- Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and in Vivo Studies
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Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 (2e/4e) with nanomolar EC50 values (0.14/0.80 μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.
- Jung, Sascha,Fuchs, Natalie,Johe, Patrick,Wagner, Annika,Diehl, Erika,Yuliani, Tri,Zimmer, Collin,Barthels, Fabian,Zimmermann, Robert A.,Klein, Philipp,Waigel, Waldemar,Meyr, Jessica,Opatz, Till,Tenzer, Stefan,Distler, Ute,R?der, Hans-Joachim,Kersten, Christian,Engels, Bernd,Hellmich, Ute A.,Klein, Jochen,Schirmeister, Tanja
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p. 12322 - 12358
(2021/09/02)
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- N-ALKOXYAMIDE CONJUGATES AS IMAGING AGENTS
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The present disclosure is directed to compounds, diagnostic agents, and related methods. In some cases, methods for treating patients are provided. More specifically, the disclosure provides compounds, diagnostic agents, and kits for detecting and/or imaging and/or monitoring elastin rich tissues. In addition, the disclosure provides methods of detecting and/or imaging and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurism, vasculitis, other diseases of the arterial wall, and/or damage or structural changes in ligaments, uterus, lungs or skin, as indicated by changes in total vessel wall area, internal lumen size, and exterior arterial perimeter.
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Paragraph 0456
(2016/10/08)
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- Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors
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We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones.
- Schirmeister, Tanja,Kesselring, Jochen,Jung, Sascha,Schneider, Thomas H.,Weickert, Anastasia,Becker, Johannes,Lee, Wook,Bamberger, Denise,Wich, Peter R.,Distler, Ute,Tenzer, Stefan,Johé, Patrick,Hellmich, Ute A.,Engels, Bernd
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supporting information
p. 8332 - 8335
(2016/07/26)
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- N-alkoxyamide conjugates as imaging agents
-
The present disclosure is directed to compounds, diagnostic agents, and related methods. In some cases, methods for treating patients are provided. More specifically, the disclosure provides compounds, diagnostic agents, and kits for detecting and/or imaging and/or monitoring elastin rich tissues. In addition, the disclosure provides methods of detecting and/or imaging and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurism, vasculitis, other diseases of the arterial wall, and/or damage or structural changes in ligaments, uterus, lungs or skin, as indicated by changes in total vessel wall area, internal lumen size, and exterior arterial perimeter.
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Page/Page column 47-48
(2016/06/01)
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- Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation
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Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess Ki values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.
- Ettari, Roberta,Pinto, Andrea,Previti, Santo,Tamborini, Lucia,Angelo, Ilenia C.,La Pietra, Valeria,Marinelli, Luciana,Novellino, Ettore,Schirmeister, Tanja,Zappalà, Maria,Grasso, Silvana,De Micheli, Carlo,Conti, Paola
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p. 7053 - 7060
(2015/11/11)
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- Synthesis of γ-oxo γ-aryl and γ-aryl α-amino acids from aromatic aldehydes and serine
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γ-Oxo α-amino acids and γ-aryl α-amino acids are compounds with very interesting biological properties and are active components of many drug molecules. Oxo amino acids are also used as synthetic precursors for a number of unnatural amino acids and amino alcohols. We report a very efficient synthesis of such compounds through the coupling of aromatic dithianes, prepared from aromatic aldehydes and an iodide derivative of serine. The dithiane groups in compounds thus obtained can be either hydrolyzed or reduced to generate 4-oxo-4-aryl or 4-aryl 2-amino butanol derivatives, respectively, which, on further transformations, can be converted into the title compounds. Starting with L-serine provides the corresponding D-amino acids with complete enantiopurity. The reported method is economically viable and complements the existing methods, which rely largely on cross-coupling reactions.
- Chacko, Shibin,Ramapanicker, Ramesh
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p. 7120 - 7128
(2013/02/21)
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- N-ALKOXYAMIDE CONJUGATES AS IMAGING AGENTS
-
The present disclosure is directed to compounds, diagnostic agents, and related methods. In some cases, methods for treating patients are provided. More specifically, the disclosure provides compounds, diagnostic agents, and kits for detecting and/or imaging and/or monitoring elastin rich tissues. In addition, the disclosure provides methods of detecting and/or imaging and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurism, vasculitis, other diseases of the arterial wall, and/or damage or structural changes in ligaments, uterus, lungs or skin, as indicated by changes in total vessel wall area, internal lumen size, and exterior arterial perimeter.
