- Microenvironmental effects on the solvent quenching rate in constrained tryptophan derivatives
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Solvent quenching is one of several environmentally sensitive nonradiative decay pathways available to the indole chromophore. It is characterized by 2-3-fold deuterium isotope effects and strong temperature dependence with frequency factors of 1015-1017 s-1 and activation energies of 11-13 kcal/mol in aqueous solution. The effects of ionization state, proximity of the amino group to the indole ring, and N-methylation of indole nitrogen on the solvent quenching rate were examined in four constrained tryptophan derivatives: 1,2,3,4-tetrahydro-2-carboline, 3-amino-1,2,3,4-tetrahydrocarbazole, 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, and 9-methyl-1,2,3,4-tetrahydro-2-carboline-3-carboxylic acid. The constrained derivatives had at most two ground-state conformations, as determined by X-ray crystallography, molecular mechanics calculations, and 1H NMR. Fluorescence lifetimes were assigned to ground-state conformations based on relative populations of conformers and amplitudes of fluorescence decays. Solvent quenching rates were determined from the temperature dependence of the fluorescence lifetime. The solvent quenching rate is decreased by protonation of the amino group in all compounds. It is slower in the carboline derivatives, where the amino group is two bonds away from the indole ring, than in the tetrahydrocarbazole derivatives, where the amino group is three bonds away. In the tetrahydrocarbazoles, the solvent quenching rate is slower in the conformer with the ammonium in the pseudoaxial position closer to the indole ring than in the conformer with the ammonium in the pseudoequatorial position pointing away from the ring. These results suggest that the water quenching rate of tryptophans on protein or peptide surfaces is modulated by proximal ammonium groups.
- Yu, Hong-Tao,Vela, Marco A.,Fronczek, Frank R.,McLaughlin, Mark L.,Barkley, Mary D.
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- Cutting short the asymmetric synthesis of the ramatroban precursor by employing ω-transaminases
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Starting from an adequate ketone precursor previous reports required three steps for the preparation of (R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine, a key intermediate for the synthesis of the antiallergic drug ramatroban. A single biocatalytic step was sufficient to prepare the target amine with >97% ee (HPLC) via reductive amination of the corresponding ketone using an ω-transaminase as biocatalyst. Since the ketone was barely soluble under the reaction conditions employed, it was provided as a solid and still the reaction went to completion within 4 h at 50 mM substrate concentration. Although 2-propylamine is regarded as an ideal amine donor, it turned out to be detrimental for the specific ketone precursor leading to the formation of various side products. These could be avoided by using (R)-1-phenylethylamine as the best suited amine donor. An alternative work-up was developed via freeze-drying of the reaction mixture, enabling the isolation of the desired (R)-amine in excellent yield (96%) and enantiopure form on a preparative scale (500 mg). No purification steps (e.g., column chromatography, crystallisation) were required.
- Busto, Eduardo,Simon, Robert C.,Grischek, Barbara,Gotor-Fernandez, Vicente,Kroutil, Wolfgang
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- Fluorescence Studies with Tryptophan Analogues: Excited State Interactions Involving the Side Chain Amino Group
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The fluorescence of a large set of tryptophan analogues, including several that are conformationally constrained, was studied.The constrained analogues include tetrahydrocarboline-3-carboxylic acid and 3-amino-3-carboxytetrahydrocarbazole.Steady state and time-resolved fluorescence measurements were made as a function of pH.The fluorescence quantum yields of the constrained analogues are higher than those for the unconstrained counterparts.The emission intensity of the constrained analogues, as well as 4-methyltryptophan, decreases with deprotonation of the side chain α-ammonium groups; this is in contrast to the increase in fluorescence of tryptophan with deprotonation of this group.These results are consistent with the existence of excited state proton transfer to carbon 4 of the indole ring as a quenching mechanism, which is sterically prohibited in the constrained analogues and 4-methyltryptophan.From quantum yield and lifetime data (most decays are nonexponential), the effective rate constant for nonradiative depopulation of the excited state was calculated.For tryptophan analogues having two side chain functional groups, there is a synergistic effect; the presence of two side chain groups causes more quenching than expected from the sum of the individual contributions.For analogues having an α-ammonium group, this synergism appears to be correlated with an induced change in the pKa of this group.Deprotonation of this α-ammonium group also caused a red shift in the emission of these compounds; this appears to be due to electrostatic repulsion between the α-NH3+ group and the excited indole dipole.
- Eftink, Maurice R.,Jia, Yiwei,Hu, Dana,Ghiron, Camillo, A.
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- INDOLE AHR INHIBITORS AND USES THEREOF
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The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.
