A N-(4-chlorophenyl)-γ-amino acid derivatives exerts in vitro anticancer activity on non-small cell lung carcinoma cells and enhances citosine arabinoside (AraC)-induced cell death via mitochondria-targeted pathway

Abstract

A Non-Small Cell Lung Cancer (NSCLC) is among the leading cause of cancer-associated morbidity and mortality worldwide. Novel treatment and drug repurposing strategies are needed. Cytosine arabinoside (AraC) is an S-phase inhibitor historically used for the treatment of leukemia. Previously AraC was not investigated as a therapeutic option for NSCLC. We explored a novel adjuvant therapy concept in vitro targeting S-phase and mitochondrial pathways. A synthetic pathway to generate novel mitochondria damaging N-(4-chlorophenyl)-γ-amino acid derivatives bearing an azole, diazole and triazole moieties was described. The resulting compounds were evaluated for their anticancer activity on well described A549 cells. Five compounds demonstrated convincing anticancer activity comparable to cytosine arabinoside (AraC). The most promising compound 7g (IC50 = 38.38 µM) bearing 3,4-dichlorophenyl moiety was able to induce the mitochondrial injury, leading to significant (p < 0.05) ROS production and inhibition of ATP synthesis. 7g synergized with AraC and significantly decreased A549 viability in comparison to AraC and 7g monotherapy or UC. The cytotoxic effect on A549 viability after AraC combination with 7g was similar to doxorubicin monotherapy. These results suggest that 7g could be potentially explored adjuvant enhancing the activity of standard chemotherapeutic agents. Further studies are needed to better understand the safety, efficacy, and precise cellular targets of of N-(4-chlorophenyl)-γ-amino acids.