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Page/Page column 68
(2011/02/24)
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- Palladium-catalyzed cross-coupling reactions in one-pot multicatalytic processes
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Palladium-catalyzed cross-coupling reactions have been investigated in multicatalytic processes to synthesize disubstituted alkenes and alkanes from carbonyl derivatives. The use of copper-catalyzed methylenation reactions is the key starting reaction to produce terminal alkenes which are not isolated, but submitted to further structure elongation. Not only is the isolation of the alkene intermediate unnecessary, but also the copper catalyst is a beneficial cocatalyst in the palladium-catalyzed cross-coupling reactions. The desired products are thus typically obtained in higher yields using this one-pot approach. We have used these processes to synthesize hydroxylated (E)-stilbenoids, which are known chemopreventive and chemotherapeutic agents, odorant-substituted indanes, and non-natural amino acids, such as homophenylalanine.
- Lebel, Helene,Ladjel, Chehla,Brethous, Lise
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p. 13321 - 13326
(2008/09/17)
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- HYDRAZIDE CONJUGATES AS IMAGING AGENTS
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The present disclosure is directed to diagnostic agents. More specifically, the disclosure is directed to compounds, diagnostic agents, compositions, and kits for detecting and/or imaging and/or monitoring a pathological disorder associated with coronary plaque, carotid plaque, aortic plaque, plaque of the arterial vessel, aneurism, vasculitis, and other diseases of the arterial wall. In addition, the disclosure is directed to methods of detecting and/or imaging and/or monitoring changes in the arterial wall, including expansive and constrictive remodeling, total vessel wall area, internal lumen size, and exterior artery perimeter.
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Page/Page column 197-198
(2010/11/25)
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- Vinylsulfones versus alkylsulfones in the addition to chiral imines. Synthesis of N-(tert-butoxycarbonyl)-L-homophenylalanine
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A study of the addition of vinylsulfones versus alkylsufones has been done, and applied to the synthesis of N-(tert-butoxycarbonyl)-L-homophenylalanine.
- Díez, David,García, Pilar,Marcos, Isidro S.,Basabe, Pilar,Garrido, Narciso M.,Broughton,Urones, Julio G.
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p. 11641 - 11648
(2007/10/03)
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- Exploration of the P1 SAR of aldehyde cathepsin K inhibitors.
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The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.
- Catalano, John G,Deaton, David N,Furfine, Eric S,Hassell, Annie M,McFadyen, Robert B,Miller, Aaron B,Miller, Larry R,Shewchuk, Lisa M,Willard Jr., Derril H,Wright, Lois L
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p. 275 - 278
(2007/10/03)
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- SULPHONYLAMINO DERIVATIVES FOR THE TREATMENT OF ALZHEIMER'S DISEASE
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A compound of formula (I), wherein R1 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, heteropolycyclyl or polycyclyl, any of which is optionally substituted with alkyl, heteroaryl, aryl or -O-aryl; R2 is alkyl, alkenyl or aryl, any of which is optionally substituted with hydroxy, halogen, aryl, heteroaryl, cycloalkyl, cycloalkenyl, -C(O)NH-aryl, heterocycloalkyl, heterocycloalkenyl, heteropolycyclyl or polycyclyl; R3 is hydrogen or aryl; R4 is alkyl, alkenyl, alkoxy, alkylthio or aryl, any of which is optionally substituted with hydroxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, thioalkyl, heterocycloalkyl, heterocycloalkenyl, heteropolycyclyl or polycyclyl; R5 is hydrogen or an alkyl or alkenyl group optionally substituted with hydroxy, aryl, -C(O)O- alkyl or -C(O)NH- alkyl; or R4-C-R5 taken together form cycloalkyl, cycloalkenyl or polycyclyl, any of which is optionally substituted with alkyl or hydroxyalkyl; R6 is hydrogen, alkyl, -alkyl-aryl or -alkyl-heteroaryl; or a pharmaceutically-acceptable salt thereof.
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- NOVEL THIAZINE OR PYRAZINE DERIVATIVES
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An object of the present invention is to synthesize novel compounds having 3-oxo-3, 4-dihydro-2H-1, 4-thiazine or 2-oxo-1, 2, 3, 4-tetrahydropyrazine as a main skeleton. The present invention relates to compounds represented by the following general formula [I] and salts thereof. In the formula, X is S or R6-(A2)n-N, R1 and R2 are H, alkyl, cycloalkyl or aryl, R3 and R4 are H, alkyl, cycloalkyl, aryl or aromatic heterocycles, R5 is H, alkyl, cycloalkyl, aryl or -A3-A4-R7, R6 is H, alkyl, cycloalkyl, OH, alkoxy, aryl, aryloxy or an aromatic heterocycle, R7 is H, alkyl, OH, alkoxy, aryl, aryloxy, amino, alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle, A1 is alkylene, A2 is carbonyl or sulfonyl, A3 is alkylene, and A4 is carbonyl or oxalyl.
