- Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy
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Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.
- Banerjee, Abhisek,Behera, Dayanidhi B.,Chakraborti, Samitabh,Das, Sanjib,Gharat, Laxmikant A.,Iyer, Pravin S.,Kadam, Pradip,Karanjai, Keya,Patil, Sandip,Pawar, Mahesh,Qadri, Mohammad Mohsin,Saini, Jagmohan S.,Velagaleti, Ranganadh,Yadav, Pravin
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supporting information
(2021/06/25)
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- Nickel-Catalyzed Asymmetric Synthesis of α-Arylbenzamides
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A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported. The use of a chiral bisimidazoline (BIm) ligand, in combination with diethoxymethylsilane and aryl halides, enables the regioselective introduction of aryl groups to the internal position of the olefin, forging a new stereogenic center α to the N atom. The use of neutral reagents and mild reaction conditions provides simple access to pharmacologically relevant motifs present in anticancer, SARS-CoV PLpro inhibitors, and KCNQ channel openers.
- Cuesta-Galisteo, Sergio,Sch?rgenhumer, Johannes,Wei, Xiaofeng,Merino, Estíbaliz,Nevado, Cristina
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supporting information
p. 1605 - 1609
(2020/12/01)
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- Photoinduced Hydroxylation of Organic Halides under Mild Conditions
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Presented in this paper is photoinduced hydroxylation of organic halides, providing a mild access to a range of functionalized phenols and aliphatic alcohols. These reactions generally proceed under mild reaction conditions with no need for a photocatalyst or a strong base and show a wide substrate scope as well as excellent functional group tolerance. This work highlights the unique role of NaI that allows a challenging transformation to proceed under mild reaction conditions.
- Cai, Yue-Ming,Xu, Yu-Ting,Zhang, Xin,Gao, Wen-Xia,Huang, Xiao-Bo,Zhou, Yun-Bing,Liu, Miao-Chang,Wu, Hua-Yue
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p. 8479 - 8484
(2019/10/16)
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- Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct
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A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.
- Rajput, Sunnia,McLean, Kirsty J.,Poddar, Harshwardhan,Selvam, Irwin R.,Nagalingam, Gayathri,Triccas, James A.,Levy, Colin W.,Munro, Andrew W.,Hutton, Craig A.
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supporting information
p. 9792 - 9805
(2019/11/13)
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- Synthesis and Explosion Hazards of 4-Azido- l -phenylalanine
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A reliable, scalable, cost-effective, and chromatography-free synthesis of 4-azido-l-phenylalanine beginning from l-phenylalanine is described. Investigations into the safety of the synthesis reveal that the Ullman-like Cu(I)-catalyzed azidation step does not represent a significant risk. The isolated 4-azido-l-phenylalanine product, however, exhibits previously undocumented explosive characteristics.
- Richardson, Mark B.,Brown, Derek B.,Vasquez, Carlos A.,Ziller, Joseph W.,Johnston, Kevin M.,Weiss, Gregory A.
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p. 4525 - 4536
(2018/04/26)
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- METHOD FOR PREPARING L-BPA
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Provided is a method for preparing L-BPA, which includes steps of: reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-methylaminoethyl)ether to obtain a reaction mixture, wherein the reaction mixture comprises N-protected (S)-4-boronophenylalanine of Formula II and the R2 group represents a protecting group; isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture; and deprotecting the R2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA, wherein the L-BPA has a structure of Formula III.
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Paragraph 0090-0096
(2018/06/15)
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- A simple, efficient, regioselective and one-pot preparation of N-hydroxy- and N-O-protected hydroxyindoles via cycloaddition of nitrosoarenes with alkynes. Synthetic scope, applications and novel by-products
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The thermal reaction between nitrosoarenes and alkynes under alkylating conditions produces N-alkoxyindoles as the major products in moderate to good yields and excellent regioselectivity. Various electrophiles are used affording different N-O-protected hydroxyindoles in a multi-component fashion. Privileged acetylenic substrates used in reactions with substituted nitrosoarenes are arylalkynes or propiolates. Potentially bioactive compounds and other classes of highly functionalizable indole products were prepared. Reactions between o-carbomethoxy-nitrosoarenes and arylacetylenes provided tricyclic compounds containing an acylaziridine indoline skeleton.
- Ieronimo, Gabriella,Mondelli, Alessandro,Tibiletti, Francesco,Maspero, Angelo,Palmisano, Giovanni,Galli, Simona,Tollari, Stefano,Masciocchi, Norberto,Nicholas, Kenneth M.,Tagliapietra, Silvia,Cravotto, Giancarlo,Penoni, Andrea
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p. 10906 - 10920
(2014/01/06)
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- Self-liganded Suzuki-Miyaura coupling for site-selective protein PEGylation
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Building with PEGs: PEG-boronic acids, in the presence of simple Pd sources, are capable of acting as direct and effective Suzuki reagents in 70-98 % yield. When combined with non-natural amino acids, they allow efficient and direct, site-selective PEGylation of proteins at predetermined positions under biologically compatible conditions without the need for exogenous ligands.
- Dumas, Anaelle,Spicer, Christopher D.,Gao, Zhanghua,Takehana, Tsuyoshi,Lin, Yuya A.,Yasukohchi, Tohru,Davis, Benjamin G.
