title: Anticancer efficacy of unique pyridine-based tetraindoles.
abstract: Results of previous studies demonstrated that the tetraindole, SK228, which has a high lipid but low water solubility, displayed moderate anticancer efficacy in a xenograft model of breast cancer. This finding led to the proposal that new, pyridine based tetraindole (PBT) analogs of SK228, containing tetraindole moieties distributed about central protonated pyridine cores, would have enhanced bioavailabilities and anticancer efficacies. Among the PBTs prepared and subjected to biological studies, 3f (FCW81) was observed to display the highest antiproliferative activity against the two triple negative breast cancer (TNBCs) cell lines, MDA-MB-231 and BT549. In addition, its mode of action was shown to involve G2/M arrest of the cell cycle along with the promotion of increased levels of cyclin B1 and p-chk2 and a decreased level of p-cdc2. DNA damage and induction of apoptosis caused by FCW81 was found to be associated with a decrease in DNA repair. Significantly, FCW81 displays therapeutic efficacy in a xenograft model of human breast cancer by not only serving to inhibit markedly the growth of cancer cells but also to block effectively cancer cell metastasis. Collectively, the results of these studies have led to the identification of novel pyridine-tetraindole based anticancer agents with potential use in TNBC therapy.
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Department of Chemistry, National Central University, Taoyuan City 32001, Taiwan.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Fu
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Hsieh
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Tzu Ting
authors.initials: TT
authors.lastname: Chang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-yi County 621, Taiwan.
authors.forename: Anne
authors.initials: A
authors.lastname: Liao
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. Electronic address: wenshan@gate.sinica.edu.tw.
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014992:Xylenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C572350:1,4-bis(di(5-hydroxy-1H-indol-3-yl)methyl)benzene; D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D014992:Xylenes; C023666:pyridine
keywords: Antiproliferative activity; Apoptosis; Cell cycle arrest; Metastasis; Pyridine-based tetraindoles; Triple negative breast cancer