A novel colchicine-myricetin heterozygous molecule: design, synthesis, and effective evaluations on the pathological models of acute lung injury in vitro and in vivo

Zhiyue Li; Xueqin Yan; Jiangchun Wei; Liuyang Pu; Guanbao Zhu; Yongkai Cao; Zhanyan Liu; Yaqian Liu; Yan Li; Limin Li; Xinping Li; Zhengzhi Wu

doi:10.3389/fphar.2023.1224906

A novel colchicine-myricetin heterozygous molecule: design, synthesis, and effective evaluations on the pathological models of acute lung injury in vitro and in vivo

Front Pharmacol. 2023 Jun 29:14:1224906. doi: 10.3389/fphar.2023.1224906. eCollection 2023.

Authors

Zhiyue Li^{1

2

3}, Xueqin Yan^{1

2}, Jiangchun Wei^{1

2}, Liuyang Pu¹, Guanbao Zhu^{1

4}, Yongkai Cao¹, Zhanyan Liu¹, Yaqian Liu¹, Yan Li¹, Limin Li¹, Xinping Li¹, Zhengzhi Wu^{1

2}

Affiliations

¹ Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
² Wu Zhengzhi Academician Workstation, Ningbo College of Health Sciences, Ningbo, China.
³ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁴ Graduate School, Guangxi University of Chinese Medicine, Nanning, China.

Abstract

Acute lung injury (ALI) is an inflammatory condition and there are no effective treatments. A novel new compound----colchicine-myricetin hybrid (CMyrH) was herein designed and synthesized. To evaluate the activity of CMyrH in ALI, we used a bleomycin (BLM) induced BEAS-2B injury model in vitro and established a well-recognized rat model of BLM-induced lung injury in vivo. The results demonstrated that colchicine-myricetin hybrid protected BEAS-2B cells against BLM-induced cell injury in an increased dose manner, and reduced wet/dry weight ratio, histological scoring, and inflammation cytokines IL-1β, IL-6, IL-18, and TNF-α levels of lung tissue of the rats. Furthermore, we found colchicine-myricetin hybrid inhibited caspase-1, ASC, GSDMD, and NLRP-3 expression in vivo. Meanwhile, we used molecular docking to analyze the binding mode of colchicine-myricetin hybrid and human neutrophil elastase (HNE), it revealed that colchicine-myricetin hybrid showed strong binding affinity toward human neutrophil elastase when compared to its parent molecules. In conclusion, It is suggested that colchicine-myricetin hybrid antagonized acute lung injury by focusing on multi-targets via multi-mechanisms, and might be served as a potential therapeutic agent for acute lung injury.

Keywords: acute lung injury; bleomycin; colchicine; colchicine-myricetin hybrid; inflammation; neutrophil elastase.

Grants and funding

This work was supported by the major new drug innovation project of the Ministry of Science and Technology of China (No. 2017ZX09301001), the China Central Finance Improvement Project for the National Key Laboratory of Traditional Chinese Medicine (China Central Finance. CS [2021] No. 151), the special key project of science, Shenzhen Basic Discipline Layout Project (JCYJ20220818101806014) and technology of Guangdong Province with strong traditional Chinese medicine (No. 20215002).