Citation: Zhexin Chen, Yuqing Shi, Fang Zhong, Kai Zhang, Furong Zhang, Shenghong Xie, Zhongbin Cheng, Qian Zhou, Yi-You Huang, Hai-Bin Luo. Discovery of amentoflavone as a natural PDE4 inhibitor with anti-fibrotic effects[J]. Chinese Chemical Letters, ;2025, 36(4): 109956. doi: 10.1016/j.cclet.2024.109956 shu

Discovery of amentoflavone as a natural PDE4 inhibitor with anti-fibrotic effects

Zhexin Chen ^{a, 1} ,
Yuqing Shi ^{a, c, 1} ,
Fang Zhong ^a ,
Kai Zhang ^{a, c} ,
Furong Zhang ^{a, c} ,
Shenghong Xie ^a ,
Zhongbin Cheng ^a ,
Qian Zhou ^{a, *,} ,
Yi-You Huang ^{a, *,} ,
Hai-Bin Luo ^{a, b, *,}

a.
Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
b.
Song Li’ Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Sanya 572000, China
c.
School of Life and Health Sciences, Hainan University, Haikou 570228, China

zhouqian@hainanu.edu.cn

hyyou@hainanu.edu.cn

hbluo@hainanu.edu.cn

Received Date: 15 March 2024
Revised Date: 26 April 2024
Accepted Date: 30 April 2024
Available Online: 1 May 2024

