Design,Synthesis,Biological Activity Study Of Curcumin-related Compounds Containing Diphenylketone

Turmeric is a traditional Chinese medicine,the main active ingredient curcumin has various bioactivities for anti-cancer,anti-inflammatory,antioxidant,treatment of cardiovascular disease,lowering blood pressure,anti-Alzheimer's disease.Due to the presence of poor water solubility,fast metabolism and poor bioavailability in vivo of curcumin limits the application,it is an effective way to design and synthesize cucumin structure analogues with single carbonyl of curcumin analogues to solve those shortages and father improve its biological activity.Because curcumin and tetrahydrocurcumin as tyrosinase inhibition were applied in skin whitening and tyrosinase-related disease treatment,in this paper,a series of curcumin analogues was designed and synthesized with symmetrical structure and asymmetric structure of curcumin analogs based on the structure of curcumin,and the stucture of all the synthetic compounds were characterized.Meanwhile,the inhibition of the synthsized curcumin analogues against tyrosinase was determined by "compound+ tyrosinase +L-DOPA" screening sysmen,and some novel lead compounds for tyrosinse inhibition with the characteristic structure of curcumin analogues were obtained.The para-hydroxyl group of curcumin analogues was finded to be critical for the inhibition of tyrosinase by the analysis of QSAR.By inhibition kinetics studies,the mechanism of the tyrosinase inhibition of curcumin analogues were found to be belonged to the mixed inhibition type.Using computer-aided molecular docking,it is found that the space and phenolic hydroxyls of curcumin molecular can be easily docked and binded to the active pocket of tyrosinase.At the same time,in this paper,a series of new curcumin analogues was designed and synthesized based on the computor-aided 3D-QSAR analysis of previous sythesized cucrumin analogues by our group and their by anti-cancer activety.In particular,some novel curcumin analogue with surfur atom were designed and synthesized in the three characterestic moities of molecule sketone based on the previous 3D-QSAR and the stucture optimization of lead compound F10,and their anti-cancer activety was determinded.The results showed that experimental data could match the computor predict data,and the substituent on the phenyl ring of curcumin analogues was the critical for anti-cancer antivity,more methoxyl substituent,more contribution to improvement of anti-cancer activity.Meanwhile,the different degrees of oxidation of the sulfur in the tetrahydrothiopyran moity can keep the same level activity of lead compound for anti-cancer activity.In brief,in this paper,the inhibition and mechanism of curcumin analogues agaist tyrosinase were systematically studied,and novel lead compounds for anti-cancer were obtained through structural optimization guided by computer-aided 3D-QSAR and molecule design,which provides a theoretical and experimental basis for further development of tyrosine inhibitors and anticancer drug candidates.