Design, synthesis, in vitro and in silico anticancer activity evaluation of novel thiosemicarbazide/butanoic acid hybrids
TL;DR
3e was found to have selective cytotoxic activity against cancer cells, which didn’t cause significant damage to non-cancerous cells, and may be effective on cancer patients without showing any side effects.
Abstract
Abstract Cancer is one of the world’s most deadly diseases. According to the American Cancer Society, 2 million people in the US are diagnosed with cancer, and nearly half of the patients died in 2024. Many challenges need to be overcome when treating cancer, such as the destructive effect of long-term treatment and drug resistance. To overcome these problems, the synthesis of 4-oxo-4-(4-(2-oxo-2-(2-(substitutedcarbamothioyl)hydrazinyl)ethoxy)phenyl)butanoic acid derivatives (3a-3f) was designed, and activity studies were performed. Nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared spectroscopy (FTIR), and high-performance liquid chromatography (HPLC) were used for structural analysis. Cytotoxicity studies of the synthesized compounds were carried out on NIH3T3 (non-cancerous mouse embryonic fibroblast), MCF7 (breast cancer), and A549 (human lung carcinoma) cells. The IC50 value of 3e was determined to be 8.495 ± 0.367 µM in A549 cells, and 50.132 ± 0.901 µM in MCF7 cells. In addition, 3e was found to have selective cytotoxic activity against cancer cells, which didn’t cause significant damage to non-cancerous cells. This way, our molecule may be effective on cancer patients without showing any side effects. In silico studies showed that 3e and 3f interacted with the allosteric cavity of the caspase-3 enzyme. Both showed similar localization on the enzyme. Consequently, both compounds have been brought to literature as potential antiproliferative molecules with selective cytotoxicity. GRAPHICAL ABSTRACTMulti-panel figure illustrating molecular structures, flow cytometry data, and interactions between 3e and enzyme.The figure contains four panels. The top left displays a reaction scheme for the transformation of a starting molecule into compound 3e, with chemical structures labeled 3a-3f. The top right shows a flow cytometry plot with FITC-A and SSC-A axes highlighting population distributions P2 (97.02%) and P3 (2.97%). The bottom left features 3D representation of interactions between 3e and enzyme, and the bottom right presents a detailed diagram of interactions among surrounding amino acids and water.