Figures(5)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality rate but effective therapeutics are still lacking. Phosphodiesterase-4 (PDE4) inhibitors were reported to be promising anti-IPF agents. Herein, series of biflavonoids isolated from Selaginella uncinate were found to be PDE4 inhibitors and the most active amentoflavone gave a half maximal inhibitory concentration (IC₅₀) of 12 nmol/L, which was further validated by isothermal titration calorimetry with K_d of 23 nmol/L. Besides, co-crystal structure of PDE4-amentoflavone was determined and gave a different binding pattern from roflumilast with multiple H-bonds between it and key residues such as Asn321/Thr333/Gln369/Gly371. So far, this was the first reported co-crystal structure of amentoflavone with its potential binding target in despite of the extensive investigations of this common natural biflavonoid. Furthermore, amentoflavone exhibited remarkable anti-IPF effects in vivo and in vitro, suggesting it as a novel anti-fibrotic agent by targeting PDE4.
- Phosphodiesterase-4,
- Inhibitor,
- Amentoflavone,
- Crystal structure,
- IPF
1. [1]
  L. Richeldi, H.R. Collard, M.G. Jones, Lancet 389 (2017) 1941–1952. doi: 10.1016/S0140-6736(17)30866-8
2. [2]
  T. Zhang, C. Sun, S. Yang, et al., Chin. Chem. Lett. 35 (2024) 109248. doi: 10.1016/j.cclet.2023.109248
3. [3]
  F. Patrucco, P. Solidoro, F. Gavelli, et al., Microorganisms 11 (2023) 895. doi: 10.3390/microorganisms11040895
4. [4]
  T. Karampitsakos, B.M. Juan-Guardela, A. Tzouvelekis, et al., EBioMedicine 95 (2023) 104766. doi: 10.1016/j.ebiom.2023.104766
5. [5]
  B. Ley, H.R. Collard, T.E. King, Am. J. Respir. Crit. Care Med. 183 (2011) 431–440. doi: 10.1164/rccm.201006-0894CI
6. [6]
  L. Richeldi, A. Azuma, V. Cottin, et al., New Engl. J. Med. 386 (2022) 2178–2187. doi: 10.1056/NEJMoa2201737
7. [7]
  J. Cortijo, A. Iranzo, X. Milara, et al., Br. J. Pharmacol. 156 (2009) 534–544. doi: 10.1111/j.1476-5381.2008.00041.x
8. [8]
  G. Sgalla, J. Simonetti, S. Cortese, et al., Expert Opin. Inv. Drug 32 (2023) 17–23. doi: 10.1080/13543784.2023.2173061
9. [9]
  Y.Y. Huang, J.H. Deng, Y.J. Tian, et al., J. Med. Chem. 64 (2021) 13736–13751. doi: 10.1021/acs.jmedchem.1c01085
10. [10]
  J. Liang, Y.Y. Huang, Q. Zhou, et al., J. Med. Chem. 63 (2020) 3370–3380. doi: 10.1021/acs.jmedchem.0c00060
11. [11]
  R. Liu, H. Zou, P. Xu, et al., Chin. Chem. Lett. 28 (2017) 1465–1468. doi: 10.1016/j.cclet.2017.03.004
12. [12]
  S. Yu, H. Yan, L. Zhang, et al., Molecules 22 (2017) 299. doi: 10.3390/molecules22020299
13. [13]
  X.F. Xiong, N. Tang, X.D. Lai, et al., Front. Pharmacol. 12 (2021) 768708. doi: 10.3389/fphar.2021.768708
14. [14]
  J.W. Yang, Z.Y. Gu, J. Zhao, et al., Lishizhen Med. Mater. Med. Res. 22 (2011) 375–376.
15. [15]
  Y. Cao, Y.P. Wu, X.Z. Weng, et al., Nat. Prod. Res. Dev. 24 (2012) 150–154.
16. [16]
  A. Coqueiro, L.O. Regasini, S.C.G. Skrzek, et al., Molecules 18 (2013) 2376–2385. doi: 10.3390/molecules18022376
17. [17]
  A.I. Suarez, B. Diaz M, F. Delle Monache, et al., Fitoterapia 74 (2003) 473–475. doi: 10.1016/S0367-326X(03)00065-0
18. [18]
  G. Skopp, G. Schwenker, Z. Naturforsch. B 41 (1986) 1479–1482. doi: 10.1515/znb-1986-1125
19. [19]
  H. Li, Y. Luo, Z. He, et al., Chin. J. Appl. Environ. Biol. 13 (2007) 188–191.
20. [20]
  C. Mohan, I. Mohammed, W. Hildebert, et al., Phytochemistry (1977) 1273.
21. [21]
  Y. Huang, X. Liu, D. Wu, et al., Biochem. Pharmacol. 130 (2017) 51–59. doi: 10.1016/j.bcp.2017.01.016
22. [22]
  S. Liao, Q. Ren, C. Yang, et al., J. Agric. Food Chem. 63 (2015) 1957–1966. doi: 10.1021/jf5019615
23. [23]
  J. Xu, X. Liu, K. Chen, Chin. Chem. Lett. 20 (2009) 939–941. doi: 10.1016/j.cclet.2009.03.046
1. [1]
  Ke-Ai Zhou , Lian Huang , Xing-Ping Fu , Li-Ling Zhang , Yu-Ling Wang , Qing-Yan Liu . Fluorinated metal-organic framework for methane purification from a ternary CH4/C2H6/C3H8 mixture. Chinese Journal of Structural Chemistry, 2023, 42(11): 100172-100172. doi: 10.1016/j.cjsc.2023.100172
2. [2]
  Han Yuan , Fengcai Zhang , Hongzhe Huang , Jiafei Wu , Yi Yang , Wanyi Huang , Dongjing Yang , Zhuoming Li , Zhe Li , Ling Huang , Yi-You Huang , Hai-Bin Luo , Lei Guo . Discovery of 3-trifluoromethyl-substituted pyrazoles as selective phosphodiesterase 10A inhibitors for orally attenuating isoprenaline-induced cardiac hypertrophy. Chinese Chemical Letters, 2025, 36(4): 109965-. doi: 10.1016/j.cclet.2024.109965
3. [3]
  Muhammad Riaz , Rakesh Kumar Gupta , Di Sun , Mohammad Azam , Ping Cui . Selective adsorption of organic dyes and iodine by a two-dimensional cobalt(II) metal-organic framework. Chinese Journal of Structural Chemistry, 2024, 43(12): 100427-100427. doi: 10.1016/j.cjsc.2024.100427
4. [4]
  Tiantian Li , Ruochen Jin , Bin Wu , Dongming Lan , Yunjian Ma , Yonghua Wang . A novel insight of enhancing the hydrogen peroxide tolerance of unspecific peroxygenase from Daldinia caldariorum based on structure. Chinese Chemical Letters, 2024, 35(4): 108701-. doi: 10.1016/j.cclet.2023.108701
