Novel 1,2,4-triazole derivatives as antitumor agents against hepatocellular carcinoma

- Novel 1,2,3-triazole derivatives were prepared.
- All compounds were screened for their anticancer activity against HEPG2 cell lines.
- The most promising derivative 12 was tested for its degree of toxicity (LD 50).
- Antitumor mechanisms of triazolothiadiazine derivative 12 are discussed.
- Derivative 12 could be promising anti HCC agent.

Fifteen novel 1,2,3-triazole derivatives were prepared in series of synthetic steps starting from 4-amino-5-hydrazino-4H-1,2,4-triazole-3-thiol 1. The structures of the obtained compounds were verified through micoanalytical and spectral data. All the compounds were screened for their anticancer activity against liver human cancer cell lines (HEPG2) using Doxorubicin as standard. The most promising triazolothiadiazine derivative 12 was further tested for its degree of toxicity by estimating the median lethal dose (LD 50) and its antitumor activity through inhibiting the angiogenesis and progression of tumor against diethylnitrosamine (DENA)/CCl4 induced hepatocellular carcinoma (HCC) in rats. To elucidate its mechanism of action, the following parameters were determined including: vascular endothelial growth factor (VEGF) as a marker of angiogenesis; hepatic tyrosine kinase (HTK) as a marker for tumor growth; serum alpha fetoprotein (AFP) as a marker for hepatocarcinoma; aspartate and alanine aminotransferases (AST & ALT) as liver function test; malondialdehyde (MDA) and glutathione (GSH) as markers of antioxidant activity. Liver histopathological analysis was also evaluated. Carcinogenic rats showed drastic elevation in all investigated parameters accompanied by reduction in hepatic glutathione. Administration of compound 12 into rats after induction of experimental HCC, improved the biochemical changes induced by DENA/CCl4. These observations were supported by histopathological study of liver sections. It was concluded that triazolothiadiazine compound 12 could be promising anti HCC agent after more investigations on higher animals.

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