Synthesis and Biological Evaluation of New Ligustrazine Derivatives as Anti-Tumor Agents

Abstract

To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the “combination principle” in drug discovery. The ligustrazine derivatives’ anti-tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin-2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (<strong>4</strong>) and 3 α,12 α-dihydroxy-5β-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (<strong>5</strong>) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD₅₀ value of the compound <strong>5</strong> exceeded 3.0 g/kg by oral administration in mice.

Keywords

• angiogenesis
• anti-tumor
• combination principles
• ligustrazine derivatives
• low toxicity