1-Isobutanoil-2-isopropylisothiourea Phosphate, T1082: A Safe and Effective Prevention of Radiotherapy Complications in Oncology

Abstract

The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till–McCulloch’s test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated β-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12–1/8 LD10), both parenterally and intragastrically. In this case, its therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses (ED84–98—141–224 mg/kg) are an order less than the maximum tolerated doses—1/16–1/10 LD10. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) β-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.

Preclinical studies of NOS inhibitor T1059 vasopressor activity on the models of acute hemorrhagic shock in rats and dogs

“…So, some time ago, while screening linear and cyclic isothioureas, we identified and synthesized a large group of isothiourea derivatives (Figure 1A) that are competitive inhibitors of NOS (Proskuryakov et al, 2002(Proskuryakov et al, , 2005Proskuryakov et al, 2010;Filimonova et al, 2012a). Further, we found that some compounds of this group (such as T1023, T1082, T1084) are promising for further pharmacological development-as hypoxic radioprotectors that provide effective prevention of hematopoietic and gastrointestinal acute radiation syndromes, and radiotherapy complications (Filimonova et al, 2020b(Filimonova et al, , 2021(Filimonova et al, , 2022bSaburova et al, 2020), as well as antitumor, antiangiogenic agents (Filimonova et al, 2019a;2019b;2022a).…”