Design, synthesis, antiproliferative activity, and cell cycle analysis of new thiosemicarbazone derivatives targeting ribonucleotide reductase

Abstract

Thiosemicarbazones are potential anticancer agents. In this study, we designed and synthesized new thiosemicarbazone derivatives as anticancer agents. The antiproliferative activity of compounds (IIIa, IIIb, IIIe, IIIh, and IIIi) selected by The National Cancer Institute (USA) was investigated in vitro in 60 cancer cell lines. The initial results of the screening of these compounds revealed encouraging anticancer activity. The enzyme inhibitory activity of the compounds against ribonucleotide reductase was then evaluated. It was found that compounds IIIa, IIIe, and IIIh show the most potent inhibitory activity with IC50 (1.51, 2.41, and 2.85 μM, respectively). Flow cytometric analysis showed that compound IIIa induced apoptosis and cell cycle arrest in the G2/M phase. Additionally, according to the gene expression report, compound IIIa upregulated p53, BAX, and caspase-3 expression and down regulated Bcl-2 expression. Thus, IIIa exerted potent inhibitory activity against RNR and a strong pro-apoptotic effect by activating the intrinsic apoptotic pathway.

Keywords

• Thiosemicarbazone
• Antitumor
• Ribonucleotide reductase
• Apoptosis
• Cell cycle arrest