Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in vitro and in vivo

Liang-Liang Wang; Lingmei Kong; Hui Liu; Yunqin Zhang; Li Zhang; Xingyong Liu; Feng Yuan; Yan Li; Zhili Zuo

doi:10.1016/j.ejmech.2019.111665

Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in vitro and in vivo

Eur J Med Chem. 2019 Nov 15:182:111665. doi: 10.1016/j.ejmech.2019.111665. Epub 2019 Aug 30.

Authors

Liang-Liang Wang¹, Lingmei Kong¹, Hui Liu², Yunqin Zhang¹, Li Zhang², Xingyong Liu², Feng Yuan¹, Yan Li³, Zhili Zuo⁴

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
² School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, China.
³ State Key Laboratory of Phytochemistry and Plant Resources in West China, Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: [email protected].
⁴ State Key Laboratory of Phytochemistry and Plant Resources in West China, Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, China. Electronic address: [email protected].

PMID: 31494469
DOI: 10.1016/j.ejmech.2019.111665

Abstract

A series of novel derivatives of artemisinin-4-(arylamino)quinazoline have been designed and synthesized, and most of them showing potent in vitro cytotoxic activity against HCT116 and WM-266-4 cell lines. Compound 32 was the most active derivative against HCT116 cell line with an IC₅₀ of 110 nM, and significantly improved the antitumor activity of the parent compounds dihydroartemisinin (DHA) (IC₅₀ = 2.85 μM) and Gefitinib (IC₅₀ = 19.82 μM). In vivo HCT116 xenografts assay showed that compound 32 exhibited potent antitumor activity with obvious tumor growth delay and tumor shrunken after 18 days treatment on xenografted mice, and especially without loss of body weight. Our results indicate that compounds 32 may represent a safe, novel structural lead for developing new chemotherapy of colorectal cancer.

Keywords: Artemisinin; Chemotherapy; Colorectal cancer; Hybridization; Quinazoline.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Artemisinins / chemical synthesis
Artemisinins / chemistry
Artemisinins / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / pathology
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
HCT116 Cells
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Artemisinins