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- Synthesis method for (R)-3-amino-1,2,3,4-tetrahydrocarbazole
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The invention discloses a synthesis method for a Ramatroban intermediate (R)-3-amino-1,2,3,4-tetrahydrocarbazole.The synthesis method includes the steps that 1,4-cyclohexanedione monoethylene acetal and phenylhydrazine are subjected to aldehyde ketone amine condensation, then cyclization is conducted to obtain 3,3-vinyl dioxo-1,2,4,9-tetrahydrocarbazole-3-ketone, then protecting groups are removed to obtain 1,2,4,9-tetrahydrocarbazole-3-ketone, 1,2,4,9-tetrahydrocarbazole-3-ketone and O-hydroxylamine hydrochloride react to obtain oxime ether, and oxime ether is subjected to low-temperature chiral selective reduction to directly obtain (R)-3-amino-1,2,3,4-tetrahydrocarbazole.A new synthesis route of the important intermediate (R)-3-amino-1,2,3,4-tetrahydrocarbazole of medicine Ramatroban is provided.The synthesis method is simple and convenient, operation conditions are mild, the reaction yield is high, an amplification reaction can be conducted, and the synthesis method is applied to industrial production.
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- Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases
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A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.
- Busto, Eduardo,Gotor-Fernandez, Vicente,Gotor, Vicente
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p. 4842 - 4848
(2012/07/31)
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- N,N-Dimethyl-[9-(arylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amines as novel, potent and selective 5-HT6 receptor antagonists
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The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT6 receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.
- Nirogi, Ramakrishna V. S.,Konda, Jagadishu Babu,Kambhampati, Ramasastry,Shinde, Anil,Bandyala, Thrinath Reddy,Gudla, Parandhama,Kandukuri, Kiran Kumar,Jayarajan, Pradeep,Kandikere, Vishwottam,Dubey, P. K.
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p. 6980 - 6985,6
(2020/09/02)
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- SYNTHESIS OF (2-AMINO)-TETRAHYDROCARBAZOLE-PROPANOIC ACID
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The present invention provides a new approach to the synthesis of 2-amino-tetrahydrocarbazole-propanoic acid, a key intermediate for the synthesis of Ramatroban. More specifically, a synthesis of 2-amino-tetrahydrocarbazole- propanoic acid which includes oxidizing an aminocyclohexanol to form an aminocyclohexanone, condensing the aminocyclohexanone to form a tetrahydrocarbazole, deprotecting the tetrahydrocarbazole to yield a racemic mixture of a tetrahydrocarbazole, resolving the racemic mixture to obtain a yield mixture with an enantiomeric excess of one enantiomer over another, alkylating the excess enantiomer to yield an alkyl ester, and hydrolyzing the alkyl ester to yield 2-amino-tetrahydrocarbazole-propanoic acid.
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Page/Page column 13
(2010/08/04)
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- NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS; PROCESSES FOR THEIR PREPARATION AND COMPOSITIONS THEREOF
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The present invention relates to novel dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (I), and their analogs, isomers, pharmaceutical compositions and therapeutic uses, methods of making the same.
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Page/Page column 27
(2010/02/11)
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- Cycloalkyl-one-containing benzenesulphonamides
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Cycloalkanol[1,2-b]indole-sulphonamides of the formula STR1 where appropriate in an isomeric form, and their salts are disclosed. These compounds are useful to inhibit platelet aggregation and to antagonize thromboxane A2.
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- Synthesis and absolute configuration of the new thromboxane antagonist (3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid and comparison with its enantiomer
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The synthesis of (3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid (Bay u 3405), a new, enantiomerically pure antagonist of thromboxane A2, is described. The determination of the absolute configuration of Bay u 3405 was performed by an X-ray analysis of compound 7 ([3((2S)-acetylamido)-3-phenylpropionamido]- 1,2,3,4-tetrahydro-carbazol). Bay u 3405 is in vitro 1 to 2 orders of magnitude more acitve than its (-)-enantiomer Bay u 3406.
- Rosentreter,Boshagen,Seuter,Perzoborn,Fiedler
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p. 1519 - 1521
(2007/10/02)
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- An Alternative Synthesis of 3-Amino-1,2,3,4-tetrahydrocarbazoles
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3-Amino-1,2,3,4-tetrahydrocarbazoles are easily prepared from the readily available 3-hydroxy-1,2,3,4-tetrahydrocarbazoles by conversion of the latter to the p-toluene- or methanesulfonate ester, followed by nucleophilic displacement with azide ion.The resulting 3-azido-1,2,3,4-tetrahydrocarbazoles are then catalytically hydrogenated to their 3-amino counterparts.
- Bird, C. W.,Wee, A. G. H.
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p. 191 - 192
(2007/10/02)
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