- Nitrogen-containing cyclic compounds as iminium ion sources for selected reaction monitoring detection of derivatized analytes
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Liquid chromatography–tandem mass spectrometry is one of the most sensitive tools for determination of trace amounts of analytes in metabolomics and proteomics. The highest sensitivity is achieved in selected reaction monitoring detection, which involves fragmentation of the molecular ion between two levels of mass selection. However, fragmentation of some compounds is complicated. Detection sensitivity of such analytes may be increased by derivatizing them with a specific moiety fragmentation of which results in product ion of high abundance. In this work, we reveal the influence of iminium ions' structures on their stability by comparing six nitrogen-containing cyclic compounds as derivatization reagents for tandem mass spectrometric analysis of amino group-containing analyte. Commercially available starting materials (piperidine, 2,6-dimethylpiperidine, 1-methylpiperazine, morpholine, pyrrolidine and 1-cyanomethyl-3-methylimidazolium ionic liquid) were used for the synthesis of corresponding carboxylic acids which were further used for derivatization of the model analyte tryptamine. Liquid chromatographic–mass spectrometric analysis of differently derivatized tryptamine was performed for the evaluation of release and stability of corresponding iminium ions under collision-induced dissociation conditions. As a result, morpholine moiety was shown being the most promising iminium ion source among tested compounds. Possible sub-fragmentation pathways of investigated iminium ions were discussed, and the structures of secondary product ions were proposed.
- ?ilionis, Andrius
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supporting information
p. 25 - 35
(2019/09/03)
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- Reagent-free continuous thermal tert-butyl ester deprotection
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Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120–240 °C and 15–40 min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.
- Cole, Kevin P.,Ryan, Sarah J.,Groh, Jennifer McClary,Miller, Richard D.
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p. 6209 - 6217
(2017/09/30)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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- Click chemistry facilitates formation of reporter ions and simplified synthesis of amine-reactive multiplexed isobaric tags for protein quantification
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We report the development of novel reagents for cell-level protein quantification, referred to as Caltech isobaric tags (CITs), which offer several advantages in comparison with other isobaric tags (e.g., iTRAQ and TMT). Click chemistry, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), is applied to generate a gas-phase cleavable linker suitable for the formation of reporter ions. Upon collisional activation, the 1,2,3-triazole ring constructed by CuAAC participates in a nucleophilic displacement reaction forming a six-membered ring and releasing a stable cationic reporter ion. To investigate its utility in peptide mass spectrometry, the energetics of the observed fragmentation pathway are examined by density functional theory. When this functional group is covalently attached to a target peptide, it is found that the nucleophilic displacement occurs in competition with formation of b-and y-type backbone fragment ions regardless of the amino acid side chains present in the parent bioconjugate, confirming that calculated reaction energetics of reporter ion formation are similar to those of backbone fragmentations. Based on these results, we apply this selective fragmentation pathway for the development of CIT reagents. For demonstration purposes, duplex CIT reagent is prepared using a single isotope-coded precursor, allyl-d5-bromide, with reporter ions appearing at m/z 164 and 169. Isotope-coded allyl azides for the construction of the reporter ion group can be prepared from halogenated alkyl groups which are also employed for the mass balance group via N-alkylation, reducing the cost and effort for synthesis of isobaric pairs. Owing to their modular designs, an unlimited number of isobaric combinations of CIT reagents are, in principle, possible. The reporter ion mass can be easily tuned to avoid overlapping with common peptide MS/MS fragments as well as the low mass cutoff problems inherent in ion trap mass spectrometers. The applicability of the CIT reagent is tested with several model systems involving protein mixtures and cellular systems.
- Sohn, Chang Ho,Lee, J. Eugene,Sweredoski, Michael J.,Graham, Robert L.J.,Smith, Geoffrey T.,Hess, Sonja,Czerwieniec, Gregg,Loo, Joseph A.,Deshaies, Raymond J.,Beauchamp
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p. 2672 - 2680
(2012/03/22)
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- INDOL-2-ONE DERIVATIVES DISUBSTITUTED IN THE 3-POSITION, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
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The present invention relates to 3-disubstituted indol-2-one derivatives, to their preparation and to their therapeutic application.
