Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1).
Tryptophan hydroxylase 1 (Tph-1) initiates the biosynthesis of peripheral serotonin. As peripheral serotonin suppresses bone formation, inhibitor of Tph-1 provides a useful tool to discover anabolic agents for osteoporosis. In the present study, series of ursolic acid (UA) derivatives were synthesized, and their inhibitory activity on serotonin biosynthesis and cytotoxicity were evaluated. Among the derivatives, 8d with potent inhibitory activity on serotonin was applied for further research. The data revealed that 8d significantly inhibited protein and mRNA expressions of Tph-1, and an SPR study indicated that 8d directly interacted to Tph-1 with a binding affinity of KD=15.09μM. Oral administration of 8d significantly prevented bone loss via suppressing serotonin biosynthesis without estrogenic side-effects in ovariectomized (OVX) rats.
State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China.
Hai-Jian
HJ
Fu
State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China.
Yang
Y
Zhao
State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China.
Yu-Ren
YR
Zhou
State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China.
Bei-Hua
BH
Bao
State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China.
Yun
Y
Du
State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China. Electronic address: lijxnju@nju.edu.cn.
Jian-Xin
JX
Li
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D062105:Molecular Docking Simulation; D010012:Osteogenesis / Q000187:drug effects*; D015663:Osteoporosis, Postmenopausal / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D010052:Ovariectomy; D011485:Protein Binding; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis* / Q000097:blood; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000097245:Ursolic Acid
D050071:Bone Density Conservation Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D012701:Serotonin; D014315:Triterpenes; D014365:Tryptophan Hydroxylase; D000097245:Ursolic Acid; C504570:tph1 protein, rat
Bone formation; Serotonin; Tryptophan hydroxylase 1 (Tph-1); Ursolic acid derivatives