Synthesis,Structural Modification And Structure-activity Relationship Of Sesquiterpenes And Nonactic Acid From Animal Intestinal Actinomycetes

Microorganisms are widely distributed in nature,their metabolic types are complex,and they are easy to reproduce and cultivate.Animal intestinal actinomycetes coexist and co-evolve with the host,and the secondary metabolites produced by them are various,structurally diverse,and exhibit good biological activities.They are one of the most important resources for discovering new drugs.Our research group isolated two actinomycetes from the fresh feces of zebras and pandas in Guangzhou Zoo in the early stage.After fermentation and culture,the chemical components of the fermentation broth and mycelium were purified and identified,and two secondary metabolites were obtained:norsesquiterpenoids and nonactic/homononactic acid,respectively.Pharmacological experiments showed the antiviral activity of the former and the antitumor activity of the latter.In this paper,the above two types of compounds were taken as the research objects,and the structure-activity relationship was summarized through derivatization synthesis and preliminary activity screening.For these norsesquiterpenoids,the Sybyl software was used to make virtual docking of these compounds with the hemagglutinin proteins(1RU7 and 3VUN)of influenza virus PR8 and H3N2,combined with previous pharmacological experiments,the possible antiviral target,HA2 subunit,was illustrated.The 3D-QSAR model of norsesquiterpenes was constructed by Schrodinger software,which provided theoretical guidance for further structural optimization of these compounds.On this basis,using Wieland Miescher ketone,which is similar to the natural product skeleton and commercially available,was used as raw materiala.after the reduction and protection of the carbonyl group,the protection and deprotection of the hydroxyl group,the Simmons-Smith cyclopropanation reaction and the acidolysis,a methyl group was introduced into its C-4 position with high efficiency(total yield 60%).In this process,the reaction route was designed and optimized,the problems in the reaction were improved.Moreover,synthesis of the new compound 13 was preliminarily explored.23 derivatives were synthesized and identified.Based on the previous pharmacological activity of nonactic/homononactic acid,that is,the antitumor activity of esters is higher than that of acids,fatty esters(amines)and aromatic esters(amides)with different chain lengths were synthesized by using condensing agents such as DCC and HBTU;According to the similarity of the structure with nucleoside antitumor drugs,heterocyclic derivatives were synthesized;On this basis,the inhibitory activity of synthetic compounds on HT-29,MCF-7,A375,K562 tumor cells and NCM460 normal cells was tested.Although these compounds show a trend of structure-activity relationship,their structureactivity relationship is not clear.The synthetic strategy of these derivatives will be further improved in order to make a better analysis and summary of the structureactivity relationship.