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

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.

Radioprotection and Radiosensitization: A Modern View on Radiomodulators in Pharmacology

“…Механизм, лежащий в основе защитного действия амифостина, комплексный, он включает в себя антирадикальное действие, усиленную защиту и репарацию ДНК, а также индукцию гипоксии [34]. Несмотря на прогресс, достигнутый в повышении эффективности амифостина, проблема его токсичности не решена, поэтому изучаются новые препараты на основе аминотиолов [35].…”

Radioprotective countermeasures for radiation injury (Review)

“…Ionizing radiation (IR) refers to energy released by atoms in the form of particles (neutrons, α or β particles) or electromagnetic waves (X-or γ-rays), which is sufficient to ionize atoms or molecules ( 1 ). Exposure to IR from these sources, including natural and artificial radiation, can have lethal consequences ( 2 , 3 ). The effects of IR are divided into deterministic effects, such as acute radiation sickness and radiation cataracts, and stochastic effects, such as radiation-induced cancer and genetic diseases ( 4 ).…”

ROS-Responsive and pH-Sensitive Aminothiols Dual-Prodrug for Radiation Enteritis

“…Much progress has been made in the synthesis and screening of radioprotective compounds, such as aminothiols [ 10 , 11 , 12 , 13 ], polyphenols [ 14 , 15 ], and growth factors [ 16 , 17 ]. As radical scavengers, aminothiols provide H atoms to scour hydroxyl radicals or other ROS [ 18 , 19 , 20 ].…”