Design,synthesis And Bioactivity Study Of Chrysamide B And Its Derivatives

Marine natural products are an important source of lead compound discovery and new drug research.The drugs developed on this basis have been applied to the treatment of cancer,infection and cardiovascular diseases,and research in anti-inflammatory and anti-tumor areas in particular is booming.Chrysamide B,a novel dimer of nitrophenyl trans-epoxyamide,was isolated from the deep-sea fungus Penicillium chrysogenum SCSIO41001.Due to the multiple plasticity structural characteristics such as the special three-dimensional shape,the dimer skeleton and the specific functional group substitution,it is possible a potential bioactive compound,but the preliminary evaluation showed that its anti-inflammatory and anti-tumor activities were weak.The low content,the weak activity of preliminary screening,as well as the narrow and shallow range of activity evaluation of natural products is a limiting reason for the transition to new drug research.Large-scale synthesis and derivatization of natural products based on chemical synthesis is an effective and necessary means to solve these problems.In this research,aiming to discover and improve its anti-inflammatory and anti-tumor activity and based on our previous works of its total synthesis,we selected the marine natural product Chrysamide B as the parent compound.After large-scale synthesis and derivatization by chemical synthesis,the anti-inflammatory activity of Chrysamide B and the anti-tumor activity of the derivative b-9 with Chrysamide B as the lead structure were found by broadening the screening range of anti-inflammatory and anti-tumor activity.These provide an idea for the development and utilization of these compounds.The specific content includes the following two parts:Part 1: Studies on anti-inflammatory activity of Chrysamide B as a novel nitric oxide production inhibitor.In order to discover and improve the anti-inflammatory activity of Chrysamide B,the optimized total synthesis route was adopted to realize the large-scale synthesis of Chrysamide B,and the screening range of anti-inflammatory activity was broadened by evaluating its influence on a variety of inflammatory mediator production.The result showed that Chrysamide B had a good antiinflammatory activity to inhibit LPS-induced nitric oxide NO production,which might be a novel inhibitor of dimerization of inducible nitric oxide synthase i NOS.The mechanism may be to inhibit the activity of i NOS by interfering with the dimerization of i NOS,thus inhibiting the production of excessive NO.Moreover,further evaluation of anti-inflammatory activity in vivo showed that it could significantly improve the paw edema induced by carrageenan in rat and the septic inflammation induced by LPS in mice.In conclusion,combined with the evaluation of internal and external antiinflammatory activity,the results indicated that Chrysamide B may be a new antiinflammatory active compound.Part 2: Studies on anti-tumor activity of Chrysamide B and derivatives.In order to find and improve the anti-tumor activity of Chrysamide B and derivatives,by using the classical modification strategies of group substitution and skeleton transformation,the three-dimensional shape,the dimer skeleton,the para-nitro substitution on the C-ring and the methyl substitution on the B-ring,at Chrysamide B were modified to obtain a series of derivatives,which realized the large-scale synthesis and derivatization of the natural products.Then,MTT assay was used to evaluate their cytotoxic effects on 5human cancer cell lines（MGC-803,SGC-7901,Hep G2,MCF-7,HCT-116）,which expanded the screening range of antitumor activity.Through the summary of structureactivity relationship,it was found that the activity of most of the compounds increased,among which compound b-9 had the best activity.Subsequently,with the compound b-9 as the target compound,a number of anti-tumor experiments in the sensitive gastric cancer MGC-803 and SGC-7901 cells were carried out,including cell proliferation assay,cell apoptosis assay,cell migration and invasion assay,immunoblot and immunofluorescence assay.The result revealed that compound b-9 can significantly affect a variety of biological characteristics of the above experimental cell lines,including inhibiting their unrestrained proliferation,reducing their ability of migration and invasion,and inducing their mitochondrial pathway apoptosis through the JAK2/STAT3/Bcl-2 pathway,so that it has a good anti-tumor effect.In conclusion,the above experimental analysis indicated that compound b-9 may be a novel antitumor activity compound.