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 R. Hellmich, Jia Zhou

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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

Bibliographical note

Funding Information:
This work was supported by grants P50 CA097007, P30 DA028821, R21 MH093844 (J.Z.), T32 DK007639-21 (M.R.H.) and K08 CA125209 (C.C.) from the National Institutes of Health, R.A. Welch Foundation Chemistry and Biology Collaborative Grant from the Gulf Coast Consortia (GCC), John Sealy Memorial Endowment Fund, Institute for Translational Sciences (ITS), and the Center for Addiction Research (CAR) at UTMB. We thank Drs. Lawrence C. Sowers, Jacob A. Theruvathu, and Tianzhi Wang for the NMR spectroscopy assistance, and Dr. Carol Nilsson for mass spectrometry assistance.

Keywords

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

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