Novel nitrogen mustard-artemisinin hybrids with potent anti-leukemia action through DNA damage and activation of GPx

Tianzhi Dai; Lan Lin; Huan Chen; Wenyu Lu; Xuelian Yang; Li Yang; Ying Liu; Jichun Cui; Dequn Sun

doi:10.1016/j.ejmech.2022.114783

Novel nitrogen mustard-artemisinin hybrids with potent anti-leukemia action through DNA damage and activation of GPx

Eur J Med Chem. 2022 Dec 15:244:114783. doi: 10.1016/j.ejmech.2022.114783. Epub 2022 Oct 7.

Authors

Tianzhi Dai¹, Lan Lin², Huan Chen³, Wenyu Lu¹, Xuelian Yang³, Li Yang³, Ying Liu⁴, Jichun Cui⁵, Dequn Sun⁶

Affiliations

¹ School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang, 621010, China; Marine College, Shandong University at Weihai, No.180, Wenhua West Road, Weihai, 264209, PR China.
² School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang, 621010, China; Institute of Materials, China Academy of Engineering Physics, Jiangyou, 621907, China.
³ School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang, 621010, China.
⁴ Institute of Materials, China Academy of Engineering Physics, Jiangyou, 621907, China. Electronic address: liuying2016@caep.cn.
⁵ School of Chemical and Chemistry Engineering, Liaocheng University, Liaocheng, 252000, PR China.
⁶ School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang, 621010, China. Electronic address: dqsun@swust.edu.cn.

PMID: 36240546
DOI: 10.1016/j.ejmech.2022.114783

Abstract

The incidence of various types of cancers is increasing every year. Among these, leukemia is extremely common, and thus, developing novel drugs to combat leukemia is crucial. In this study, we designed and synthesized several hybrids and obtained a new lead molecule 5a, with a strong therapeutic effect on leukemia. The results indicated that most hybrids effectively inhibited the growth of leukemia cells, HCT-116, and A549 cancer cells with an IC₅₀ of <10 μM. Among these hybrids, 5a and 4h showed significant anticancer activity against CCRF-CEM, with IC₅₀ values of 0.895 μM and 0.555 μM, respectively. Particularly, 5a had lower toxicity to L02 than chlorambucil (CLB) and doxorubicin (Dox), and the high selectivity was also reflected in the normal human B lymphoblast cell line (IM9). Upon investigating the mechanism of action, we found that 5a downregulated Bcl-2 and caused DNA double-stranded breaks (DSBs) to induce several genotoxic stress responses. The results of the flow cytometry assay showed that 5a was a non-specific molecule in the cell cycle. Furthermore, 5a did not affect total ROS levels but significantly improved the activity of glutathione peroxidase (GPx). Preliminary studies showed that nitrogen mustard exerted an efficient effect, and 5a can combine the advantages of artemisinin and nitrogen mustard and exhibit effects superior to either. This study showed that 5a should be further investigated as a therapeutic compound against leukemia.

Keywords: Artemisinin; DNA damage; GPx; Leukemia; Nitrogen mustard; ROS.

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Apoptosis
Artemisinins* / pharmacology
Cell Line, Tumor
DNA Damage
Glutathione Peroxidase
Humans
Leukemia* / drug therapy
Mechlorethamine / pharmacology
Neoplasms* / drug therapy

Substances

Mechlorethamine
Glutathione Peroxidase
artemisinin
Artemisinins
Antineoplastic Agents