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- Synthesis of unusual amino acids: N-(tert-butoxycarbonyl)-L-vinyl glycine and N-(tert-butoxycarbonyl)-L-homophenylalanine
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The synthesis of the unusual amino acids N-(tert-butoxycarbonyl)-L-vinyl glycine and N-(tert-butoxycarbonyl)-L-homophenylalanine starting from commercially available D-xylose via an alkylative fragmentation method is described.
- Chandrasekhar,Raza, Abbas,Takhi, Mohamed
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p. 423 - 428
(2007/10/03)
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- Enantiomerically pure α-amino acid synthesis via hydroboration - Suzuki cross-coupling
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The Garner aldehyde-derived methylene alkene 5 and the corresponding benzyloxycarbonyl compound 25 undergo hydroboration with 9-BBN-H followed by palladium-catalyzed Suzuki coupling reactions with aryl and vinyl halides. After one-pot hydrolysis -oxidation, a range of known and novel nonproteinogenic amino acids were isolated as their N-protected derivatives. These novel organoborane homoalanine anion equivalents are generated and transformed under mild conditions and with wide functional group tolerance: electron-rich and -poor aromatic iodides and bromides (and a vinyl bromide) all undergo efficient Suzuki coupling. The extension of this methodology to prepare meso-DAP, R,R-DAP, and R,R-DAS is also described.
- Collier, Philip N.,Campbell, Andrew D.,Patel, Ian,Raynham, Tony M.,Taylor, Richard J. K.
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p. 1802 - 1815
(2007/10/03)
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- New synthesis and ring opening of cis-3-alkylaziridine-2-carboxylates
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Syntheses of cis-3-alkylaziridine-2-carboxylates including cis-3-benzyl- and cis-3-phenylaziridine-2-carboxylates were achieved from the reaction of α-aminonitrile and alkyldiazoacetate in the presence of a Lewis acid. Asymmetric version of this reaction with the chiral α-methylbenzylamine was also successful for the preparation of chiral aziridines that were used for the synthesis of various amino acids including homophenylalanine, β-amino-α-hydroxy acid, α,β-diamino acid, and α-amino-β-hydroxy acid via regioselective aziridine ring openings.
- Lee, Kwang-Deuk,Suh, Jang-Min,Park, Jae-Hoon,Ha, Hyun-Joon,Choi, Hwan Gun,Park, Chan Sun,Chang, Jae Won,Lee, Won Koo,Dong, Yongkwan,Yun, Hoseop
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p. 8267 - 8276
(2007/10/03)
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- The synthesis of novel amino acids via hydroboration-suzuki cross coupling
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The Gamer aldehyde-derived methylene alkene has been hydroborated using 9-BBN and the resulting organoborane employed in palladium-catalysed Suzuki coupling reactions to produce, after hydrolysis-oxidation, a range of novel amino acids as their N-BOC protected derivatives.
- Campbell, Andrew D.,Raynham, Tony M.,Taylor, Richard J. K.
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p. 5263 - 5266
(2007/10/03)
-
- Fibrinogen receptor antagonists
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Fibrinogen receptor antagonists having the structure, for example, of STR1 for example STR2
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- Synthetic Elaboration of the Side Chain of (R)-2,2-Dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine: A New Regio- And Stereoselective Strategy to δ-Functionalized β-Amino Alcohols
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An investigation of the reactivity of ethynyloxazolidine 2 is presented. Functionalization at the acetylenic position has been found to occur very easily using the mild Sonogashira conditions. Addition of tributyltin cuprate 1 provided the corresponding stannylated (E)-ethenyloxazolidine 3, a new chiral building block which has been reacted with electrophiles under Pd catalysis. The reaction sequence occurred without racemization and showed an easy and mild procedure for the regio- and stereoselective synthesis of unsaturated amino alcohols.
