21887-64-9Relevant articles and documents
The microenvironment and pKaperturbation of aminoacyl-tRNA guided the selection of cationic amino acids
Hazra, Bibhas,Prasad, Mahesh,Roy, Rajat,Tarafdar, Pradip K.
supporting information, p. 8049 - 8056 (2021/10/04)
The proteinogenic lysine (Lys) and arginine (Arg) have multiple methylene groups between α-carbon and the terminal charged centre. Why nature did not select ornithine (Orn), 2,4-diamino butyric acid (Dab) and 2,3-diamino propionic acid (Dpr) with fewer methylene groups in the side chain remains an important question! The propensity of aminoacyl-tRNA (aa-tRNA) model substrates towards self-degradationviaintramolecular lactamization was studied using UV spectroscopy and1H-NMR titration, which showed that Lys and Arg remain stable, and Orn and Dab cyclize to lactam. Hydrophobicity-assisted surface mediated model peptide formation highlighted that the microenvironment and pKaperturbation led to poor regioselectivity (α-aminevs.terminal amine) in Dpr and other non-proteinogenic analogues. The α-selectivity became even poorer in the presence of phosphate, making them ill-suited for peptide synthesis. Superior regioselectivity of the Lys aa-tRNA model substrate suggests that the extra methylene bridge helped nature to separate the microenvironments of the α-amine and ε-amine to synthesize the peptide backbone.
METHODS AND COMPOUNDS FOR THE TREATMENT OF GENETIC DISEASE
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Paragraph 00844; 001290; 001291; 001292, (2021/08/13)
The present disclosure relates to compounds and methods for modulating the expression of dmpk, and treating diseases and conditions in which dmpk plays an active role. The compound can be a transcription modulator molecule having a first terminus, a second terminus, and oligomeric backbone, wherein: a) the first terminus comprises a DNA-binding moiety capable of noncovalently binding to a nucleotide repeat sequence CAG or CTG; b) the second terminus comprises a protein-binding moiety binding to a regulatory molecule that modulates an expression of a gene comprising the nucleotide repeat sequence CAG or CTG; and c) the oligomeric backbone comprising a linker between the first terminus and the second terminus.
Two Distinct Mechanisms for C-C Desaturation by Iron(II)- and 2-(Oxo)glutarate-Dependent Oxygenases: Importance of α-Heteroatom Assistance
Dunham, Noah P.,Chang, Wei-Chen,Mitchell, Andrew J.,Martinie, Ryan J.,Zhang, Bo,Bergman, Jonathan A.,Rajakovich, Lauren J.,Wang, Bo,Silakov, Alexey,Krebs, Carsten,Boal, Amie K.,Bollinger, J. Martin
, p. 7116 - 7126 (2018/05/15)
Hydroxylation of aliphatic carbons by nonheme Fe(IV)-oxo (ferryl) complexes proceeds by hydrogen-atom (H?) transfer (HAT) to the ferryl and subsequent coupling between the carbon radical and Fe(III)-coordinated oxygen (termed rebound). Enzymes that use H?-abstracting ferryl complexes for other transformations must either suppress rebound or further process hydroxylated intermediates. For olefin-installing C-C desaturations, it has been proposed that a second HAT to the Fe(III)-OH complex from the carbon α to the radical preempts rebound. Deuterium (2H) at the second site should slow this step, potentially making rebound competitive. Desaturations mediated by two related l-arginine-modifying iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) oxygenases behave oppositely in this key test, implicating different mechanisms. NapI, the l-Arg 4,5-desaturase from the naphthyridinomycin biosynthetic pathway, abstracts H? first from C5 but hydroxylates this site (leading to guanidine release) to the same modest extent whether C4 harbors 1H or 2H. By contrast, an unexpected 3,4-desaturation of l-homoarginine (l-hArg) by VioC, the l-Arg 3-hydroxylase from the viomycin biosynthetic pathway, is markedly disfavored relative to C4 hydroxylation when C3 (the second hydrogen donor) harbors 2H. Anchimeric assistance by N6 permits removal of the C4-H as a proton in the NapI reaction, but, with no such assistance possible in the VioC desaturation, a second HAT step (from C3) is required. The close proximity (≤3.5 ?) of both l-hArg carbons to the oxygen ligand in an X-ray crystal structure of VioC harboring a vanadium-based ferryl mimic supports and rationalizes the sequential-HAT mechanism. The results suggest that, although the sequential-HAT mechanism is feasible, its geometric requirements may make competing hydroxylation unavoidable, thus explaining the presence of α-heteroatoms in nearly all native substrates for Fe/2OG desaturases.
