850209-98-2

Upstream product

• 1237769-99-1 N,N-dibenzyl-D-glutamic acid dibenzyl ester 
• 100-39-0 benzyl bromide 
• 56-86-0 L-glutamic acid 
• 1609011-54-2 N,N-dibenzylglutamic acid α-benzyl ester 
• 167905-35-3 (S)-2-dibenzylaminopentanedioic acid dibenzyl ester 

Downstream Products

• 850209-99-3 2-dibenzylamino-5-oxo-pentanoic acid benzyl ester 
• 1327254-70-5 (S)-N-[3,5-bis(benzyloxy)phenethyl]-2-(dibenzylamino)-5-hydroxypentanamide 
• 1327254-73-8 (S)-1-(3,5-bis(benzyloxy)phenethyl)-3-(dibenzylamino)-3,4-dihydropyridin-2(1H)-one 
• 1327254-72-7 (3S,11bS)-9,11-bis(benzyloxy)-3-(dibenzylamino)-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one 
• 1327254-59-0 (3S)-1-[3,5-bis(benzyloxy)phenethyl]-3-(dibenzylamino)-6-hydroxypiperidin-2-one 
• 1160861-03-9 (S)-2-dibenzylamino-5-hydroxypentanoic acid N-allylamide 
• 157618-75-2 (-)-(3S,9S,14aR)-9-benzyl-3-[(R)-7-hydroxy-6-oxooctyl]-6,6-dimethyldecahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetraone 
• 874384-21-1 (R)-1-((S)-2-{2-[(2S,9R)-2-tert-Butoxycarbonylamino-9-(tert-butyl-dimethyl-silanyloxy)-8-oxo-decanoylamino]-2-methyl-propionylamino}-3-phenyl-propionyl)-pyrrolidine-2-carboxylic acid 
• 874384-22-2 (R)-1-{(S)-2-[2-((2S,9R)-2-Amino-9-hydroxy-8-oxo-decanoylamino)-2-methyl-propionylamino]-3-phenyl-propionyl}-pyrrolidine-2-carboxylic acid 
• 874384-07-3 (2S,9S,E)-2-(dibenzylamino)-9-(tert-butyldimethylsilyloxy)-8-oxo-6-decenoic acid benzyl ester 
• 874384-08-4 benzyl (2S)-2-(dibenzylamino)-8-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-8-oxo-6-octenoate 
• 874384-05-1 2-(S)-(dibenzylamino)-8-oxo-6-decenoic acid benzyl ester 
• 874384-02-8 (S)-2-(dibenzylamino)-6-oxohexanoic acid benzyl ester 
• 874384-03-9 (E)-(S)-2-Dibenzylamino-6-methoxy-hex-5-enoic acid benzyl ester 

Relevant academic research and scientific papers

Photo Cross-Linking Probes Containing ?-N-Thioacyllysine and ?-N-Acyl-(δ-aza)lysine Residues

Posttranslational modifications (PTMs) are important in the regulation of protein function, trafficking, localization, and marking for degradation. This work describes the development of peptide activity/affinity-based probes for the discovery of proteins that recognize novel acyl-based PTMs on lysine residues in the proteome. The probes contain surrogates of ?-N-acyllysine by introduction of either hydrazide or thioamide functionalities to circumvent hydrolysis of the modification during the experiments. In addition to the modified PTMs, the developed chemotypes were analyzed with respect to the effect of peptide sequence. The photo cross-linking conditions and subsequent functionalization of the covalent adducts were systematically optimized by applying fluorophore labeling and gel electrophoresis (in-gel fluorescence measurements). Finally, selected probes, containing the ?-N-glutaryllysine and ?-N-myristoyllysine analogues, were successfully applied for the enrichment of native, endogenous proteins from cell lysate, recapitulating the expected interactions of SIRT5 and SIRT2, respectively. Interestingly, the latter mentioned was able to pull down two different splice variants of SIRT2, which has not been achieved with a covalent probe before. Based on this elaborate proof-of-concept study, we expect that the technology will have broad future applications for pairing of novel PTMs with the proteins that target them in the cell.

Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight

The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.

Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1-Selective Inactivators

Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide 3 is a mechanism-based LSD1 inhibitor. Furthermore, peptides 37 and 38, which consist of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1.

Direct synthesis of polybenzylated glutamic acid monoesters: Disambiguation of N, N -dibenzylglutamic acid α- And γ-benzyl esters

In this study, we explored the regioselective benzylation of l-glutamic acid under substoichiometric amounts of the alkylating agent. Our results demonstrate unambiguously that N,N-dibenzylglutamic acid γ-benzyl ester was not obtained by direct benzylatio

Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors

LSD1 is a flavin-dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily which utilize molecular oxygen to transform amines to iminjes that are hydrolytically cleaved to formaldehyde. In prior studies, it has been shown that monoamine oxidase inhibitory scaffolds such as propargylamines and cyclopropylamines can serve as mechanism-based inactivators of LSD1. Propargylamine-histone H3 peptide analogues are potent LSD1 inhibitors, whereas small molecule antidepressant MAO acetylenic inhibitors like pargyline do not inhibit LSD1. In contrast, the small molecule MAO cyclopropylamine inhibitor tranylcypromine is a timedependent LSD1 inhibitor but exo-cyclopropylamine- peptide substrate analogue is not. To provide further insight into small molecule versus peptide relationships in LSD1 inhibition, herein we further our analysis of warheads in peptide scaffolds to include the chlorovinyl, endo-cyclopropylamine, and hydrazinefunctionalities as LSD1 inactivators. We find that chlorovinyl-H3 is a mechanism-based LSD1 inactivator whereas encto-cyclopropylamine-H3 does not show time-dependent inactivation. The hydrazine-H3 was shown to be the most potent LSD1 suicide inhibitor yet reported, more than 20-fold more efficient in inhibiting demethylation than propargylamine-H3 derivatives. We re-explored MAO antidepressant agent phenelzine (phenethylhydrazine), previously reported to be a weak LSD1 inhibitor, and found that it is far more potent than previously appreciated. We show that phenelzine can block histone H3K4Me demethylation in cells, validating it as a pharmacologic tool and potential lead structure for anticancer therapy.

Facile syntheses of three AHP-type building blocks with complementary reactivities

Two protected 3-amino-6-hydroxy-2-piperidone derivatives (Ahp, 12 and 6), as well as a thioether analogue (7) were synthesized starting from L-glutamic acid in four, five, and six steps respectively. The Ahp derivatives 12 and 6 are not only the structura

Synthesis of 2-amino-8-oxodecanoic acids (Aodas) present in natural hystone deacetylase inhibitors

Differently substituted 2-amino-8-oxodecanoic acids (Aodas), present in naturally occurring inhibitors of hystone deacetylase (HDAC), have been prepared using a convergent approach. The configuration in position 2 was derived from enantiomerically pure allylglycine or glutamic acid, whereas the stereochemistry of the substituent in position 9 derived from lactic acid or glyceraldehyde derivatives. Starting from allylglycine, (S)-Aodas, protected at the nitrogen as Boc or Fmoc, were obtained in four steps in about 30% overall yield. These products have been used to prepare a simplified analogue of a natural cyclic tetrapeptide HDAC inhibitor by SPPS.

A simple procedure for the transformation of L-glutamic acid into the corresponding γ-aldehyde

2-Dibenzylamino-5-oxopentanoic acid benzyl ester has been obtained in good yields by complete benzylation of L-glutamic acid in NaOH and Na 2CO3, selective reduction of the γ-ester into alcohol with DIBAL and further transformation into aldehyde using Swern oxidation. The overall three-step procedure from Glu gave aldehyde in 49% yield. Georg Thieme Verlag Stuttgart.