title: Synthesis and biological activity of obatoclax derivatives as novel and potent SHP-1 agonists.
abstract: 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.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chen
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D007211:Indoles; D015394:Molecular Structure; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011758:Pyrroles; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C520962:obatoclax