Synthesis, antitumor activity evaluation, and DNA-binding study of coumarin-based agents

A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, ¹ H NMR, ¹³ C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60-cell line panel according to the US NCI-DTP protocol or a selection of human tumor cell lines: breast cancer (MCF-7), liver cancer (HepG-2), and colorectal cancer (HCT-116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with K_SV  = 4.27 × 10⁵  M^-1 . Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with K_SV 4.27 × 10⁵ , 3.96 × 10⁵ , and 3.51 × 10⁵  M^-1 , respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL-60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC₅₀ value of 24.9 μg/mL against the HepG-2 cell line.