Metabolism-based synthesis, biologic evaluation and SARs analysis of O-methylated analogs of quercetin as thrombin inhibitors.
In blood, quercetin is mainly found in metabolized forms. In order to study the activities of these quercetin metabolites in cardiovascular disease, 17 methylquercetin derivatives were synthesized based on metabolism in vivo, their thrombin inhibition activity were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). The results showed that 6 methylquercetin derivatives had stronger inhibitory activities than that of quercetin. Preliminary SARs analysis showed that hydroxyl groups at C-3' and C-4' position in the B-ring and hydroxyl group at C-3 position in the C-ring played key roles in the thrombin inhibitory activity. The findings of this study would provide information for the exploitation and utilization of quercetin as thrombin inhibitor for thrombotic disease treatment.
Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, China.
Zhi-Hao
ZH
Shi
Nian-Guang
NG
Li
Yu-Ping
YP
Tang
Wei-Li
Lian-Yin
Jian-Ping
JP
Yang
Hao-Tang
Jin-Ao
JA
Duan
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D060326:Chemistry Techniques, Synthetic; D005340:Fibrinogen / Q000378:metabolism; D008297:Male; D008745:Methylation; D062105:Molecular Docking Simulation; D010100:Oxygen / Q000737:chemistry*; D011487:Protein Conformation; D011794:Quercetin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000925:Anticoagulants; D005340:Fibrinogen; D011794:Quercetin; D013917:Thrombin; D010100:Oxygen