An Allyl Protection and Improved Purification Strategy Enables the Synthesis of Functionalized Phosphonamidate Peptides
Cramer, Jonathan,Klebe, Gerhard
supporting information, p. 1857 - 1866 (2017/04/06)
For modern biophysical methods such as isothermal titration calorimetry, high purity of the inhibitor of interest is indispensable. Herein, we describe a procedure for the synthesis and purification of functionalized phosphonamidate peptides that is able to generate inhibitors for the metalloprotease thermolysin for use in biophysical experiments. The method utilizes an allyl ester/alloc protection strategy and takes advantage of a fast and effective solid-phase extraction (SPE) purification step. Applying this strategy, we were able to synthesize a series of highly polar inhibitors featuring amino- and hydroxy-functionalized side chains in excellent purity.
A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds
Isidro-Llobet, Albert,Hadje Georgiou, Kathy,Galloway, Warren R. J. D.,Giacomini, Elisa,Hansen, Mette R.,Méndez-Abt, Gabriela,Tan, Yaw Sing,Carro, Laura,Sore, Hannah F.,Spring, David R.
supporting information, p. 4570 - 4580 (2015/04/14)
Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.
TUMOUR RADIOLABELLING IMAGING AGENTS COMPRISING ORNITHINE AND DERIVATIVES THEREOF
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Page/Page column 21-22, (2011/11/06)
The present invention relates to a radiolabelling imaging agent comprising ornithine and derivatives thereof modified to incorporate a Technetium (99n,Tc) radiolabel. The radioiabelled imaging agents are substrates for Ornithine Decarboxylase (ODC) and can be used for imaging of cancers in which ODC expression is upregulated.
Stapling of a 310-helix with click chemistry
Jacobsen, yvind,Maekawa, Hiroaki,Ge, Nien-Hui,Goerbitz, Carl Henrik,Rongved, Pal,Ottersen, Ole Petter,Amiry-Moghaddam, Mahmood,Klaveness, Jo
supporting information; experimental part, p. 1228 - 1238 (2011/04/24)
Short peptides are important as lead compounds and molecular probes in drug discovery and chemical biology, but their well-known drawbacks, such as high conformational flexibility, protease lability, poor bioavailability and short half-lives in vivo, have prevented their potential from being fully realized. Side chain-to-side chain cyclization, e.g., by ring-closing olefin metathesis, known as stapling, is one approach to increase the biological activity of short peptides that has shown promise when applied to 310-and α-helical peptides. However, atomic resolution structural information on the effect of side chain-to-side chain cyclization in 310-helical peptides is scarce, and reported data suggest that there is significant potential for improvement of existing methodologies. Here, we report a novel stapling methodology for 310-helical peptides using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in a model aminoisobutyric acid (Aib) rich peptide and examine the structural effect of side chain-to-side chain cyclization by NMR, X-ray diffraction, linear IR and femtosecond 2D IR spectroscopy. Our data show that the resulting cyclic peptide represents a more ideal 310-helix than its acyclic precursor and other stapled 310-helical peptides reported to date. Side chain-to-side chain stapling by CuAAC should prove useful when applied to 3 10-helical peptides and protein segments of interest in biomedicine.(Figure Presented)
AMINOGLYCOSIDE DERIVATIVES
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Page/Page column 48, (2011/12/02)
The present invention relates to antimicrobial and antibiotic aminoglycoside derivatives. The compounds of the present application have the following chemical structures. The invention also relates to compositions, methods of preparation and methods of treatment of bacterial infections using the above aminoglycoside derivative.
Inhibitors of N α-acetyl-l-ornithine deacetylase: Synthesis, characterization and analysis of their inhibitory potency
Hlavacek,Picha,Vanek,Jiracek,Slaninova,Fucik,Budesinsky,Gilner,Holz
experimental part, p. 1155 - 1164 (2010/08/06)
A series of N α-acyl (alkyl)- and N α- alkoxycarbonyl-derivatives of l- and d-ornithine were prepared, characterized, and analyzed for their potency toward the bacterial enzyme N α-acetyl-l-ornithine deacetylase (ArgE). Ar
