Synthesis and Anticancer Potential of New Hydroxamic Acid Derivatives as Chemotherapeutic Agents

Abstract

Histone deacetylase (HDAC) inhibitors have been shown to induce differentiation, cell cycle arrest, and apoptosis due to their low toxicity, inhibiting migration, invasion, and angiogenesis in many cancer cells. Studies show that hydroxamic acids are generally used as anticancers. For this reason, it is aimed to synthesize new derivatives of hydroxamic acids, to examine the anticancer properties of these candidate inhibitors, and to investigate the inhibition effects on some enzymes that cause multidrug resistance in cancer cells. For this reason, new (4-amino-2-methoxy benzohydroxamic acid (a), 4-amino-3-methyl benzohydroxamic acid (b), 3-amino-5-methyl benzohydroxamic acid (c)) amino benzohydroxamic acid derivatives were synthesized in this study. The effects on healthy fibroblast, lung (A549), and cervical (HeLa) cancer cells were investigated. In addition, their effects on TRXR1, GST, and GR activities, which are important for the development of chemotherapeutic strategies, were also examined. It was determined that molecule b was the most effective molecule in HeLa cancer cells with the lowest IC₅₀ value of 0.54. It was determined that molecule c was the most effective molecules for A549 and HeLa cancer cells, with the lowest IC₅₀ values of 0.78 mM and 0.25 mM, respectively. It was determined that b and c molecules directed cancer cells to necrosis rather than apoptosis. c molecule showed anticancer effect in A549 and HeLa cancer cells. It was found that molecule c significantly suppressed both GR and TRXR1 activities. In GST activities, however, inhibitors did not have a significant effect on cancer cells.

Keywords: Anticancer; Enzyme activity; HDAC inhibitors; Hydroxamic acid.