5. [5]
  Xinyi Cao , Yucheng Jin , Hailong Wang , Xu Ding , Xiaolin Liu , Baoqiu Yu , Xiaoning Zhan , Jianzhuang Jiang . A tetraaldehyde-derived porous organic cage and covalent organic frameworks: Syntheses, structures, and iodine vapor capture. Chinese Chemical Letters, 2024, 35(9): 109201-. doi: 10.1016/j.cclet.2023.109201
6. [6]
  Lu LIU , Huijie WANG , Haitong WANG , Ying LI . Crystal structure of a two-dimensional Cd(Ⅱ) complex and its fluorescence recognition of p-nitrophenol, tetracycline, 2, 6-dichloro-4-nitroaniline. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1180-1188. doi: 10.11862/CJIC.20230489
7. [7]
  Jinfeng Chu , Lan Jin , Yu-Fei Song . Exploration and Practice of Flipped Classroom in Inorganic Chemistry Experiment: a Case Study on the Preparation of Inorganic Crystalline Compounds. University Chemistry, 2024, 39(2): 248-254. doi: 10.3866/PKU.DXHX202308016
8. [8]
  Yan Liu , Yuexiang Zhu , Luhua Lai . Introduction to Blended and Small-Class Teaching in Structural Chemistry: Exploring the Structure and Properties of Crystals. University Chemistry, 2024, 39(3): 1-4. doi: 10.3866/PKU.DXHX202306084
9. [9]
  Junqiao Zhuo , Xinchen Huang , Qi Wang . Symbol Representation of the Packing-Filling Model of the Crystal Structure and Its Application. University Chemistry, 2024, 39(3): 70-77. doi: 10.3866/PKU.DXHX202311100
10. [10]
  Yuyao Wang , Zhitao Cao , Zeyu Du , Xinxin Cao , Shuquan Liang . Research Progress of Iron-based Polyanionic Cathode Materials for Sodium-Ion Batteries. Acta Physico-Chimica Sinica, 2025, 41(4): 100035-. doi: 10.3866/PKU.WHXB202406014
11. [11]
  Wenyan Dan , Weijie Li , Xiaogang Wang . The Technical Analysis of Visual Software ShelXle for Refinement of Small Molecular Crystal Structure. University Chemistry, 2024, 39(3): 63-69. doi: 10.3866/PKU.DXHX202302060
12. [12]
  Xiaofen GUAN , Yating LIU , Jia LI , Yiwen HU , Haiyuan DING , Yuanjing SHI , Zhiqiang WANG , Wenmin WANG . Synthesis, crystal structure, and DNA-binding of binuclear lanthanide complexes based on a multidentate Schiff base ligand. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2486-2496. doi: 10.11862/CJIC.20240122
13. [13]
  Yao HUANG , Yingshu WU , Zhichun BAO , Yue HUANG , Shangfeng TANG , Ruixue LIU , Yancheng LIU , Hong LIANG . Copper complexes of anthrahydrazone bearing pyridyl side chain: Synthesis, crystal structure, anticancer activity, and DNA binding. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 213-224. doi: 10.11862/CJIC.20240359
14. [14]
  Zhaodong WANG . In situ synthesis, crystal structure, and magnetic characterization of a trinuclear copper complex based on a multi-substituted imidazo[1,5-a]pyrazine scaffold. Chinese Journal of Inorganic Chemistry, 2025, 41(3): 597-604. doi: 10.11862/CJIC.20240268
15. [15]
  Yiran Tao , Chunlei Dai , Zhaoxiang Xie , Xinru You , Kaiwen Li , Jun Wu , Hai Huang . Redox responsive polymeric nanoparticles enhance the efficacy of cyclin dependent kinase 7 inhibitor for enhanced treatment of prostate cancer. Chinese Chemical Letters, 2024, 35(8): 109170-. doi: 10.1016/j.cclet.2023.109170
16. [16]
  Jia Chen , Yun Liu , Zerong Long , Yan Li , Hongdeng Qiu . Colorimetric detection of α-glucosidase activity using Ni-CeO₂ nanorods and its application to potential natural inhibitor screening. Chinese Chemical Letters, 2024, 35(9): 109463-. doi: 10.1016/j.cclet.2023.109463
17. [17]
  Chao Chen , Wenwen Yu , Guangen Huang , Xuelian Ren , Xiangli Chen , Yixin Li , Shenggui Liang , Mengmeng Xu , Mingyue Zheng , Yaxi Yang , He Huang , Wei Tang , Bing Zhou . Asymmetric macrocyclization enabled by Rh(Ⅲ)-catalyzed CH activation: Enantioenriched macrocyclic inhibitor of Zika virus infection. Chinese Chemical Letters, 2024, 35(11): 109574-. doi: 10.1016/j.cclet.2024.109574
18. [18]
  Shuheng Zhang , Yuanyuan Zhang , Wanyu Wang , Yuzhu Hu , Xinchuan Chen , Bilan Wang , Xiang Gao . A combination strategy of DOX and VEGFR-2 targeted inhibitor based on nanomicelle for enhancing lymphoma therapy. Chinese Chemical Letters, 2024, 35(12): 109658-. doi: 10.1016/j.cclet.2024.109658
19. [19]
  Jisheng Liu , Junli Chen , Xifeng Zhang , Yin Wu , Xin Qi , Jie Wang , Xiang Gao . Red blood cell membrane-coated FLT3 inhibitor nanoparticles to enhance FLT3-ITD acute myeloid leukemia treatment. Chinese Chemical Letters, 2024, 35(9): 109779-. doi: 10.1016/j.cclet.2024.109779
20. [20]
  Weizhong LING , Xiangyun CHEN , Wenjing LIU , Yingkai HUANG , Yu LI . Syntheses, crystal structures, and catalytic properties of three zinc(Ⅱ), cobalt(Ⅱ) and nickel(Ⅱ) coordination polymers constructed from 5-(4-carboxyphenoxy)nicotinic acid. Chinese Journal of Inorganic Chemistry, 2024, 40(9): 1803-1810. doi: 10.11862/CJIC.20240068

Get Citation

PDF

XML

Metrics

PDF Downloads(1)
Abstract views(70)
HTML views(3)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142