- Predicting the Substrate Scope of the Flavin-Dependent Halogenase BrvH
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The recently described flavin-dependent halogenase BrvH is able to catalyse both the bromination and chlorination of indole, but shows significantly higher bromination activity. BrvH was annotated as a tryptophan halogenase, but does not accept tryptophan as a substrate. Its native substrate remains unknown. A predictive model with the data available for BrvH was analysed. A training set of compounds tested in vitro was docked into the active site of a complete protein model based on the X-ray structure of BrvH. The atoms not resolved experimentally were modelled by using molecular mechanics force fields to obtain this protein model. Furthermore, docking poses for the substrates and known non-substrates have been calculated. Parameters like distance, partial charge and hybridization state were analysed to derive rules for predicting activity. With this model for activity of the BrvH, a virtual screening suggested several structures for potential substrates. Some of the compounds preselected in this way were tested in vitro, and several could be verified as convertible substrates. Based on information on halogenated natural products, a new dataset was created to specifically search for natural products as substrates/products, and virtual screening in this database yielded further hits.
- Neubauer, Pia R.,Pienkny, Silke,Wessjohann, Ludger,Brandt, Wolfgang,Sewald, Norbert
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- Synthesis and biological evaluation of analogs of the marine alkaloids granulatimide and isogranulatimide
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A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC50 growth inhibitory concentrations ranging between 10 and 20 μM, displayed cytostatic, not cytotoxic, anticancer effects.
- Deslandes, Sebastien,Lamoral-Theys, Delphine,Frongia, Celine,Chassaing, Stefan,Bruyere, Celine,Lozach, Olivier,Meijer, Laurent,Ducommun, Bernard,Kiss, Robert,Delfourne, Evelyne
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- Synthesis of two series of pyrazolic analogues of the marine alkaloids granulatimide and isogranulatimide as potent Checkpoint 1 kinase inhibitors
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Two series of regioisomeric pyrazolic analogues of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the first series was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrazole followed by addition of the intermediates on dibromomaleimide, the so-obtained acyclic adducts being finally photochemically cyclised to the desired analogues. Compounds of the second series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclisation of the adducts.
- Deslandes, Sébastien,Chassaing, Stefan,Delfourne, Evelyne
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- Synthesis and anti-tumor activity of marine alkaloids
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Marine alkaloids were divided into five categories from the perspective of anti-tumor activity. The optimization process, chemical synthesis, anti-tumor activity evaluation and structure–activity relationship of various compounds were discussed.
- Zhou, Shiyang,Huang, Gangliang,Chen, Guangying
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- PhI(OAc)2/NaX-mediated halogenation providing access to valuable synthons 3-haloindole derivatives
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This paper describes a mild phenyliodine diacetate mediated method for selective chlorination, bromination, and iodination of indole C-H bonds using sodium halide as a source for analogous halogenations. The combination of NaX and phenyliodine diacetate provides an invincible system for halogenation of indoles. This protocol was compatible with a wide array of indole substrates and provides straight forward access to potential halogenated arenes.
- Himabindu, Vittam,Parvathaneni, Sai Prathima,Rao, Vaidya Jayathirtha
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p. 18889 - 18893
(2018/11/27)
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