Synthesis of Novel Baicalein Amino Acid Derivatives and Biological Evaluation as Neuroprotective Agents.

Xiaohui Jia,Wenbo Guo,Haomiao Ren,Menglu Jia,Desheng Cai,Wenxi Zhang,Jinchai Qi,Xuemei Huang,Tao Ma,Yuqin Yang,Haimin Lei,Di Wang,Shuqi Zhou,Fei Zhou,Penglong Wang,Bing Xu,Hongshan Chen

doi:10.3390/molecules24203647

Abstract

Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin (Scutellaria altissima L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neuroprotective effect against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells and toxicity on the normal H9C2 cell line by standard methylthiazol tetrazolium (MTT) assay. In addition, all of the newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and high resolution mass spectrometry (HR-MS). The results showed that most of the compounds provided more potent neuroprotection than baicalein, and were equivalent to the positive drug edaravin. They showed no obvious cytotoxicity on normal H9C2 cells. Notably, the most active compound 8 displayed the highest protective effect (50% effective concentration (EC50) = 4.31 μM) against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells, which was much better than the baicalein (EC50 = 24.77 μM) and edaravin (EC50 = 5.62 μM). Further research on the chick chorioallantoic membrane (CAM) model indicated that compound 8 could significantly increase angiogenesis, which might promote neurovascular proliferation. The detection of apoptosis analysis showed that compound 8 could dramatically alleviate morphological manifestations of cell damage. Moreover, the benzyloxycarbonyl (cbz)-protected baicalein amino acid derivatives showed better neuroprotective activity than the t-Butyloxy carbonyl (boc)-protected derivatives.

Highlights

Neurodegenerative diseases have become some of the most challenging diseases, which has attracted the attention of scientists all over the world in recent years [1,2,3,4,5]
All of them were characterized by 1 H-NMR, 13 C-NMR, and HRMS (Figure S6), and tested for biological activities against SH-SY5Y and H9C2 cells, as well as a chorioallantoic membrane (CAM) model
The results indicate that most of the synthesized baicalein amino acid derivatives were more potent than the positive drugs baicalein, and were equivalent to the positive drug edaravone

Summary

Introduction

Neurodegenerative diseases have become some of the most challenging diseases, which has attracted the attention of scientists all over the world in recent years [1,2,3,4,5]. The severe side to treat them, such as dopaminergic treatments, antipsychotic drugs, and brain stimulation [8,9,10,11]. Effects of these drugs have greatly hindered their further clinical application [12,13]. The severe side effects of these drugs have greatly hindered their further clinical application for neuroprotective drugs with high efficiency and low toxicity to treat neurodegenerative diseases [12,13]. The search for neuroprotective drugs with high efficiency and low toxicity to treat from natural resources is an important research direction in the future [14,15,16,17,18]

Methods

Results

Conclusion