Anti-tumor and anti-metastatic properties of bromo- and bis(2-chloroethyl)amino-substituted derivatives of N-methyl ethyl esters of indole-3-carboxylic acid in the S-37 sarcoma mouse model

The Laboratory of Radiation Pharmacology has previously developed water-­soluble dialkylaminoalkyl esters of indole‑3‑carboxylic acid, which demonstrated high immunomodulatory, antiviral, and antitumor activity. Based on these established properties, we aimed to enhance their antitumor effect by incorporating cytotoxic alkylating bromo- or bis(2‑chloroethyl)amino substituents into their molecular structure. Compounds T1167 and T1089 were successfully synthesized. Purpose of the study . To investigate the antitumor and antimetastatic properties of bromo-, bis(2‑chloroethyl)amino-substituted derivatives of N-methyl ethyl esters of indole‑3‑carboxylic acid (T1089 and T1167). Materials and methods . The study was performed on 65 mice with subcutaneously transplanted lymphogenously metastasizing sarcoma S‑37 (9 × 10 5 cells/mouse). Compounds were administered intraperitoneally: T1089 at 40 mg/kg, T1167 at 30 mg/kg. Antitumor efficacy was assessed by primary tumor growth dynamics, morphometric and histological parameters. Results . The studied compounds inhibited primary tumor growth of sarcoma S‑37 (TGI for T1089–22,4 %, for T1167–30,5 %), increased dystrophic and necrotic changes in tumors (T1089 – by 36 %, T1167 – by 55 %), reduced mitotic index by 2‑fold, and exhibited antimetastatic activity, decreasing metastatic areas in inguinal lymph nodes (day 10: T1089 – by 76 %, T1167 – by 89 %) and iliac lymph nodes (day 10: T1089 – by 28,7 %, T1167 – by 60,8 %; day 16: T1089 – by 53,3 %, T1167 – by 45,6 %). Conclusion . Antitumor and antimetastatic activity of compounds T1089 and T1167 was demonstrated in the sarcoma S‑37 model. The obtained data indicate the promise of compounds combining alkylating cytotoxicity with the immunomodulatory potential inherent to this class. Further research will involve preclinical development including safety assessment, expansion of the range of tumor models studied, and detailed investigation of the mechanisms of action.