Design, Synthesis, and Biological Evaluation of a Novel Aminothiol Compound as Potential Radioprotector.

Xuejiao Li,Renbin Yuan,Longfei Miao,Xinxin Wang,Jingming Ren,Yuying Guo,Yichi Huang,Hongqi Tian,Swaran J. S. Flora

doi:10.1155/2021/4714649

Abstract

The risk of radiation damage has increased with the rapid development of nuclear technology and radiotherapy. Hence, research on radioprotective agents is of utmost importance. In the present study, a novel aminothiol compound 12, containing a linear alkylamino backbone and three terminal thiols, was synthesized. Owing to the appropriate capped groups in the chains, it has an improved permeability and oral bioavailability compared to other radioprotective agents. Oral administration of compound 12 improved the survival of mice that received lethal doses of γ-irradiation. Experimental results demonstrated that compound 12 not only mitigated total body irradiation-induced hematopoietic injury by increasing the frequencies of hematopoietic stem and progenitor cells but also prevented abdominal irradiation-induced intestinal injury by increasing the survival of Lgr5+ intestinal cells, lysozyme+ Paneth cells, and Ki67+ cells. In addition, compound 12 decreased oxidative stress by upregulating the expression of Nrf2 and NQO1 and downregulating the expression of NOX1. Further, compound 12 inhibited γ-irradiation-induced DNA damage and alleviated G2/M phase arrest. Moreover, compound 12 decreased the levels of p53 and Bax and increased the level of Bcl-2, demonstrating that it may suppress radiation-induced apoptosis via the p53 pathway. These results indicate that compound 12 has the possibility of preventing radiation injury and can be a potential radioprotector for clinical applications.

Highlights

Humans may be exposed to ionizing radiation (IR) during radiological attacks and accidents, exploration of the universe, and radiation therapy [1,2,3]
It has been reported that the hematopoietic system and gastrointestinal (GI) tissues are especially sensitive to IR; it is extremely essential to develop countermeasures to protect these tissues from radiation injury [7, 8]
Our results demonstrated that compound 12 could improve the survival rates of mice that received fatal doses of irradiation

Summary

Introduction

Humans may be exposed to ionizing radiation (IR) during radiological attacks and accidents, exploration of the universe, and radiation therapy [1,2,3] Under these cases, IR can cause damage to macromolecules in cells through two mechanisms: direct action, in which direct deposition of radiant energy on biological molecules cause their ionization or excitation, or the indirect action, in which radiant energy acts on water molecules and produces reactive oxygen species (ROS), which can disrupt the structure of biomolecules [4]. The most effective aminothiol radioprotector is amifostine [8] It has a narrow preexposure time window and can only be administered via intravenous injection [14].

Methods

Discussion

Conclusion