BA-12 Inhibits Angiogenesis via Glutathione Metabolism Activation.

Herong Cui,Shenglan Wang,Guoping Li,Yuwei Yang,Wenbo Guo,Fuhao Chu,Tong Li,Haimin Lei,Na Zhang,Wuwen Feng,Beibei Zhang,Yanyan Yuan,Penglong Wang,Bing Xu

doi:10.3390/ijms20164062

Abstract

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine–betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional Prunella vulgaris plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and Caenorhabditis elegans. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.

Highlights

Despite many advances in recent decades, drug development remains slow, expensive, and risky [1]
In order to yield 2-(chloromethyl)-3,5,6-trimethylpyrazine, (3,5,6-trimethylpyrazin-2-yl)methanol was reacted with tosyl chloride (TsCl) in 4-dimethylaminopyridine (DMAP), trimethylamine (TEA), and tetrahydrofuran (THF)
The in vitro antitumor activity of these derivatives was evaluated on T24 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the half maximal inhibitory concentration (IC50) values were shown as Figure 2C

Summary

Introduction

Despite many advances in recent decades, drug development remains slow, expensive, and risky [1]. Screening a small molecule to become a drug candidate typically takes 4–5 years, costs $14–25 million, and has a loss rate of more than 50%. Recent estimates show a loss rate of up to 97% from drug candidates to commercialized products, with total costs of drug development (including loss costs and capital costs) exceeding $2.6 billion [2]. New drug discovery centers around the world invested heavily in translational science to more effectively validate the role of biological targets in human disease and identify the most appropriate patient populations for evaluating potential drugs [4]. Some targets with a strong biological basis are very challenging for the current small-molecule drug discovery technology [6,7]. It is urgent to establish an efficient and low-cost drug discovery and design mode

Methods

Results

Conclusion