Designing Xanthohumol And Other Natural Products-directed Anti-inflammatory And Anti-cancer Agents And Exploring Their Action Mechanisms

Inflammation especially chronic inflammation plays an important role in the occurrence and development of cancer.Therefore,to some extent,inhibition of inflammation can avoid the occurrence of cancer.Also,reactive oxygen species(ROS)are closely involved in development of cancer.Compared with normal cells,cancer cells harbor higher ROS levels to maintain their malignant phenotypes such as uncontrolled proliferation,invasion,and metastasis due to carcinogen stimulation,increased metabolic activity,and mitochondrial dysfunction.As such,cancer cells are more vulnerable to prooxidant-induced further ROS production,reaching their toxic threshold.Natural products with extraordinarily diverse chemical scaffolds provide an important source of inspiration for drug discovery and development.In this work,we selected dietary xanthohumol(XN),curcumin and resveratrol as the leads to develop anti-inflammatory and prooxidative anti-cancer agents.The main contents are summarized as follows:(1)XN has been identified as a potent anti-inflammatory agent,but structural determinants and mechanisms underlying its activity remain to be elucidated.Hereby,we designed and synthesized XN and its analogues,and selected the LPS-stimulated RAW264.7 cells as a model of inflammation to probe its structural determinants and mechanisms.Structure-activity relationship studies show that the Michael acceptor unit is essential for recapitulating anti-inflammatory activity observed for XN,but its isopentene group is not necessary for the activity.Furthermore,other groups including hydroxyl and methoxyl on the two aromatic rings contribute to the Michael acceptor-dependent anti-inflammatory activity of XN possibly by assisting its binding ability to target proteins and thereby transforming the reactivity of the Michael acceptor with them into anti-inflammatory response.Mechanistic investigation implies that by virtue its Michael acceptor unit,XN exerts anti-inflammatory activity through inhibition of IKK/NF-?B signaling pathway and activation of autophagy.The inhibition of IKK/NF-?B signaling by XN is achieved at various stages by:(i)preventing phosphorylation of IKK?/?,(ii)blocking MAPKs activation and(iii)thereby stabilizing the suppressor protein IkB? and interfering with subsequent nuclear translocation of NF-?B.(2)Based on omitting a labile methylene group of curcumin,we designed and synthesized its piperidone analogs,among which CN-4F,surfaced as a lead exhibiting higher stability and cytotoxicity against NCI-H460 cells than this parent curcumin.In comparison with curcumin,this molecule was identified as a more potent Michael acceptor-type prooxidant capable of inducing higher accumulation of ROS(H2O2),leading to more effective mitochondria-dependent apoptosis and G0/G1 phase arrest,of NCI-H460 cells.(3)From an Nrf2 activation point of view,we have previously designed a catechol-type resveratrol analog(3,4-DHS)to clarify the reason why dietary polyphenols with catechol skeleton tend to exhibit cancer chemopreventive activity.Considering 3,4-DHS being a 3,4-substituted catechol,in this work,we synthesized two 2,3-substituted catechols(2,3-DHS and 2,2',3,3'-THS)to probe their anti-inflammatory activity in the LPS-stimulated RAW264.7 cells.Intersetingly,despite of 2,2',3,3'-THS bearing two catechol moieties,it was far less effective in inhibiting NO production,decreasing iNOS and COX-2 expression levels or blocking NF-?B into nucleus than 2,3-DHS bearing only one catechol moiety,probably due to its instability in vitro.