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Takacs D.,Hungarian Academy of Sciences | Nagy I.,Hungarian Academy of Sciences | Nagy I.,Bioblocks Magyarorszag Kft | Bombicz P.,Hungarian Academy of Sciences | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

N-dienylphenothiazines synthesized from tetrazolo[1,5-a]pyridinium salts by treatment with phenothiazine were subjected to catalytic hydrogenation to yield N-butylphenothiazines, whereas transformation of these dienes with borane dimethyl sulfide (BH3 × Me2S) resulted in selective hydroboration of one double bond and full reduction of the other double bond to give 2-hydroxybutylphenothiazines. Position of the hydroxyl group was supported by NMR spectroscopy and verified by X-ray analysis. Comparison of MDR modulatory activity of the new derivatives revealed that the hydroxybutyl compounds are promising candidates for development of novel MDR inhibitors. © 2012 Elsevier Ltd. All rights reserved.

Boganyi B.,BioBlocks Magyarorszag Kft. | Boganyi B.,Eötvös Loránd University | Kaman J.,BioBlocks Magyarorszag Kft.
Tetrahedron | Year: 2013

The indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3), and isoneocryptolepine (4) are important tools in traditional medicine. Now, their precursors 1a-4a were synthesized in two steps starting from the corresponding bromo-iodoquinolines. Our strategy is based on palladium-catalyzed reactions, applying regioselective Buchwald-Hartwig amination on 2,3- and 3,4-dihaloquinolines followed by an intramolecular Heck-type reaction. Both steps were carried out under microwave irradiation. © 2013 Elsevier Ltd. All rights reserved.

Zsila F.,Institute of Biomolecular Chemistry | Kaman J.,BioBlocks Magyarorszag Kft. | Boganyi B.,BioBlocks Magyarorszag Kft. | Jozsvai D.,Institute of Biomolecular Chemistry
Organic and Biomolecular Chemistry | Year: 2011

Non-covalent binding of planar aromatic molecules into the S1 specificity pocket of the serine protease α-chymotrypsin (αCHT) can be detected by measuring induced circular dichroism (CD) spectroscopic signals. Utilizing this phenomenon, αCHT association of proflavine (PRF), the well known serine protease inhibitor has been investigated together with plant-derived compounds including isoquinoline, pyridocarbazole and indoloquinoline alkaloids, of which αCHT binding has never been reported. Non-degenerate exciton coupling between π-π* transitions of the ligand molecules and two tryptophan residues (Trp172 and Trp215) near to the binding site is proposed to be responsible for the induced CD activity. The association constants calculated from CD titration data indicated strong αCHT association of sanguninarine, ellipticine, desmethyl-isocryptolepine and isoneocryptolepine (Ka ≈ 105 M-1) while berberine, coptisine and chelerythrine bind to the enzyme with lower, PRF-like affinity (K a ≈ 104 M-1). PRF-trypsin and ellipticine-trypsin binding interactions have also been demonstrated. The binding of the alkaloids into the S1 pocket of αCHT has been confirmed by CD competition experiments. Molecular docking calculations showed the inclusion of PRF as well as the alkaloid molecules in the S1 cavity where they are stabilized by hydrophobic and H-bonding interactions. These novel nonpeptidic scaffolds can be used for developing selective inhibitors of serine proteases having chymotrypsin-like folds. Furthemore, the results provide a novel, CD spectroscopic based approach for probing the ligand binding of αCHT and related proteases. © 2011 The Royal Society of Chemistry.

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