Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo.
Accumulating evidence suggests that activated pancreatic stellate cells (PSC) play an important role in chronic pancreatitis (CP), and inhibition of the activated PSC is considered as a potential strategy for the treatment and prevention of CP. Herein, we disclose our findings that apigenin and its novel analogues suppress the proliferation and induce apoptosis in PSC, which reduce the PSC-mediated fibrosis in CP. Chemical modifications of apigenin have been directed to build a focused library of O-alkylamino-tethered apigenin derivatives at 4'-O position of the ring C with the attempt to enhance the potency and drug-like properties including aqueous solubility. A number of compounds such as 14, 16, and 24 exhibited potent antiproliferative effects as well as improved aqueous solubility. Intriguingly, apigenin, new analogues 23 and 24 displayed significant efficacy to reduce pancreatic fibrosis even at a low dose of 0.5mg/kg in our proof-of-concept study using a preclinical in vivo mouse model of CP.
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
Haijun
H
Chen
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States.
Amy A
AA
Mrazek
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States.
Xiaofu
X
Wang
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
Chunyong
C
Ding
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
Ye
Y
Ding
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States.
Laura J
LJ
Porro
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
Huiling
H
Liu
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States.
Celia
C
Chao
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: mhellmic@utmb.edu.
Mark R
MR
Hellmich
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.
Jia
J
Zhou
D047310:Apigenin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005355:Fibrosis / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D015394:Molecular Structure; D058954:Pancreatic Stellate Cells / Q000166:cytology / Q000187:drug effects*; D050500:Pancreatitis, Chronic / Q000188:drug therapy* / Q000473:pathology; D012995:Solubility; D013329:Structure-Activity Relationship
D047310:Apigenin
Apigenin; Apigenin analogues; Chronic pancreatitis; Fibrosis; Pancreatic stellate cells; Therapy