Second generation β-elemene nitric oxide derivatives with reasonable linkers: potential hybrids against malignant brain glioma

Renren Bai; Junlong Zhu; Ziqiang Bai; Qing Mao; Yingqian Zhang; Zi Hui; Xinyu Luo; Xiang-Yang Ye; Tian Xie

doi:10.1080/14756366.2021.2016734

Second generation β-elemene nitric oxide derivatives with reasonable linkers: potential hybrids against malignant brain glioma

J Enzyme Inhib Med Chem. 2022 Dec;37(1):379-385. doi: 10.1080/14756366.2021.2016734.

Authors

Renren Bai^{1

2}, Junlong Zhu^{1

2}, Ziqiang Bai^{1

2}, Qing Mao^{1

2}, Yingqian Zhang^{1

2}, Zi Hui^{1

2}, Xinyu Luo^{1

2}, Xiang-Yang Ye^{1

2}, Tian Xie^{1

2}

Affiliations

¹ School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China.
² Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.

Abstract

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, β-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of β-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the β-elemene structure and designed six series of new generation β-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro, displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and β-elemene is a feasible strategy to improve the in vivo anti-tumour activity of β-elemene.

Keywords: NO donor; anti-tumour; malignant glioma; natural product; β-Elemene.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Brain Neoplasms / drug therapy*
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Glioma / drug therapy*
Glioma / pathology
Humans
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Nitric Oxide / chemical synthesis
Nitric Oxide / chemistry
Nitric Oxide / pharmacology*
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Sesquiterpenes / chemical synthesis
Sesquiterpenes / chemistry
Sesquiterpenes / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oxadiazoles
Sesquiterpenes
beta-elemene
furoxans
Nitric Oxide

Grants and funding

This project was supported by the National Natural Science Foundation of China (81730108 and 81973635), Scientific Research Foundation for Scholars of HZNU (2021QDL026 and 2019QDL003), the Ministry of Science and Technology of China (High-end foreign experts program, G20200217005 and G2021017004), and Hangzhou City “115” plan to introduce overseas intelligence projects (20200215).