The Synthesis And Anti-Live Fibrosis Activity Of Benzoquinone Imide Derviatives

There are many pharmacophores in natural products,and quinones are a very important natural compound.They have a conjugated diketone structure and have redox properties.They can reversibly hydrogenate and dehydrogenate,and participate in the reaction through electron transfer processes.The redox process in the cells has a certain biological activity.Liver fibrosis is a self-repairing reaction after the liver is injured by many chronic inflammatory stimuli,and it is a necessary stage for many chronic liver inflammations or liver diseases to become cirrhosis.Therefore,the synthesis of a series of new quinones by adjusting the redox potential,and the exploration of its anti-fibrotic activity is very meaningful.In this paper,a series of new benzoquinone imine compounds were synthesized.Through the in vitro experiments,the mouse macrophages(RAW264.7)were used to study its partial activity against hepatic fibrosis.Methods:(1)Taking into account the effect of oxygen-reducing properties on the activity,the replacement of an oxygen atom with a nitrogen atom that having a weaker electronegativity than oxygen atom,to modulates the redox potential of the compound,thereby changing its redox properties.The two carbonyl oxygen atoms in phenylhydrazine do not have derivatization potential,and the use of nitrogen atoms instead of oxygen atoms allows them to be directly derivatized on the bulk of the oxime.The linking of alkyl and triphenylphosphine changes its membrane permeability and targeting properties,and synthesizes new benzoquinone imine derivatives;(2)Examines phenylhydrazine imine derivatives on mouse macrophages by CCK-8 experiment Toxic,select the appropriate concentration for the next experiment;(3)Determine NO content by Griess reagent,and detect ROS by laser confocal microscopy;(4)Detect interleukin the content of IL-1β and IL-1α by ELISA kit.;(5)The expression of FLIP and caspase-3 was examined by Western blotting.Results:(1)NBQ,NBQ’,ENBQ’,and PNBQ’ derivatives were successfully synthesized;(2)IC50(half inhibitor concentration)values were TQ:6.932 μM,NBQ:10.019μM,NBQ’:9.208μM,ENBQ’:4.852μM,PNBQ’:8.723μM;(3)Four compounds can reduce the content of oxidants in cells;(4)Four compounds can reduce the content of IL-1α and IL-1β;(5)The four compounds all inhibited the expression of FLIP protein.Compared with the LPS group,the inhibitory effect of PNBQ’ was over 50%.At the same time,they both promoted the activation of caspase-3 and induced the mouse macrophage apoptosis.Among them,the role of PNBQ’ is most obvious,reaching more than 40%.Conclusion:Four compounds with stronger antioxidant properties have been successfully synthesized.In vitro experiments have shown that the new compounds NBQ,NBQ’,ENBQ’,and PNBQ’ can inhibit inflammatory cell activity by reducing oxidants and inflammatory factors,and reduce inflammation by inhibiting FLIP expression,promoting caspase-3 activation,and promoting inflammatory cell apoptosis.The reaction has potential anti-fibrotic activity.