Abstract
Bivalent and polyvalent inhibitors can be used as antitumor agents. In this experiment, eight ligustrazine dimers and seven ligustrazine tetramers linked by alkane diamine with different lengths of carbon chain lengths were synthesized. After screening their antiproliferation activities against five cancer cell lines, most ligustrazine derivatives showed better cytotoxicity than the ligustrazine monomer. In particular, ligustrazine dimer 8e linked with decane-1,10-diamine exhibited the highest cytotoxicity in FaDu cells with an IC50 (50% inhibiting concentration) value of 1.36 nM. Further mechanism studies suggested that 8e could induce apoptosis of FaDu cells through the depolarization of mitochondrial membrane potential and S-phase cell cycle arrest. Inspired by these results, twenty-seven additional small molecule heterocyclic dimers linked with decane-1,10-diamine and nine cinnamic acid dimers bearing ether chain were synthesized and screened. Most monocyclic and bicyclic aromatic systems showed highly selective anti-proliferation activity to FaDu cells and low toxicity to normal MCF 10A cells. The structure-activity relationship revealed that the two terminal amide bonds and the alkyl linker with a chain length of 8–12 carbon were two important factors to maintain its antitumor activity. In addition, the ADMET calculation predicted that most of the potent compounds had good oral bioavailability.
Highlights
Natural products play a vital role in the development of the drug, especially anticancer drugs [1].Ligustrazine (2,3,5,6-tetramethylpyrazine, TMP), an important component of the Chinese traditional medicinal herb Chuanxiong (Ligusticum chuanxiong Hort), has been of wide clinical use for cardiovascular and cerebrovascular diseases [2]
Many ligustrazine derivatives with potent antitumor activity have been developed in the past few years, like monocarbonyl ligustrazine-curcumin hybrids [5], ligustrazine-betulinic acid hybrids [6], and ligustrazine-rhein derivatives [7]
As ligustrazine dimer 8e had the most potent antiproliferative activity in all synthesized compounds, the colony formation assay in FaDu cells was conducted
Summary
Natural products play a vital role in the development of the drug, especially anticancer drugs [1]. FaDu cell in this field has designed and synthesized several ligustrazine dimers linked by cyclohexanone diamine, which had potent anti-proliferative ability in FaDu or A549 cell lines. Their IC50 in FaDuand cell lines less μM, in and nM oxime [14], curcumin or triterpenes [16],of had(benzothiophene-2-carboxyl). This demonstrated the dimers and tetramers linked with different alkyl diamines and screened their anti-proliferation the same alkyl chain with two terminal ester bonds instead of amide bonds This demonstrated the vital of amide bonds in activity. Vital role role on of two-terminal two-terminal amide bondscell in antitumor antitumor activity Based on these experimental results, the linked importance of similar small molecular heterocyclic rings inhibition of compounds compounds. FaDu cells than orthoorthoand metameta- substituted substituted analogs
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