Synthesis, characterization andanticancer activity of 2-pyridineformamide derived Thiosemicarbazones

Abstract

Cancer is the leading cause of death worldwide and is presently responsible for about 25% of deaths in developed countries and for 13% of deaths in developing countries. A suitable and well established target for cancer therapy is Ribonucleotide Reductase (RR), the key enzyme involved in reduction of ribonucleotides into deoxyribonucleotides during DNA synthesis. Heterocyclic Thiosemicarbazones (HCTs) are the most potent inhibitor of RR. Many HCTs have been synthesized and are found to be active against selected cell lines resistant to the clinically used drugs hydroxyurea and gemcitabine. There is need to improve the potency of drugs in clinical use and search for the new and more effective drug candidates. In this research work a series of 2-pyridineformamide thiosemicarbazones with variations in pyridyl ring and N(4)-substitution were synthesized through transamination reaction and characterized by partial elemental analysis, IR, 1 H-

and 13 C-NMR spectroscopic techniques and HRFAB mass spectrometry. The synthesized compounds were evaluated for their anticancer activity against HeLa human cervical cancer cell line and also against PANC-1 human pancreatic cancer cell line utilizing antiausterity strategy. All the compounds exhibited potent cytotoxic activity. The compounds showed less potency against HeLa cells than the positive control paclitaxel. Conversely they exhibited potency higher than the controls paclitaxel and gemcitabine against PANC-1 cells under nutrient-deprived conditions. The potency of all compounds against PANC-1 cells under nutrient-deprived conditions was comparable with that of positive control arctigenin and nine of these compounds (compound no. 1, 6, 7, 12, 13, 17, 21, 22 and 23) were found to exhibit more potent preferential cytotoxicity than arctigenin. Morphological assessment of N'-(4-(pyridin-2-yl)piperazine-1-carbonothioyl)picolinohydrazonamide (compound 6) showed a dramatic alteration in the PANC-1 cell

morphology in ethidium bromide (EB)/acridine Orange (AO) staining assay. It was found to induce apoptosis against PANC-1 cells which was further supported by annexin-V (AV)/propidium iodide (PI) fluoresecence imaging assay. The present study indicated that 2-pyridineformamide thiosemicarbazones can be considered as powerful antiausterity agents for the development of therapeutics against deadly pancreatic cancers.

 R' Compounds H- 4-Me 5-F 6-Me

1 7 13 18

2 8 - 19

3 9 14 20

4 10 15 21

5 11 16 22 6 12 17 23