Synthesis Of Piperlongumine Analogs And Study On Their Structure-activity Relationship Of Cancer Chemoprevention

Cancer, a disease that seriously threatens human health, is one of the leading causes of death. Chemotherapy is one of the main means for treatment of cancer, and discovery of effective anticancer agents for the chemotherapy is thus of great importance. Piperlongumine, a naturally product isolated from rhizomes of Piper longum Linn, was recently identified as an electrophile to be toxic selectively to cancer cells by promoting generation of cellular ROS. Therefore, to find more active anti-cancer agents than piperlongumine, we synthesized more than thirty analogs and evaluated their antiproliferative activity against cancer cells, thioredoxin reductase (TrxR)-and cytochrome P450 family 1(CYP1)-inhibitory activities. Here we found from the study of structure-activity relationship (SAR) that:(1) Compared to this parent molecule, piperlongumine analogs (PL-ON and PLC1) show slightly high or equal ability in inhibiting human lung cancer (NCI-H460), hepatoma (HepG2) and sarcoma (HT1080) cells; Michael acceptor moieties in and outside the ring contributes to the observed effects on cells, and the former is more important for cell growth inhibition than the latter; Substituent groups on the aromatic ring have a little impact upon antiproliferative activity of piperlongumine.(2) Piperlongumine is a potent TrxR inhibitor, and inhibited this target for cancer therapy more effectively than curcumin, an active ingredient of turmeric powder. Moreover, its Michael acceptor moieties in and outside the ring, aromatic ring and three methoxy groups jointly contribute to the effective inhibition of TrxR.(3) Piperlongumine could selectively inhibit CYP1A1 and CYP1B1 and has no any activity against CYP1A2 under the same conditions. The SAR study reveals that its Michael acceptor moieties in and outside the ring, aromatic ring and three methoxy groups is critical for the inhibition.