Synthesis And Research Of Nitrostyrene And Xanthone Compounds Targeting Nuclear Receptors RXRα And ERα

Nuclear receptors have become an increasingly important target for drug development.Retinoid X receptor(RXR)and estrogen receptor(ER)are both very important members of the nuclear receptor superfamily,which also play an important role in the process of cell and life activity.The previous research found that the Nitro derivatives Z10 and xanthone derivatives NOR extracted from anoectochilus have good binding and transcriptional activity to RXRa and ERa,respectively.To further investigate its structure-activity relationship,derivatives of Z10 and NOR were designed and synthesized in this paper.To expand the synthesis of nitroalkenes substrates,the novel synthesis method of nitroalkene was also studied in this paper,using alcohol as raw material.The methodology for research is to find a reagent that can be directional oxidation of alcohol and catalyze the Henry reaction.Through a mass of research,we have found that the grinding of CrO3 and nano-SiO2 as oxidation-catalytic reagents,and a way to synthesize nitroalkenes in one step with alcohol as raw material.What’s more,the yield is optimized from 0 to 61.5%.This provides method support for the synthesis of more nitroalkenes.46 derivatives were designed with Z10 as the parent nucleus,and then 30 compounds were isolated and purified with yield from 23%to 88%.The structure of compounds was verified by 1H-NMR,13C-NMR,HR-MS,while the purity was verified by HPLC or GC.Through related data of biological experiments,we summarized the structure-activity relationship of nitroalkenes:the replacement of position 2 in Z10 has better binding and transcriptional activation activity for RXRa than the replacement of position 4.Replacement of hydrocarbon oxygen at position 2 and position 4 of Z10 is superior to other substituents.The ethoxy-substituted derivative Z36 at position 2 of Z10 has better activity than other derivatives and has a certain therapeutic effect on Alzheimer’s disease(AD)mice.In this paper,the synthetic route of natural product NOR was determined by inverse synthesis analysis method.After three steps of reaction,the total yield of NOR was 27%.In order to study the structure-activity relationship,five derivatives of NOR-directed defunctionalization groups were designed and synthesized(respectively removing the 8-position methyl group,1,3,and 6-position hydroxyl groups and breaking the ether bond).The total yield of five derivatives was from 7%to 65%.We preliminarily draw a conclusion that NOR-2,the 8-methyl derivative of NOR,also activated ERa transcription activity,which was slightly weaker than NOR.The structure-activity relationship of other derivatives is still under study.