Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

Abstract

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds <b>3c</b> and <b>4a</b> were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC₅₀ values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, <b>3c</b> inhibited seven different kinases and <b>4a</b> strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that <b>3c</b> and <b>4a</b> caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound <b>3</b><b>c</b> induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound <b>4a</b> inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).