Design and synthesis of β-carboline and combretastatin derivatives as anti-neutrophilic inflammatory agents

Sunil Kumar; Yi-Hsuan Wang; Po-Jen Chen; Yu-Chia Chang; Hemant K Kashyap; Ya-Ching Shen; Huang-Ping Yu; Tsong-Long Hwang

doi:10.1016/j.bioorg.2021.104846

Design and synthesis of β-carboline and combretastatin derivatives as anti-neutrophilic inflammatory agents

Bioorg Chem. 2021 Jun:111:104846. doi: 10.1016/j.bioorg.2021.104846. Epub 2021 Mar 26.

Authors

Sunil Kumar¹, Yi-Hsuan Wang², Po-Jen Chen³, Yu-Chia Chang⁴, Hemant K Kashyap⁵, Ya-Ching Shen⁶, Huang-Ping Yu⁷, Tsong-Long Hwang⁸

Affiliations

¹ School of Pharmacy, College of Medicine, National Taiwan University, Taipei City 100, Taiwan; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
² Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Department of Cosmetic Science, Providence University, Taichung 43301, Taiwan.
⁴ Research Center for Chinese Herbal Medicine, Graduate Institute of Healthy Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan.
⁵ Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
⁶ School of Pharmacy, College of Medicine, National Taiwan University, Taipei City 100, Taiwan. Electronic address: ycshen@ntu.edu.tw.
⁷ College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan. Electronic address: yuhp2001@adm.cgmh.org.tw.
⁸ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, Graduate Institute of Healthy Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan. Electronic address: htl@mail.cgu.edu.tw.

PMID: 33813149
DOI: 10.1016/j.bioorg.2021.104846

Abstract

A series of β-carboline derivatives was synthesized by the Pictet-Spengler reaction with or without the combretastatin skeleton. The structures of these derivatives were elucidated by spectroscopic techniques. All synthesized compounds were evaluated for their anti-inflammatory activity in human neutrophils. Among them, two compounds, NTU-228 and HK-72, showed significant inhibitory effects on N-formyl-Met-Leu-Phe (fMLF)-induced superoxide anion generation in human neutrophils with IC₅₀ values of 5.58 ± 0.56 and 2.81 ± 0.07 μM, respectively. Neither NTU-228 nor HK-72 caused cytotoxicity in human neutrophils. NTU-228 inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and intracellular Ca²⁺ levels ([Ca²⁺]_i) in fMLF-activated human neutrophils. Additionally, HK-72 selectively inhibited the fMLF-induced phosphorylation of p38 and [Ca²⁺]_i in human neutrophils. Molecular docking analysis showed a favorable binding affinity of HK-72 toward p38 MAPK. The proposed synthetic strategy opens up new opportunities for the synthesis of novel potential candidates against neutrophilic inflammation.

Keywords: Anti-inflammatory agents; Combretastatin; Molecular docking; Neutrophils; Organic synthesis; p38 MAPK; β-carboline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Bibenzyls / chemistry
Bibenzyls / pharmacology*
Carbolines / chemistry
Carbolines / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Inflammation / drug therapy*
Inflammation / metabolism
Molecular Structure
Neutrophils / drug effects*
Neutrophils / metabolism
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Bibenzyls
Carbolines
combretastatin
norharman