Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

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.

Tetramethylpyrazine: An Active Ingredient of Chinese Herbal Medicine With Therapeutic Potential in Acute Kidney Injury and Renal Fibrosis

“…TMP has the effects of inhibiting platelet aggregation, reducing blood viscosity, increasing coronary flow, scavenging free radicals, protecting cerebral vessels, and expanding renal vessels ( Zou et al, 2018 ). The pyrazine ring on the TMP molecule is the key group for its pharmacological effect, but the methyl group in its side chain is easily excreted by oxidative metabolism, which leads to the short half-life of TMP and weakens its pharmacological effect ( Wang et al, 2019 ). Pharmacokinetic studies have shown that after oral or intravenous injection, TMP is mainly distributed in tissues such as liver, brain, kidney, and small intestine, and is eventually excreted from urine through the kidney ( Lou et al, 1986 ; Pan et al, 2021 ).…”

Design, synthesis, and biological evaluation of benzo[b]thiophene 1,1‐dioxide derivatives as potent STAT3 inhibitors

“…3,5,6‐Trimethylpyrazine‐2‐carboxylic acid and 2‐(bromomethyl)‐3,5,6‐trimethylpyrazine were prepared from tetramethylpyrazine (Ligustrazine). Details can be found in the reported method (Chen et al., 2015; Wang et al., 2019).…”

Unique indolizidine alkaloid securinine is a promising scaffold for the development of neuroprotective and antitumor drugs

“…[99][100][101] Numerous series of derivatives have been synthesized on the basis of ligustrazine including dimeric ones. 100,102,103 The patent 94 describes in detail the synthesis of bivalent compounds based on ligustrazine and securinine (Scheme 15) with the preliminary production of 2,5-bis(bromomethyl)-3,6dimethylpyrazine and aminosecurinine followed by their combination into a bivalent derivative. Thus, the use of a bivalent strategy for the synthesis of securinine derivatives is one of the promising trends for the production of active compounds.…”