Citation: Yi-You Huang, Xiang Luo, Kai Zhang, Yulan Liang, Furong Zhang, Guochao Liao, Shenghong Xie, Pei-Luo Huang, Siyu Hou, Qian Zhou, Yong Zou, Hai-Bin Luo. Structure-based optimization of isoaurostatin as novel PDE4 inhibitors with anti-fibrotic effects[J]. Chinese Chemical Letters, ;2025, 36(8): 110586. doi: 10.1016/j.cclet.2024.110586 shu

Structure-based optimization of isoaurostatin as novel PDE4 inhibitors with anti-fibrotic effects

Yi-You Huang ^{a, 1} ,
Xiang Luo ^{b, c, 1} ,
Kai Zhang ^{a, e, 1} ,
Yulan Liang ^c ,
Furong Zhang ^{a, e} ,
Guochao Liao ^c ,
Shenghong Xie ^a ,
Pei-Luo Huang ^a ,
Siyu Hou ^a ,
Qian Zhou ^{a, *,} ,
Yong Zou ^{b, *,} ,
Hai-Bin Luo ^{a, d, *,}

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.
State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
c.
Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
d.
Song Li's Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Sanya 572000, China
e.
School of Life and Health Science, Hainan University, Haikou 570228, China

zhouqian@hainanu.edu.cn

zouyong3@mail.sysu.edu.cn

hbluo@hainanu.edu.cn

Received Date: 24 August 2024
Revised Date: 22 October 2024
Accepted Date: 27 October 2024
Available Online: 29 October 2024

Figures(6)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents. Herein, structure-based hit-to-lead optimization of natural isoaurostatin (8.98 µmol/L) resulted in several potent inhibitors of PDE4 with half maximal inhibitory concentration (IC₅₀) values ranging from 35 nmol/L to 126 nmol/L. Co-crystal structures revealed that isoaurostatin compounds exhibited different binding patterns from the classic PDE4 inhibitor rolipram and the analogues would favor to be Z configurations other than the corresponding E isomers. Finally, lead 2–9 showed remarkable in vitro/in vivo anti-fibrotic effects indicating its potential as a novel anti-IPF agent.
- PDE4,
- Isoaurone,
- Structural optimization,
- Crystal structure,
- IPF
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