title: Copper-obatoclax derivative complexes mediate DNA cleavage and exhibit anti-cancer effects in hepatocellular carcinoma.
abstract: Obatoclax is an indole-pyrrole compound that induces cancer cell apoptosis through targeting the anti-apoptotic Bcl-2 protein family. Previously, we developed a series of obatoclax derivatives and studied their STAT3 inhibition-dependent activity against cancer cell lines. The obatoclax analog, prodigiosin, has been reported to mediate DNA cleavage in cancer cells by coordinating with copper complexes. To gain an understanding of copper-obatoclax complex activity, we applied obatoclax derivatives to examine their copper-mediated nuclease activity as a means to establish a basis for structure activity relationship. Replacement of the indole ring of obatoclax with furanyl, thiophenyl or Boc-indolyl rings reduced the DNA cleavage ability. The same effect was achieved through the replacement of the obatoclax pyrrolyl ring with thiazolidinedione and thioacetal. Among the compounds tested, we demonstrated that the complex of obatoclax or compound 7 with copper exhibited potent DNA strand scission which correlated with HCC cell growth inhibition.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jung-Hua
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Cell Engineering Lab, Biomedical Technology and Device Research Labs, I Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Department of Chemistry, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Peter P-Y
authors.initials: PP
authors.lastname: Chen
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan. Electronic address: phtseng@ym.edu.tw.
authors.forename: Ping-Hui
authors.initials: PH
authors.lastname: Tseng
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan. Electronic address: cwshiau@ym.edu.tw.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D053837:DNA Cleavage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009942:Organometallic Compounds; D011758:Pyrroles; D003300:Copper; C520962:obatoclax
keywords: Copper; DNA cleavage; Obatoclax