159766-56-0Relevant articles and documents
Towards a selective Boc deprotection on acid cleavable Wang resin
Lejeune, Valérie,Martinez, Jean,Cavelier, Florine
, p. 4757 - 4759 (2003)
Deprotection of the Boc group of an amino acid attached to the Wang resin has been investigated. Several conditions, including bases, solvents and reaction time, were studied. Quantitative yield of Boc deprotection was achieved with less than 10% loss of resin loading with trimethylsilyltriflate. This reagent allows the replacement of tert-butyl to TMS group, leading to a new temporary urethane protection readily hydrolyzed.
Optimization of a PEGylated glucuronide-monomethylauristatin E linker for antibody-drug conjugates
Burke, Patrick J.,Hamilton, Joseph Z.,Jeffrey, Scott C.,Hunter, Joshua H.,Doronina, Svetlana O.,Okeley, Nicole M.,Miyamoto, Jamie B.,Anderson, Martha E.,Stone, Ivan J.,Ulrich, Michelle L.,Simmons, Jessica K.,McKinney, Erica E.,Senter, Peter D.,Lyon, Robert P.
, p. 116 - 123 (2017)
The emergence of antibody-drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a b-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo. Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo. Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs.
Synthesis and Evaluation of a Stable Isostere of Malonyllysine**
Jing, Yihang,Bergholtz, Sarah E.,Omole, Anthony,Kulkarni, Rhushi A.,Zengeya, Thomas T.,Yoo, Euna,Meier, Jordan L.
, (2021/11/09)
Lysine malonylation is a recently characterized post-translational modification involved in the regulation of energy metabolism and gene expression. One unique feature of this post-translational modification is its potential susceptibility to decarboxylation, which poses possible challenges to its study. As a step towards addressing these challenges, we report the synthesis and evaluation of a stable isostere of malonyllysine. First, we find that synthetic substitution of the malonyl group with a tetrazole isostere results in amino acid's resistant to thermal decarboxylation. Next, we demonstrate that protected variants of this amino acid are readily incorporated into peptides. Finally, we show that tetrazole isosteres of malonyllysine can be recognized by anti-malonyllysine antibodies and histone deacylases, validating their ability to mimic features of the endogenous lysine modification. Overall, this study establishes a new chemical strategy for stably mimicking a metabolite-derived post-translational modification, providing a foothold for tool development and functional analyses.
Preparation method of Nalpha-[(9H-fluorene-9-ylmethoxy)carbonyl]-Nepsilon-acetyl-L-lysine
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Paragraph 0026; 0029; 0035; 0038, (2019/02/10)
The invention discloses a preparation method of Nalpha-[(9H-fluoren-9-ylmethoxy)carbonyl]-Nepsilon-acetyl-L-lysine. The preparation method is mainly used for solving the technical problems of complexity, long cycle, low yield, high cost and the like in an original process. The preparation method provided by the invention comprises the following steps: 1, lysine hydrochloride and copper salt reactto form a lysine-copper complex; 2, the lysine-copper complex and an acetyl donor react to prepare an Nepsilon-acetyl-L-lysine-copper complex; 3, the Nepsilon-acetyl-L-lysine-copper complex is subjected to copper removal to obtain an Nepsilon-acetyl-L-lysine aqueous solution; and 4, the Nepsilon-acetyl-L-lysine aqueous solution and a protective agent of fmoc-group are mixed, in the presence of anorganic solvent, a pH value is adjusted to 8-9 through an alkali compound sodium carbonate aqueous solution, reaction is carried out, and thus Nalpha-[(9H-fluorene-9-ylmethoxy)carbonyl]-Nepsilon-acetyl-L-lysine is prepared. The preparation method provided by the invention adopts a reasonable process route to prepare the Nalpha-[(9H-fluorene-9-ylmethoxy)carbonyl]-Nepsilon-acetyl-L-lysine, so that the preparation method is suitable for mass production.
Random-coil:α-helix equilibria as a reporter for the Lewis X-LewisX interaction
Altamore, Timothy M.,Fernandez-Garcia, Christian,Gordon, Andrew H.,Huebscher, Tina,Promsawan, Netnapa,Ryadnov, Maxim G.,Doig, Andrew J.,Woolfson, Derek N.,Gallagher, Timothy
, p. 11167 - 11171 (2012/02/02)
Probing weak interactions: A peptide random-coil:α-helix equilibrium has been used to identify a weak carbohydrate-carbohydrate interaction (CCI). Glucose and lactose destabilized the helical conformer while LewisX trisaccharide led to increased helicity. Though small, the trend observed indicates that this peptide reporter can detect a single CCI in isolation. Copyright
Nε-Modified lysine containing inhibitors for SIRT1 and SIRT2
Huhtiniemi, Tero,Suuronen, Tiina,Lahtela-Kakkonen, Maija,Bruijn, Tanja,J??skel?inen, Sanna,Poso, Antti,Salminen, Antero,Lepp?nen, Jukka,Jarho, Elina
supporting information; experimental part, p. 5616 - 5625 (2010/09/14)
Sirtuins catalyze the NAD+ dependent deacetylation of N ε-acetyl lysine residues to nicotinamide, O′-acetyl-ADP- ribose (OAADPR) and Nε-deacetylated lysine. Here, an easy-to-synthesize Ac-Ala-Lys-Ala sequence has been used as a probe for the screening of novel Nε-modified lysine containing inhibitors against SIRT1 and SIRT2. Nε-Selenoacetyl and N ε-isothiovaleryl were the most potent moieties found in this study, comparable to the widely studied Nε-thioacetyl group. The Nε-3,3-dimethylacryl and Nε-isovaleryl moieties gave significant inhibition in comparison to the Nε-acetyl group present in the substrates. In addition, the studied Nε- alkanoyl, Nε-α,β-unsaturated carbonyl and N ε-aroyl moieties showed that the acetyl binding pocket can accept rather large groups, but is sensitive to even small changes in electronic and steric properties of the Nε-modification. These results are applicable for further screening of Nε-acetyl analogues.
