106930-51-2Relevant articles and documents
Structural Basis for α-Helix Mimicry and Inhibition of Protein–Protein Interactions with Oligourea Foldamers
Cussol, Léonie,Mauran-Ambrosino, Laura,Buratto, Jérémie,Belorusova, Anna Y,Neuville, Maxime,Osz, Judit,Fribourg, Sébastien,Fremaux, Juliette,Dolain, Christel,Goudreau, Sébastien R.,Rochel, Natacha,Guichard, Gilles
supporting information, p. 2296 - 2303 (2020/12/07)
Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein–protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide–oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization.
Urea based foldamers
Yoo, Sung Hyun,Li, Bo,Dolain, Christel,Pasco, Morgane,Guichard, Gilles
, p. 59 - 92 (2021/06/25)
N,N′-linked oligoureas are a class of enantiopure, sequence-defined peptidomimetic oligomers without amino acids that form well-defined and predictable helical structures akin to the peptide α-helix. Oligourea-based foldamers combine a number of features—such as synthetic accessibility, sequence modularity, and folding fidelity—that bode well for their use in a range of applications from medicinal chemistry to catalysis. Moreover, it was recently recognized that this synthetic helical backbone can be combined with regular peptides to generate helically folded peptide-oligourea hybrids that display additional features in terms of helix mimicry and protein-surface recognition properties. Here we provide detailed protocols for the preparation of requested monomers and for the synthesis and purification of homo-oligoureas and peptide-oligourea hybrids.
Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production
Reddy Guduru, Shiva Krishna,Chamakuri, Srinivas,Raji, Idris O.,MacKenzie, Kevin R.,Santini, Conrad,Young, Damian W.
, p. 11777 - 11793 (2018/09/27)
The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 a? 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp3-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.
Pd-catalyzed reductive cleavage of N-N bond in dibenzyl-1-alkylhydrazine-1,2-dicarboxylates with PMHS: Application to a formal enantioselective synthesis of (R)-sitagliptin
Dey, Soumen,Gadakh, Sunita K.,Ahuja, Brij Bhushan,Kamble, Sanjay P.,Sudalai, Arumugam
supporting information, p. 684 - 687 (2016/01/26)
An environmentally benign approach involving Pd-catalyzed reductive N-N bond cleavage in dibenzyl-1-alkylhydrazine-1,2-dicarboxylates leading to the synthesis of N-(tert-butoxy)carbamates under very mild conditions has been described. PMHS serves as an inexpensive source of hydride in MeOH/deionized H2O medium. This protocol has been successfully applied in the formal synthesis of (R)-sitagliptin, an anti-diabetic drug.
Structure-based design of substituted piperidines as a new class of highly efficacious oral direct renin inhibitors
Ehara, Takeru,Irie, Osamu,Kosaka, Takatoshi,Kanazawa, Takanori,Breitenstein, Werner,Grosche, Philipp,Ostermann, Nils,Suzuki, Masaki,Kawakami, Shimpei,Konishi, Kazuhide,Hitomi, Yuko,Toyao, Atsushi,Gunji, Hiroki,Cumin, Frederic,Schiering, Nikolaus,Wagner, Trixie,Rigel, Dean F.,Webb, Randy L.,Maibaum, Jurgen,Yokokawa, Fumiaki
supporting information, p. 787 - 792 (2014/08/05)
A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.
Synthesis of imidacloprid derivatives with a chiral alkylated imidazolidine ring and evaluation of their insecticidal activity and affinity to the nicotinic acetylcholine receptor
Nishiwaki, Hisashi,Kuriyama, Mituhiro,Nagaoka, Hikaru,Kato, Akira,Yamauchi, Satoshi,Shuto, Yoshihiro,Akamatsu, Miki
, p. 6305 - 6312,8 (2012/12/11)
A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5-position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified.
The first synthesis of β-amino phosphonates using cyclic sulfamidates
Das, Biswanath,Reddy, Cheruku Ravindra,Nagendra, Siddavatam,Lingaiah, Maram
scheme or table, p. 3496 - 3498 (2011/07/08)
Cyclic sulfamidates (prepared from α-amino acids and β-amino alcohols) have been used for the first time for the synthesis of novel β-amino phosphonates (chiral and achiral) by treatment with dialkyl phosphites using sodium hydride. 2-Substituted and 1,2-disubtituted β-amino phosphonates have efficiently been prepared following this method. The products are formed in high yield (79-84%) within 8-12 h.
Resolution of N-Protected amino alcohols by porcine pancreatic lipase
Magrioti, Victoria,Fotakopoulou, Irene,Athinaios, Nicolaos,Anastasopoulou, Panoula,Constantinou-Kokotou, Violetta,Kokotos, George
scheme or table, p. 159 - 162 (2010/08/19)
The resolution of 2-amino alcohols protected by urethane-type groups either via porcine pancreatic lipase (PPL) hydrolysis of the corresponding racemic acetates or via PPL catalyzed transesterification of racemic alcohols was studied. In both cases, Boc protecting group led to better chemical yields and enantiopurities than Z and Fmoc protecting groups. Furthermore, a simple and efficient method for the synthesis of the medicinally interesting optically pure (R)-2- aminohexadecanol was developed.
Amphoteric amino aldehydes reroute the Aza-Michael reaction
Hili, Ryan,Yudin, Andrei K.
supporting information; experimental part, p. 16404 - 16406 (2010/02/15)
(Chemical Equation Presented) Amphoteric amino aldehydes, which exist as stable dimers, participate in an aza-Michael/aldol domino reaction with α,β-unsaturated aldehydes to afford stable 1,5-aminohydroxyaldehydes in high yields and diastereoselectivies.
