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 (4) and 3 α,12 α-dihydroxy-5β-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD₅₀ value of the compound 5 exceeded 3.0 g/kg by oral administration in mice.

Scheme 1

Synthesis routes to ligustrazine derivatives.

Figure 1

Microvascular proliferation of 4 and 5 on CAM (×50). (a) Control for compound 4 group. (b) 10 μg/egg for compound 4 group. (c) 40 μg/egg for compound 4 group. (d) Control for compound 5 group. (e) 10 μg/egg for compound 5 group. (f) 40 μg/egg for compound 5 group.