Design, synthesis and apoptosis-related antiproliferative activities of chelidonine derivatives

Xueyan Huang; Keguang Cheng; Lilin Liu; Xu Hu; Xiang Gao; Haonan Li; Fanxing Xu; Zhanlin Li; Huiming Hua; Dahong Li

doi:10.1016/j.bmcl.2019.126913

Design, synthesis and apoptosis-related antiproliferative activities of chelidonine derivatives

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126913. doi: 10.1016/j.bmcl.2019.126913. Epub 2019 Dec 23.

Authors

Xueyan Huang¹, Keguang Cheng², Lilin Liu¹, Xu Hu¹, Xiang Gao¹, Haonan Li¹, Fanxing Xu³, Zhanlin Li¹, Huiming Hua⁴, Dahong Li⁵

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
² State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, and School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Raod, Guilin 541004, PR China.
³ Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: fanxing0011@163.com.
⁴ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: huimhua@163.com.
⁵ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: lidahong0203@163.com.

PMID: 31883693
DOI: 10.1016/j.bmcl.2019.126913

Abstract

To get chelidonine derivatives with enhanced antiproliferative activity and selectivity, a series of nitric oxide donating derivatives (10a-f and 11a-j) were designed, synthesized and biologically evaluated. Compared with chelidonine, these compounds exhibited lower IC₅₀ values against human hepatoma cells HepG2, breast cancer cells MCF-7, colon cancer cells HCT-116, as well as leukemia cells K562. Compound 11j displayed the strongest antiproliferative activity with IC₅₀ values of 3.91, 6.90, 4.36 and 1.12 μM against the above four cells, respectively. Nevertheless, it showed an IC₅₀ value >40 μM against human peripheral blood mononuclear cells (PBMCs), which demonstrated high selectivity between normal and cancer blood cells. In further mechanism studies, 11j showed the capability to induce K562 cells apoptosis, S phase cell cycle arrest and mitochondrial membrane potential disorder. Besides, 11j was found to be effective in promoting the expression of proapoptotic protein Bad and suppressing the expression of anti-apoptotic proteins Bcl-xL, catalase, survivin, claspin and clusterin.

Keywords: Antiproliferative; Apoptosis; Chelidonine; Nitric oxide.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzophenanthridines / chemistry*
Benzophenanthridines / pharmacology
Cell Line, Tumor
Drug Design*
Drug Screening Assays, Antitumor
Humans
Leukocytes, Mononuclear / cytology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Membrane Potential, Mitochondrial / drug effects
Nitric Oxide / metabolism
S Phase Cell Cycle Checkpoints / drug effects
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzophenanthridines
Nitric Oxide
chelidonine