Synthesis of novel 1-phenyl-benzopyrrolizidin-3-one derivatives and evaluation of their cytoneuroprotective effects against NMDA-induced injury in PC12 cells

Lishou Yang; Qian Yang; Enhua Wang; Juan Yang; Qiji Li; Jiafu Cao; Li Wang; Xiu Liao; Yan Yang; Xiaosheng Yang

doi:10.1016/j.bmc.2022.116675

Synthesis of novel 1-phenyl-benzopyrrolizidin-3-one derivatives and evaluation of their cytoneuroprotective effects against NMDA-induced injury in PC12 cells

Bioorg Med Chem. 2022 Apr 1:59:116675. doi: 10.1016/j.bmc.2022.116675. Epub 2022 Feb 18.

Authors

Lishou Yang¹, Qian Yang², Enhua Wang², Juan Yang¹, Qiji Li¹, Jiafu Cao¹, Li Wang¹, Xiu Liao¹, Yan Yang¹, Xiaosheng Yang³

Affiliations

¹ State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China.
² Department of Medicine and Food, Guizhou Vocational College of Agriculture, Guiyang 550041, PR China.
³ State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China. Electronic address: gzcnp@sina.cn.

PMID: 35202968
DOI: 10.1016/j.bmc.2022.116675

Abstract

A range of novel 1-phenyl-benzopyrrolizidin-3-one derivatives were synthesized and evaluated for neuroprotective effects against N-methyl-ᴅ-aspartate (NMDA)-induced injury in PC12 cells. Interestingly, derivatives that 1-phenyl moiety bearing electron-donating group, especially benzyloxy, and the trans-forms exhibited better protective activity against NMDA-induced neurotoxicity. Compound 11 m demonstrated the best neuroprotective potency and shown a dose-dependent prevention. The increased intracellular calcium (Ca²⁺) influx caused by NMDA in PC12 cells was reversed in the case of compound 11 m pretreatment at 15 μM. These results suggested that the synthesized 1-phenyl-benzopyrrolizidin-3-one derivatives exerted neuroprotective effect on NMDA-induced excitotoxicity in PC12 cells associated with inhibition of Ca²⁺ overload and can be further optimized for the development of neuroprotective agents.

Keywords: 1-Phenyl-benzopyrrolizidin-3-one; Excitotoxicity; N-methyl-ᴅ-aspartate; Neuroprotective effect; PC12 cells.

Publication types

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

MeSH terms

Animals
Calcium / metabolism
N-Methylaspartate* / toxicity
Neuroprotective Agents* / pharmacology
PC12 Cells
Rats
Receptors, N-Methyl-D-Aspartate

Substances

Neuroprotective Agents
Receptors, N-Methyl-D-Aspartate
N-Methylaspartate
Calcium