150438-78-1Relevant academic research and scientific papers
Protecting group free synthesis of glycosyl thiols from reducing sugars in water; application to the production of N-glycan glycoconjugates
Alexander,Lim,Amso,Brimble,Fairbanks
, p. 2152 - 2156 (2017)
Glycosyl thiols may be accessed from the corresponding reducing sugars in water without recourse to any sugar projecting groups by way of a DMC mediated reaction with thioacetic acid in the presence of base, and hydrolysis of the anomeric thioacetate. Glycosyl thiols produced by this method may be used to access glycoconjugates, such as glycopeptides by use of the thiol-ene click reaction.
Facile and E-selective intramolecular ring-closing metathesis reactions in 310-helical peptides: A 3D structural study
Boal, Amie K.,Guryanov, Ivan,Moretto, Alessandro,Crisma, Marco,Lanni, Erica L.,Toniolo, Claudio,Grubbs, Robert H.,O'Leary, Daniel J.
, p. 6986 - 6987 (2007)
The ring-closing metathesis reaction can be used to cross-link allylated serine residues situated at the i and i + 3 positions in 310-helical peptides containing the helicogenic amino acid, ∞-aminoisobutyric acid (Aib). An octapeptide with the sequence Boc-Aib-Aib-Aib-Ser(Al)-Aib-Aib-Ser(Al)-Aib-OMe was found to undergo a facile and >20:1 E-selective ring-closing metathesis (RCM) reaction catalyzed by the Grubbs second-generation catalyst to yield an 18-membered macrocycle. The formation of this cross-link does not significantly disturb the peptide's native 310-helicity, as judged by an X-ray diffraction study of the acyclic diene, the E-olefin RCM product, and its hydrogenated derivative. A heptapeptide system with the sequence Boc-Val-Ser(Al)-Leu-Aib-Ser(Al)-Val-Leu-OMe also underwent an efficient RCM reaction, albeit with diminished E-selectivity. It is apparent from these studies that a minimal, RCM-derived, macrocyclic constraint can be readily incorporated into 310-helical peptides. Copyright
Clickable glutathione using tetrazine-alkene bioorthogonal chemistry for detecting protein glutathionylation
Kekulandara, Dilini N.,Samarasinghe, Kusal T. G.,Munkanatta Godage, Dhanushka N. P.,Ahn, Young-Hoon
, p. 10886 - 10893 (2016)
Protein glutathionylation is one of the major cysteine oxidative modifications in response to reactive oxygen species (ROS). We recently developed a clickable glutathione approach for detecting glutathionylation by using a glutathione synthetase mutant (GS M4) that synthesizes azido-glutathione (γGlu-Cys-azido-Ala) in situ in cells. In order to demonstrate the versatility of clickable glutathione and to increase the chemical tools for detecting glutathionylation, we sought to develop clickable glutathione that uses tetrazine-alkene bioorthogonal chemistry. Here we report two alkene-containing glycine surrogates (allyl-Gly and allyl-Ser) for the biosynthesis of clickable glutathione and their use for detection, enrichment, and identification of glutathionylated proteins. Our results provide chemical tools (allyl-Gly and allyl-Ser for GS M4) for versatile characterization of protein glutathionylation. In addition, we show that the active site of GS can be tuned to introduce a small size chemical tag on glutathione for exploring glutathione function in cells.
In Search of the Optimal Macrocyclization Site for Neurotensin
Sousbie, Marc,Besserer-Offroy, élie,Brouillette, Rebecca L.,Longpré, Jean-Michel,Leduc, Richard,Sarret, Philippe,Marsault, éric
, p. 227 - 232 (2018)
Neurotensin exerts potent analgesic effects following activation of its cognate GPCRs. In this study, we describe a systematic exploration, using structure-based design, of conformationally constraining neurotensin (8-13) with the help of macrocyclization and the resulting impacts on binding affinity, signaling, and proteolytic stability. This exploratory study led to a macrocyclic scaffold with submicromolar binding affinity, agonist activity, and greatly improved plasma stability.
N-(tert-Butoxycarbonyl)-O-allyl-l-seryl -α- aminoisobutyryl-l-valine methyl ester: A protected tripeptide with an allylated serine residue
Gebreslasie, Hadgu Girmay,Jacobsen, oyvind,Goerbitz, Carl Henrik
, p. o359-o363 (2011)
The title compound [systematic name (6S,12S)-methyl 6-(allyloxymethyl)-12- isopropyl-2,2,9,9-tetramethyl-4,7,10-tri-oxo-3-oxa-5,8,11-triazatridecan-13- oate], C21H37N3O7, con-taining the little studied O-allyl-l-serine residue [Ser(All)], crystallizes in the monoclinic space group C2 with one molecule in the asymmetric unit. The compound is an analogue of the Ser140-Val142 segment of the water channel aqua-porin-4 (AQP4). It forms a distorted type-II Β-turn with a PII-3 10L -PII backbone conformation (PII is polyproline II). The overall backbone conformation is markedly different from that of the CO(Pro139)-Val142 stretch of rat AQP4, but is quite similar to the corresponding segment of human AQP4, despite significant differences at the level of the individual residues. The side chain of the Ser(All) residue adopts a gauche conformation relative to the backbone CO - Cα and Cα - N bonds. The H atoms of the two CH2 groups in the Ser(All) side chain are almost eclipsed. The crystal packing of the title compound is divided into one-molecule-thick layers, each layer having a hydro-philic core and distinct hydrophobic interfaces on either side.
Application of ring-closing metathesis for the synthesis of macrocyclic peptidomimetics as inhibitors of HCV NS3 protease
Velazquez, Francisco,Venkatraman, Srikanth,Wu, Wanli,Blackman, Melissa,Prongay, Andrew,Girijavallabhan, Viyyoor,Shih, Neng-Yang,Njoroge, F. George
, p. 3061 - 3064 (2007)
An efficient synthetic approach for the preparation of macrocyclic peptidomimetics for inhibition of HCV NS3 is presented. The macrocyclic core is built using ring-closing metathesis (RCM) of a tripeptidic diene. The presented approach allows the introduction of heteroatoms in strategic places along the macrocyclic ring. The methyl ester moiety in the RCM products was synthetically manipulated to install a ketoamide moiety via a Passerini reaction.
In search of small molecules that selectively inhibit mboat4
Ding, Hui,Harran, Patrick G.,Hollibaugh, Ryan A.,Liu, Haixia,Murzinski, Emily S.,Saha, Ishika,Strugatsky, David,Tontonoz, Peter
, (2021/12/24)
Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.
COMPOUNDS AND USES THEREOF
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Page/Page column 355, (2021/08/06)
The present disclosure features compounds and methods useful for the treatment of BAF complex-related disorders.
Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure
Otani, Takuya,Hattori, Yasunao,Akaji, Kenichi,Kobayashi, Kazuya
, (2021/11/22)
Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 β-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1′ position further improved the activity.
Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template
Gall, Flavio M.,Hohl, Deborah,Frasson, David,Wermelinger, Tobias,Mittl, Peer R. E.,Sievers, Martin,Riedl, Rainer
supporting information, p. 4051 - 4055 (2019/02/16)
De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50: 170 nm) and MMP-9 (IC50: 140 nm).
