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

doi:10.1016/j.bmc.2014.04.043

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 journal › Article › peer-review

33 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 language	English (US)
Pages (from-to)	3393-3404
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	13
DOIs	https://doi.org/10.1016/j.bmc.2014.04.043
State	Published - Jul 1 2014
Externally published	Yes

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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Chen, H., Mrazek, A. A., Wang, X., Ding, C., Ding, Y., Porro, L. J., Liu, H., Chao, C., Hellmich, M. R., & Zhou, J. (2014). Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Bioorganic and Medicinal Chemistry, 22(13), 3393-3404. https://doi.org/10.1016/j.bmc.2014.04.043

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

Research output: Contribution to journal › Article › peer-review

Chen, H, Mrazek, AA, Wang, X, Ding, C, Ding, Y, Porro, LJ, Liu, H, Chao, C, Hellmich, MR & Zhou, J 2014, 'Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo', Bioorganic and Medicinal Chemistry, vol. 22, no. 13, pp. 3393-3404. https://doi.org/10.1016/j.bmc.2014.04.043

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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.",

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

Abstract

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Keywords

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