revealed that 12a could induce intracellular calcium influx, the generation of ROS, arrest the cell proliferation at the G1 phase, and activate the apoptotic signaling caspase-8, which eventually activate the apoptotic effector caspase-3 and cause the later nuclear apoptosis.