Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo

Haijun Chen, Amy A. Mrazek, Xiaofu Wang, Chunyong Ding, Ye Ding, Laura J. Porro, Huiling Liu, Celia Chao, Mark Hellmich, Jia Zhou

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 0.5 mg/kg in our proof-of-concept study using a preclinical in vivo mouse model of CP.

Original languageEnglish (US)
Pages (from-to)3393-3404
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2014

Fingerprint

Pancreatic Stellate Cells
Apigenin
Chronic Pancreatitis
Cell proliferation
Fibrosis
Cell Proliferation
Solubility
Chemical modification
Apoptosis
Derivatives
In Vitro Techniques
Pharmaceutical Preparations

Keywords

  • Apigenin
  • Apigenin analogues
  • Chronic pancreatitis
  • Fibrosis
  • Pancreatic stellate cells
  • Therapy

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. / Chen, Haijun; Mrazek, Amy A.; Wang, Xiaofu; Ding, Chunyong; Ding, Ye; Porro, Laura J.; Liu, Huiling; Chao, Celia; Hellmich, Mark; Zhou, Jia.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 13, 01.07.2014, p. 3393-3404.

Research output: Contribution to journalArticle

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