Preclinical studies of cytotoxicity and cytostatic activity of five new imidazotriazine derivatives in MDA-MB231, BT474, and MCF-7 breast cancer cell cultures

Background. The results of the study of new imidazotriazine derivatives are presented to support their use as antitumor agents, including for breast cancer (BC) chemotherapy. The study is relevant due to the high prevalence and mortality of BC and other socially significant cancers. Antitumor drugs have limitations in their efficacy due to the primary or acquired drug resistance. As a result, 30% to 50% of patients do not receive adequate treatment, determining the need to develop new antitumor drugs. Aim. To evaluate the antitumor potential of 5 new imidazotriazine derivatives by testing their cytotoxic (CTA) and cytostatic (CSA) activity on BC cell cultures. Materials and methods. Culture of MCF-7, MDA-MB231, BT474, and MCF-10a cells and determination of CTA and CSA of imidazotriazine derivatives at concentrations ranging from 0.25 to 10.0 mmol/L. Results. For the MCF-7 culture, the maximum cell survival inhibition by the comparator (temozolomide) was 2.44, and the concentration causing 50% cell death (IC50) was 6.81 mmol/L; for other cell cultures, CTAs were slightly lower. Imidazotriazine 2 and imidazotriazine 3 showed values below or close to temozolomide; IC50 was not achieved in most cases. These two derivatives were considered to have low CTA and moderate CSA. Imidazotriazine 4 and imidazotriazine 5 showed higher activity than the comparator and were considered compounds with moderate CTA and CSA. Finally, imidazotriazine 1 showed the highest CTA and CSA values with a maximum cell survival inhibition of 4.35 and an IC50 of 1.94 mmol/L. Conclusion. Based on the results of the in vitro study, five new imidazotriazine derivatives have CTA and CSA in the following ascending order: imidazotriazine 2, imidazotriazine 3 temozolomide imidazotriazine 4 imidazotriazine 5 imidazotriazine 1. Therefore, 4-aminoimidazo[5,1-c][1,2,4]triazine-3,8-dicarboxylic acid diethyl ether (imidazotriazine 1) is the most promising new imidazotriazine derivative and is recommended for further preclinical studies.