Novel 1,3,4-thiadiazole–chalcone hybrids containing catechol moiety: synthesis, antioxidant activity, cytotoxicity and DNA interaction studies

Abstract

Hybrid compounds that combine the 1,3,4-thiadiazole-containing catechol moiety with a chalcone motif were synthesized and examined for their antioxidant activity, cytotoxicity, and DNA-binding activity. A series of thirteen compounds showed strong antioxidant and cytotoxic effects on human acute promyelocytic leukemia HL-60 cells. Several compounds exerted good cytotoxic activities on cervical adenocarcinoma HeLa cells. The treatment of HeLa cells with IC₅₀ and double IC₅₀ concentrations of the compounds <b>5a</b>, <b>5c</b>, <b>5f</b>, and <b>5m</b> induced a statistically significant increase in the percentage of cells within a subG1 cell cycle phase. The examined compounds caused G2/M cell cycle arrest in HeLa cells. Each of these compounds triggered apoptosis in HeLa cells through activation of caspase-3, the main effector caspase, caspase-8, which is involved in the extrinsic apoptotic pathway, and caspase-9, which is involved in the intrinsic apoptotic pathway. All of the examined compounds decreased the expression levels of MMP2 in HeLa cells and levels of protumorigenic miR-133b. Compounds <b>5a</b> and <b>5m</b> lowered the expression level of oncogenic miR-21 in HeLa cells. In addition, compounds <b>5a</b>, <b>5f</b>, and <b>5m</b> decreased the expression levels of oncogenic miR-155 while the treatment of HeLa cells with compounds <b>5a</b>, <b>5c</b>, and <b>5f</b> increased expression of tumor-suppressive miR-206. Observed effects of these compounds on expression levels of four examined miRNAs suggest their prominent cancer-suppressive activity. An investigation by absorption and fluorescence spectroscopy showed more efficient calf thymus DNA binding activity of the compound <b>5m</b> in comparison to other tested compounds. Results of a pUC19 plasmid cleavage study and comet assay showed DNA damaging activities of compounds <b>5a</b> and <b>5c</b>.