Nano-cuprous oxide catalyzed one-pot synthesis of a carbazole-based STAT3 inhibitor: a facile approach via intramolecular C-N bond formation reactions

In this study, we report the one-pot synthesis of substituted carbazole derivatives using nano cuprous oxide as a catalyst via intramolecular C-N bond forming reactions. Among the synthesized carbazoles, 3'-((3-acetyl-6-chloro-9H-carbazol-9-yl) methyl)-[1,10-biphenyl]-2-carbonitrile (ACB) was identified as a lead antiproliferative agent against lung cancer cell lines A549 and LLC with an IC50 of 13.6 and 16.4 mu M respectively. Furthermore, we found that the lead compound suppresses the constitutive phosphorylation of STAT3 (Tyr-705) in A549, HCC-2279 and H1975 cells. We analyzed the levels of phospho-STAT3 and LSD1 in the nuclear extract of ACB treated HCC-2279 cells to evaluate the transcriptional activity of STAT3. We found the downregulation of phospho-STAT3 without any change in the expression of LSD1 indicating that ACB downregulates the transcriptional activity of STAT3. Molecular docking analysis revealed that ACB makes a favorable interaction with Arg-609 and Ser-613 in the pTyr site of the SH2 domain of STAT3.