Even though phenazines have been extensively reported as anticancer molecules, the molecular target of these compounds is severely lagging behind. Our study consequently focuses on the anticancer target of a phenazine analogue (
CPUL1
) for its potently antitumor activities in initial stage. Along with redox status courses of Hep G2 cells, thioredoxin reductase I (TrxR1) was speculated as anticancer target of
CPUL1
. By virtue of zymologic, immunological and molecular biological experiments, we demonstrated that TrxR1 could be the anticancer target of
CPUL1
. The knowledge on phenazine targeting to TrxR1 have not been reported previously. Thus, it can provide valuable information for further development of the TrxR1 inhibitors.
Aim and Objective:
Small molecule targeted drugs can effectively reduce the toxicity
and side effects of drugs, and improve the efficacy of drugs by their specific antitumor activity.
Hence, the development of small molecular targeted drugs for cancer has important significance.
This study was undertaken to design and synthesize novel phenazine-chromene hybrid molecules
in order to optimize the structure and improve the efficacy of this kind of hybrids.
Materials and Methods:
O-diaminobenzene was used as starting material to synthesize twentyfour
heterocyclic compounds designed as hybrid molecules of phenazine and 4H-chromene
pharmacophores by facile methods. The structures of the compound were confirmed by 1H NMR,
13C NMR and HRMS. Furthermore, the synthesized compounds were evaluated for in vitro activity
against four human cancer cell lines and two non-cancer cell lines by MTT test.
Results:
Some compounds showed strong cytotoxic activities against HepG2 and A549 cancer
lines (IC50 = 5-10 µM). Comparing 2i with 2l, the introduction of hydrophilic groups on the
phenazine core could not improve the antiproliferative activity significantly. Except 2d and 3c,
compounds owning chlorine substituent on the 4H-chromene pharmacophore seemingly contribute
to enhance the compounds’ antiproliferative activity. Specially, compound 3c showed highest
cytotoxicity against A549 cells with IC50 values of 3.3±0.4 µM. Furthermore, all compounds
showed low or no cytotoxicity against HUVEC and L02 non-cancer cells in vitro.
Conclusion:
Compound 3c may be used as potential lead molecule against A549 cancer cells.
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