Synthesis And Tyrosinase Inhibition Activities Of Curcumin Analogues

Tyrosinase is a multifunctional copper-containing enzyme widely distributed in animals and plants, it performs very important role in the metabolism of tyrosine and other phenolic compounds as well as in the biosynthesis of melanin. It is the key enzyme involes in the human body pigmentation sickness, oxidation of vegetables and insect ecdysis. Therefore, tyrosinase inhibitors have become increasingly important in cosmetic industry, medication, food protection and insect plague control. Curcumin is the mian active constitute of turmeric and is noted for its widespread biological activities, it was reported that curcumin had the ability to suppress melanophore cell B16 and had tyrosinase inhibition activity.However various limitations are associated with curcumin, such as low stability in formulation, low bioavilability and medium tyrosinase inhibition activity, which limit its practical application. In order to find leading compounds as potential drugs, it is necessary to carry out some modification to its structure.With curcumin as the lead compound this paper synthesized a series of enone analogues of curcumin.These included:(1) curcumin analogues with a 5-carbon spacer and a carbonyl group; (2) curcumin analogues with a 5-carbon spacer and a carbonyl group, introducing a saturated five-membered ring, a saturated six-membered ring or heterocyclic ring; (3) unsymmetrical curcumin analogues with a 5-carbon spacer and a carbonyl group or a carbonyl group with a saturated five-membered ring. The tyrosinase inhibition activities of all the synthesized compounds were tested using L-DOPA as substrate, the dynamics process of some of the compounds that had the most potent abilities and typical structures were studied.The tyrosinase inhibition test of the symetrical curcumin analogues demonstrated that the number and position of the phenolic hydroxyl groups played major role in the inhibition activities of these compounds. When the aromatic ring had a mono phenolic function, the phenolic hydroxyl located at the 4-position of the aromatic ring possessed more potent inhibitory activity than that placed on the 2-position, and the properties of the substitution groups on the ortho position of the 4-phenolic hydroxyl group had much influence on their abilities, small volume and electronic donating group (OH) could greatly increase the activity, introducing a OCH3, C(CH3)3 or Br group induce the ability decreased.When the aromatic ring had a diphenols function, the activity increased greatly compared with that contain a mono one, and the compounds that contain a para-diphenols (2,4-dihydroxy) groups displayed more potential tyrosinase inhibition than that bear an ortho-diphenols (3,4-dihydroxy) groups. The ketone linker between the aromatic rings had little influence on their abilities, the activity trend of all the five series were a>b>d>c>e.Compared with the symmetrical curcumin analogues, the unsymmetrical analogues had the same structure and activity relationship with a bit difference, the inhibition activities of compounds 3e and 4e with o-dimethoxyphenoxyl group on the B ring were better than the compounds 3b and 4b with o-methoxyphenoxyl group on the B ring, which needed further study.Inhibition kinetics study indicated that the tyrosinase inhibition type of compounds a6 and b6 with ortho-diphenols group and 3c with 4-phenolic hydroxyl group on the A ring and ortho-diphenols group on B ring were non-competitive; compounds b11 with para-diphenols group and 3d with 4-phenolic hydroxyl on the A ring and a para- diphenols group on the B ring were competitive; compound 3i with a 4-OH-3-OCH3 group on the A ring and an o-diphenols group on the B ring was mixed type.