Study On Effects Of Nitrogen/sulfur-containing Block On The Biological Activity Of Isopimaric Acid

Isopimaric acid is a kind of important pimaric type resin acid isolated from rosin acid.Isopimaric acid has a variety of biological activities,and its chemical structure containing carboxyl and double bond functional group.Therefore,it can be used as chemical intermediates or its structure as a pharmacological activity center to develop new type of isopimaric acid derivatives with more widely and high biological activity through modification or transformation of its structure,which has a great significance to improve the utilization rate of isopimaric acid and rosin.In this study,four block structures(amide,acylhydrazone,thiourea and sulfonamide)containing nitrogen/sulfur heteroatoms were constructed and introduced into isopimaric acid molecule,and synthesized 57 isopimaric acid derivatives with isopimaric acid as the parent molecule and the carboxyl group as the reaction sites.The structures of isopimaric acid derivatves were characterized and identified by FT-IR,1H NMR,13 C NMR,HRMS and elemental analysis.Atimicrobial activities of isopimaric acid derivatives against Staphylococcus aureus,Escherichia coli and Candida albicans were tested by broth dilution method.Results showed that all the isopimaric acid derivatives showed poor inhibitory activity than isopimaric acid against two bacteria.However,most of the amide,acylhydrazone and thriourea derivatives of isopimaric acid exhibited better inhibitory activity than isopimaric acid against Candida albicans.Amone all the three series of isopimaric acid derivatives,compound 2e with MIC value of 3.9 mg/L showed the same inhibitory activity as the positive control rifampicin.In addition,the MIC values of compounds 2j,3i and 4l against Candida albicans were 7.8 mg/L,and they also showed significant inhibitory activity.Several of the above compounds are expected to be used as a precursor structure for the molecular structure design of isopimaric acid derivatives with antifungal activity.The cells proliferation inhibitory activitives of four series of isopimaric acid derivatives against four human tumor cells(HepG-2,MDA-MB-231,PC-3 and Hela)were evaluated by MTT method.The results showed that some amides,acylhydrazones and sulfonamides showed better anticancer activity than isopimaric acid.Among these compounds,3b with IC50 value5.79 μmol/L against HepG-2 cells,showing a better anticancer effect than the positive control drug taxol and 5-FU,and it also exhibited strong inhibitory effects on MDA-MB-231 and PC-3cells,with the IC50 values 18.63 and 10.51 μmol/L,respectively;in addition,compound 2d with IC50 value 15.80 μmol/L against HepG-2 cells,3j with IC50 values 8.04 and 18.48 μmol/L against MDA-MB-231 and PC-3,respectively,these two compounds also showed strong anticancer activities.The structure-activity relationship between the block structure and the antifungal activity of the isopimaric acid derivatives against Candida albicans was studied.It was found that the introduction of substituents on the heterocyclic group introduced with splicing substructures which led to the increase of the antifungal activity of isopimaric acid.When the phenyl was introduced with splicing substructures,the introduction of substituents on the amides phenyl group which usually can further improve the antifungal activity of isopimaric acid;when the substituents were introduced on the acylhydrazone phenyl group,the partial sunstituents can further improve the antifungal activity of isopimaric acid;when the substituents were introduced on the thiourea phenyl group,most of them can’t be further improve the antifungal activity of isopimaric acid.Among all the compounds,the introduction of OCH3 and chloro atom on the amides pyrimidine group showed the greatest contribution to the antifungal activity of isopimaric acid,and the antifungal activity of isopimaric acid was improved to 16 times.In addition,a fluorine atom was introduced at the ortho-position of phenyl group of the amide or acylhydrazone,and a CH3 was introduced on the amide thiazole group,made the antifungal activity of isopomaric acid increased to 8 times.The structure-activity relationship between the block structure and the anticancer activity of the isopimaric acid derivatives on the anticancer activity of four human tumor cells was studied.The results showed that the introduction of amide and acylhydrazone on the moleculesof isopimaric acid had partially broadened the range of effective anticancer activity of isopimaric acid,and the introduction of sulfonamide on the molecules of isopimaric acid generally widened the range of effective anticancer activity of isopimaric acid.It was found that the introduction of substituents on the heterocyclic group introduced with splicing substructures which led to the increase of the antifungal activity of isopimaric acid.When the phenyl was introduced with splicing substructures,the introduction of electron-withdrawing substituents on the phenyl group were generally enhanced the anticancer activity isopimaric acid,and some of the electron donor groups were beneficial to improve the anticancer activity of isopimaric acid.Among them,anticancer activitives of isopimaric acid against HepG-2,MDA-MB-231 and PC-3 cell lines were enhanced by the introduction of OH in the prtho-position acylhydrazone phenyl group.In addition,the introduction of two OCH3 on the amide pyrimidine group also improved the anticancer activity of isopimaric acid against HepG-2 cells,and the introduction of a NO2 at the ortho-position of acylhydrazone phenyl group increased the anticancer activity of isopimaric acid against MDA-MB-231 and PC-3 cells.