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Page/Page column 11
(2010/08/22)
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- Antiproliferative compounds and therapeutic uses thereof
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Inhibitors of the oncogenic tyrosine kinase ALK and of the Bcr-Abl mutant T315I Bcr-Abl, such as a compound of formula (I): wherein Q, T, W, K, J, Y, X, Z are independently selected from C, N, S, O, provided that the corresponding rings are (hetero)aromatic; n = 0 or 1; q = 1 or 2; pharmaceutical compositions containing the same and their use for the treatment of hyper-proliferative diseases.
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Page/Page column 26
(2009/10/18)
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- NK1 and NK3 antagonists
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The invention is to a compound exhibiting neurokinin inhibitory properties, a pharmaceutical composition comprising same and a method of treatment for neurokinin-mediated conditions.
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Page/Page column 27
(2010/02/14)
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- Insertion of an aspartic acid moiety into cyclic pseudopeptides: Synthesis and biological characterization of potent antagonists for the human tachykinin NK-2 receptor
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A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED50 = 0.27 nmol/kg and 0.15 nmol/kg, respectively).
- Fedi, Valentina,Altamura, Maria,Balacco, Giuseppe,Canfarini, Franca,Criscuoli, Marco,Giannotti, Danilo,Giolitti, Alessandro,Giuliani, Sandro,Guidi, Antonio,Harmat, Nicholas J. S.,Nannicini, Rossano,Pasqui, Franco,Patacchini, Riccardo,Perrotta, Enzo,Tramontana, Manuela,Triolo, Antonio,Maggi, Carlo Alberto
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p. 6935 - 6947
(2007/10/03)
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- Substituted anilides
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The invention is directed to physiologically active compounds of formula (I): wherein: R1is hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; X1, X2and X6independently represent N or CR10; and one of X3, X4and X5represents CR11and the others independently represents N or CR10; where R10is hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, nitro or trifluoromethyl; and R11represents a group —L1—Ar1—L2—Y; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).
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- Synthesis and in vitro evaluation of novel morpholinyl- and methylpiperazinylacyloxyalkyl prodrugs of 2-(6-methoxy,2-naphthyl)propionic acid (naproxen) for topical drug delivery
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Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c- f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1- piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1- 26 min) to naproxen in human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4-and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-ionized under neutral and slightly acidic conditions, and thus, a desirable combination is achieved in terms of aqueous solubility and lipophilicity. Moreover, the resulting combination of biphasic solubility and fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave improved topical delivery of naproxen.
- Rautio, Jarkko,Nevalainen, Tapio,Taipale, Hannu,Veps?l?inen, Jouko,Gynther, Jukka,Laine, Krista,J?rvinen, Tomi
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p. 1489 - 1494
(2007/10/03)
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- Method for lowering total serum cholesterol and treating hypercholesterolemia with aminoacetylmercapto derivatives
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The present invention relates to the use of certain aminoacetylmercapto derivatives in treating patients suffering from hypercholesterolemia.
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- Prodrugs of 5,5-diphenylhydantoin as antiepileptic and antiarrhythmic agents
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The present invention deals with a product with the formula (I) which is a new prodrug of phenytoin, as well as its therapeutically acceptable solvates and addition salts. This product shows a solubility significantly higher than phenytoin itself. In addi
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- Heterocyclic amines useful in the therapy of asthma and imflammation of the respiratory tract
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Compounds of the formula STR1 wherein A, Y, X, B and D are described in the specification are disclosed. The compounds possess activity in treating asthma and other pathologies of the respiratory tract.
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- AMINOACETYLMERCAPTO DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
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The present invention relates to novel aminoacetylmercapto derivatives useful as inhibitors of enkephalinase and ACE.
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- Dopamine-β-hydroxylase inhibitors
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Potent dopamine-β-hydroxylase inhibitors having the Formula STR1 that are useful to inhibit dopamine-β-hydroxylase activity, pharmaceutical compositions including these inhibitors, and methods of using these inhibitors to inhibit dopamine-β-hydroxylase ac
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