- Reginato, Gianna,Mordini, Alessandro,Caracciolo, Massimo
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p. 6187 - 6192
(2007/10/03)
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- Reduction of 4-Oxo-α-Amino Acids as a Route to 4-Hydroxylated α-Amino Acids. Concise Approaches to the Synthesis of Clavalanine, erythro-4-Hydroxyornithine and (+)-Bulgecinine
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The stereochemical course of reduction of derivatives of 4-oxo-α-amino acids 3 to give cis- and trans-γ-substituted α-aminobutano-4-lactones 9 and 10 using a range of hydride reducing agents is reported.Athough reduction with sodium boranuide (sodium borohydride) in protic solvents proceeds with low stereoselectivity, use of triethylsilane-boron trifluoride-diethyl ether gives good selectivity in favour of the cis-isomer, provided that the 4-substituent is phenyl.Moderate to excellent stereoselectivity in favour of the trans-isomer may be obtained by using L-Selectride in tetrahydrofuran.The presence of an additional stereogenic centre at C-5 completely overwhelms the effect of the α-centre.Applications of this method in approaches to the synthesis of clavalanine, erythro-4-hydroxyornithine and (+)-bulgecinine are described.
- Jackson, Richard F. W.,Rettie, Alan B.,Wood, Anthony,Withes, Martin J.
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p. 1719 - 1726
(2007/10/02)
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- A short enantioselective synthesis of N-Boc-α-amino acids from epoxy alcohols
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A new and efficient enantioselective synthesis of Boc-α-amino acids has been developed. Starting from an enantiomerically enriched epoxy alcohol the sequence involves a regioselective nucleophilic epoxide opening by diphenylmethylamine (benzhydrilamine), hydrogenolysis/ protection of the amino group, and oxidation of the diol moiety.
- Poch, Marta
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p. 7781 - 7784
(2007/10/02)
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- Preparation of Enantiomerically Pure Protected 4-Oxo-α-amino Acids and 3-Aryl-α-amino Acids from Serine
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The organozinc reagent 13, prepared from the protected β-iodo alanine derivative 3c using ultrasonic activation, is efficiently acylated using acid chlorides in the presence of bis(triphenylphosphine)palladium dichloride to give enantiomerically pure protected 4-oxo-α-amino acids 17 in 39-90percent yield (13 examples).Zinc reagent 13 can also be coupled with aryl iodides in the presence of bis(tri-o-tolylphosphine)palladium dichloride to give enantiomerically pure protected phenylalanine analogues 26, 29, and 30 in 10-67percent yield (11 examples).The reaction tolerates the presence of a variety of functional groups in the acid chloride and the aryl iodide and provides derivatives which can be easily deprotected, at either the carboxyl or amino terminus, to give intermediates suitable for peptide synthesis.
- Jackson, Richard F. W.,Wishart, Neil,Wood, Anthony,James, Keith,Wythes, Martin J.
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p. 3397 - 3404
(2007/10/02)
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- Synthesis of Chiral Building Blocks from D-Glucosamine Hydrochloride
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Wittig-reaction of 2-acetamido-2-deoxy-D-glucose (1) with the semistabilized ylide Ph3P=CHPh yielded the epimeric chain-elongated derivatives 2 and 3 in different amounts depending on the reaction conditions.Reaction of 2-(tert-butoxycarbonylamino)-2-deoxy-D-glucose (5) with Ph3P=CHPh yielded the compound 8, or after intramolecular cyclisation, the derivatives 6 or 7.Compound 3 was transformed in three steps into the amino alcohol 10.The 3-amino-1,2-diol derivative 17 and also the N,O-protected α-hydroxy-β-amino acid derivative 16 were obtained from 7.The N-protected homophenylalanine derivatives 12 and 14 were available in two steps from 2 or 8. - Key Words: Amino sugars / Amino alcohols / Amino acids / Wittig reaction
- Giannis, Athanassios,Henk, Thomas
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p. 789 - 793
(2007/10/02)
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- A NOVEL APPROACH TO THE SYNTHESIS OF OPTICALLY PURE NON PROTEIN α-AMINO ACIDS IN BOTH L AND D CONFIGURATIONS FROM L-SERINE
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Efficient syntheses of (2R)-2-Boc-amino-3-phenylsulfonyl-1-propanol 3 and its enantiomer 9 from L-serine are described.The potential of these compounds in a novel general method for the synthesis of optically pure non protein α-amino acids in both the L and D configurations is exemplified by the preparation of N-Boc-L-and D-homophenylalanine,-norvaline and -norleucine.
- Sasaki, N.Andre,Hashimoto, Chiyomi,Potier, Pierre
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p. 6069 - 6072
(2007/10/02)
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