Design and synthesis of biphenyl derivatives as mushroom tyrosinase inhibitors.
Two new series of biphenyls, analogs of aglycone of natural product fortuneanoside E, were prepared using Suzuki-Miyaura cross-coupling and selective magnesium iodide demethylation/debenzylation, and their mushroom tyrosinase inhibitory activity was evaluated. Most of the 4-hydroxy-3,5-dimethoxyphenyl biphenyl compounds (series II, 20-36) were in general more active than 3,4,5-trimethoxyphenyl biphenyl compounds (series I, 1-19). Structure-activity relationships study showed that monosaccharide substituents, such as glucose, were not necessary and the presence of 4-hydroxy-3,5-dimethoxyphenyl moiety was crucial for inhibitory activity. Among the compounds synthesised, compound 21 (IC50=0.02 mM) was found to be the most active one, which exhibited an activity that was 7 times higher than that of fortuneanoside E (IC50=0.14 mM) and 10 times higher than that of arbutin (IC50=0.21 mM), known as potent tyrosinase inhibitors. The inhibition kinetics analyzed by Lineweaver-Burk plots revealed that compound 21 was a competitive inhibitor (Ki=0.015 mM).
Bao
Kai
K
Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510632, PR China.
Dai
Yi
Y
Zhu
Zhi-Bin
ZB
Tu
Feng-Juan
FJ
Zhang
Wei-Ge
WG
Yao
Xin-Sheng
XS
D000363:Agaricales / Q000201:enzymology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D014442:Monophenol Monooxygenase; D012459:Salicylates; C554530:3,4'-dihydroxy-3',5'-dimethoxybiphenyl-4-carboxylic acid; C010574:biphenyl