Synthesis and biological activity of obatoclax derivatives as novel and potent SHP-1 agonists

Obatoclax is a linear oligopyrrole compound which antagonizes the antiapoptotic effects of the Bcl-2 family. Herein we describe the synthesis of obatoclax derivatives by replacement of the pyrrole and indole ring of obatoclax with thiophene, furan and thiazolidinedione. The in vitro cytotoxicity of the newly synthesized compounds is evaluated against hepatocellular carcinoma cells. Pyrrole and indole substituents of obatoclax analogues exhibited potent inhibition of cell growth. Among the tested compounds, 5d and 5e were active at 6.3 and 13.2 μM against PLC5 cells. Further assays confirmed a correlation between cell death, and p-STAT3 inhibition and SHP-1 activation by these analogues.

Oligopyrrole derivatives was synthesized with two steps. Sixteen Oligopyrrole derivatives were synthesized and evaluated for cytotoxicities against the PLC5 cell line by MTT assay. Compounds 5d and 5e had more significant antiproliferative ability and downregulation of p-STAT3.Figure optionsDownload as PowerPoint slideHighlights
► Synthesized 16 oligopyrrole derivatives which contain heterocyclic rings.
► Oligopyrrole derivatives have the cytotoxicity against HCC.
► The derivatives activate SHP-1 and suppress phosphorylation of STAT3.
► The derivatives repress downstream signals, cyclin D1 and Mcl-1, in PLC5 cells.