title: Nature-inspired design of tetraindoles: Optimization of the core structure and evaluation of structure-activity relationship.
abstract: Building on the initial successful optimization of a novel series of tetraindoles, a second generation of the compounds with changes in the core phenyl ring was synthesized to improve anticancer properties. 17 new compounds with different rigidity, planarity, symmetry and degree of conjugation of their core structures to 5-hydroxyindole units were synthesized. All the compounds were fully characterized and tested against breast cancer cell line (MDA-MB-231). The results revealed that the core structure is required for activity and it should be aromatic, rigid, planar, symmetrical and conjugated for optimal activity. Compound 29, which has strong anticancer activity against various tumor-derived cell lines, including Mahlavu (hepatocellular), SK-HEP-1 (hepatic), HCT116 (colon), MIA PaCa-2 (pancreatic), H441 (lung papillary), A549 (lung), H460 (non-small cell lung) and CL1-5 (lung carcinoma) with IC50 values ranging from 0.19 to 3.50μM, was generated after series of successive optimizations. It was found to induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in the non-obese diabetic-severe combined immunodeficiency (NOD/SCID) mice bearing xenografted MIA PaCa-2 human pancreatic cancer.
authors: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors: Hajjaj H M
authors: HHM
authors: Abdu-Allah
authors: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.
authors: Shih-Ting
authors: ST
authors: Huang
authors: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors: Tzu Ting
authors: TT
authors: Chang
authors: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors: Chia-Ling
authors: CL
authors: Chen
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan. Electronic address: hcw0928@gate.sinica.edu.tw.
authors: Han-Chung
authors: HC
authors: Wu
authors: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. Electronic address: wenshan@gate.sinica.edu.tw.
authors: Wen-Shan
authors: WS
authors: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D013329:Structure-Activity Relationship; D014992:Xylenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C572350:1,4-bis(di(5-hydroxy-1H-indol-3-yl)methyl)benzene; D007211:Indoles; D014992:Xylenes
keywords: Anticancer; Apoptosis; Core; Planarity; Tetraindoles