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p. 3916 - 3921
(2013/05/22)
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- C-Glycosyl amino acids through hydroboration-cross-coupling of exo-glycals and their application in automated solid-phase synthesis
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O-Glycosylation is one of the most important post-translational modifications of proteins. The attachment of carbohydrates to the peptide backbone influences the conformation as well as the solubility of the conjugates and can even be essential for binding to specific ligands in cell-cell interactions or for active transport over membranes. This makes glycopeptides an interesting class of compounds for medical applications. To enhance the long-term availability of these molecules in vivo, the stabilization of the glycosidic bond between the amino acid residue and the carbohydrate is of interest. The described modular approach affords β-linked C-glycosyl amino acids by a sequence of Petasis olefination of glyconolactones, stereoselective hydroboration and a mild B-alkyl-Suzuki coupling reaction. The coupling products were transformed to C-glycosyl amino acid building-blocks suitable for solid-phase synthesis and successfully incorporated into a partial sequence of the tumor-associated MUC1-glycopeptide. The resulting C-glycopeptides are candidates for the development of long-term stable mimics of O-glycopeptide vaccines. Copyright
- Koch, Stefan,Schollmeyer, Dieter,L?we, Holger,Kunz, Horst
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p. 7020 - 7041
(2013/07/05)
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- Palladium-mediated cell-surface labeling
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Benign C-C bond formation at various sites in cell-surface channels has been achieved through Suzuki-Miyaura coupling of genetically positioned unnatural amino acids containing aryl halide side chains. This enabled site-selective cell surface manipulation of Escherichia coli; the phosphine-free catalyst caused no cell death at required Pd loadings, suggesting future in vivo application of catalytic metal-mediated bond formation in more complex organisms.
- Spicer, Christopher D.,Triemer, Therese,Davis, Benjamin G.
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p. 800 - 803
(2012/03/07)
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- Enzymatic basis of ribosomal peptide prenylation in cyanobacteria
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The enzymatic basis of ribosomal peptide natural product prenylation has not been reported. Here, we characterize a prenyltransferase, LynF, from the TruF enzyme family. LynF is the first characterized representative of the TruF protein family, which is responsible for both reverse- and forward-O-prenylation of tyrosine, serine, and threonine in cyclic peptides known as cyanobactins. We show that LynF reverse O-prenylates tyrosine in macrocyclic peptides. Based upon these results, we propose that the TruF family prenylates mature cyclic peptides, from which the leader sequence and other enzyme recognition elements have been excised. This differs from the common model of ribosomal peptide biosynthesis, in which a leader sequence is required to direct post-translational modifications. In addition, we find that reverse O-prenylated tyrosine derivatives undergo a facile Claisen rearrangement at 'physiological' temperature in aqueous buffers, leading to forward C-prenylated products. Although the Claisen rearrangement route to natural products has been chemically anticipated for at least 40 years, it has not been demonstrated as a route to prenylated natural products. Here, we show that the Claisen rearrangement drives phenolic C-prenylation in at least one case, suggesting that this route should be reconsidered as a mechanism for the biosynthesis of prenylated phenolic compounds.
- McIntosh, John A.,Donia, Mohamed S.,Nair, Satish K.,Schmidt, Eric W.
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supporting information; experimental part
p. 13698 - 13705
(2011/10/12)
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- Substituted amidine derivatives as inhibitors of cell adhesion
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Compounds of Formula I are antagonists of VLA-4 and/or α4β7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes.
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- Substituted cyclic amidine derivatives as inhibitors of cell adhesion
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Compounds of Formula I are antagonists of VLA-4 and/or α4β7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes.
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- Biarylalkanoic acids as cell adhesion inhibitors
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Compounds of Formula I are antagonists of VLA-4 and/or α4β7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.
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- Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design
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Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH2CN (19, IC50 = 62 μM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P1, P2, and P3 substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S2′ pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon α to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.
- Greenspan,Clark,Tommasi,Cowen,McQuire,Farley,Van Duzer,Goldberg,Zhou,Du,Fitt,Coppa,Fang,Macchia,Zhu,Capparelli,Goldstein,Wigg,Doughty,Bohacek,Knap
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p. 4524 - 4534
(2007/10/03)
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- Synthesis of optically active arylene bis-alanine derivatives carrying orthogonal protecting groups
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Derivatives of para- and meta-phenylene bis-alanine and related biphenyl systems, carrying four orthogonal protecting groups, were synthesised via combinations of Heck couplings and asymmetric hydrogenations. The intermediate unsaturated arylalanine derivatives were hydrogenated using [Rh(COD)((R,R)-DIPAMP)]+BF4- or [Rh(COD)(Me-DuPHOS)]+X- as catalysts to produce the optically active, protected amino acid derivatives in ≤98% e.e. as analysed by chiral phase HPLC.
- Ritzen, Andreas,Basu, Basudeb,Chattopadhyay, Shital K.,Dossa, Fahreen,Frejd, Torbjoern
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p. 503 - 512
(2007/10/03)
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- Cholecystokinin B antagonists. Synthesis and quantitative structure-activity relationships of a series of C-terminal analogues of CI-988
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A study of structure-activity relationships of a series of 'dipeptoid' CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-α-methyl-R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum π near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.
- Augelli-Szafran, Corinne E.,Horwell, David C.,Kneen, Clare,Ortwine, Daniel F.,Pritchard, Martyn C.,Purchase, Terri S.,Roth, Bruce D.,Trivedi, Bharat K.,Hill, David,Suman-Chauhan, Nirmala,Webdale, Louise
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p. 1733 - 1745
(2007/10/03)
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