161010-97-5Relevant academic research and scientific papers
Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain
Brand, Michael,Clayton, James,Moroglu, Mustafa,Schiedel, Matthias,Picaud, Sarah,Bluck, Joseph P.,Skwarska, Anna,Bolland, Hannah,Chan, Anthony K. N.,Laurin, Corentine M. C.,Scorah, Amy R.,See, Larissa,Rooney, Timothy P. C.,Andrews, Katrina H.,Fedorov, Oleg,Perell, Gabriella,Kalra, Prakriti,Vinh, Kayla B.,Cortopassi, Wilian A.,Heitel, Pascal,Christensen, Kirsten E.,Cooper, Richard I.,Paton, Robert S.,Pomerantz, William C. K.,Biggin, Philip C.,Hammond, Ester M.,Filippakopoulos, Panagis,Conway, Stuart J.
, p. 10102 - 10123 (2021/07/31)
CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activa
Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library
Catalano, Marco,Moroglu, Mustafa,Balbi, Petra,Mazzieri, Federica,Clayton, James,Andrews, Katrina H.,Bigatti, Martina,Scheuermann, J?rg,Conway, Stuart J.,Neri, Dario
supporting information, p. 1752 - 1756 (2020/08/21)
DNA-encoded chemical libraries (DECLs) are collections of chemical moieties individually coupled to distinctive DNA barcodes. Compounds can be displayed either at the end of a single DNA strand (i. e., single-pharmacophore libraries) or at the extremities of two complementary DNA strands (i. e., dual-pharmacophore libraries). In this work, we describe the use of a dual-pharmacophore encoded self-assembly chemical (ESAC) library for the affinity maturation of a known 4,5-dihydrobenzodiazepinone ring (THBD) acetyl-lysine (KAc) mimic for the cyclic-AMP response element binding protein (CREB) binding protein (CREBBP or CBP) bromodomain. The new pair of fragments discovered from library selection showed a sub-micromolar affinity for the CREBBP bromodomain in fluorescence polarization and ELISA assays, and selectivity against BRD4(1).
OXAZOLO [5, 4 -B] PYRIDIN- 5 -YL COMPOUNDS AND THEIR USE FOR THE TREATMENT OF CANCER
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Page/Page column 7-8, (2012/06/16)
The present invention provides oxazolo[5,4-b]pyridin-5-yl compounds useful in the treatment of cancer.
Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics
Zhang, Wenjun,Ntai, Ioanna,Bolla, Megan L.,Malcolmson, Steven J.,Kahne, Daniel,Kelleher, Neil L.,Walsh, Christopher T.
supporting information; experimental part, p. 5240 - 5243 (2011/06/17)
Pacidamycins are a family of uridyl peptide antibiotics that inhibit the translocase MraY, an essential enzyme in bacterial cell wall biosynthesis that to date has not been clinically targeted. The pacidamycin structural skeleton contains a doubly inverted peptidyl chain with a β-peptide and a ureido linkage as well as a 3′-deoxyuridine nucleoside attached to DABA 3 of the peptidyl chain via an enamide linkage. Although the biosynthetic gene cluster for pacidamycins was identified recently, the assembly line of this group of peptidyl nucleoside antibiotics remained poorly understood because of the highly dissociated nature of the encoded nonribosomal peptide synthetase (NRPS) domains and modules. This work has identified a minimum set of enzymes needed for generation of the pacidamycin scaffold from amino acid and nucleoside monomers, highlighting a freestanding thiolation (T) domain (PacH) as a key carrier component in the peptidyl chain assembly as well as a freestanding condensation (C) domain (PacI) catalyzing the release of the assembled peptide by a nucleoside moiety. On the basis of the substrate promiscuity of this enzymatic assembly line, several pacidamycin analogues were produced using in vitro total biosynthesis.
Double asymmetric induction as a mechanistic probe: The doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure α,β-unsaturated esters and enantiopure α,β-unsaturated hydroxamates
Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Thomson, James E.,Yin, Jingda
experimental part, p. 6382 - 6403 (2011/09/19)
The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure α,β-unsaturated esters [derived from Corey's 8-phenylmenthol chiral auxiliary] and enantiopure α,β-unsaturated hydroxamates [derived from our 'chiral Weinreb amide' auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert- butylhydroxylamine] has been used as a mechanistic probe to determine the reactive conformations of these acceptors.
Enantioselective synthesis of α-fluoro-β3-amino esters: Synthesis of enantiopure, orthogonally protected α-fluoro- β3-lysine
Duggan, Peter J.,Johnston, Martin,March, Taryn L.
experimental part, p. 7365 - 7372 (2011/02/23)
The scope of a tandem conjugate addition-fluorination sequence performed on α,β-unsaturated esters using the enantiopure lithium amide derived from (S)-N-benzyl-N-(α-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide h
Parallel synthesis of homochiral β-amino acids
Davies, Stephen G.,Mulvaney, Andrew W.,Russell, Angela J.,Smith, Andrew D.
, p. 1554 - 1566 (2008/02/09)
The parallel asymmetric synthesis of an array of 30 β-amino acids of high enantiomeric purity using the conjugate addition of homochiral lithium N-benzyl-N-(α-methylbenzyl)amide as the key step is accomplished. The experimental simplicity and highly practical nature of the protocol is demonstrated by the efficient parallel conversion of 15 α,β-unsaturated esters to both enantiomeric series of the corresponding β-amino acids in high overall yields and selectivities with minimal purification involved in each step of the reaction protocol.
Homochiral lithium amides for the asymmetric synthesis of β-amino acids
Davies, Stephen G.,Garrido, Narciso M.,Kruchinin, Dennis,Ichihara, Osamu,Kotchie, Luke J.,Price, Paul D.,Mortimer, Anne J. Price,Russell, Angela J.,Smith, Andrew D.
, p. 1793 - 1811 (2007/10/03)
Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing (R)-β-amino butyric acid, (R)-β-amino pentanoic acid, (S)-β-leucine, (R)-β-amino octanoic acid, (S)-β-phenylalanine, (S)-β-tyrosine methyl ether, (S)-β-tyrosine hydrochloride and (S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products (R)-β-DOPA and (R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.
Synthesis of N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl} amine
Fleck, Thomas J.,McWhorter Jr., William W.,DeKam, Richard N.,Pearlman, Bruce A.
, p. 9612 - 9617 (2007/10/03)
N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl} amine (1)1 is a key intermediate in the preparation of premafloxacin (2), which was under development as an antibiotic for use against pathogens of veterinary importance. This paper describes the development of a practical, efficient, and stereoselective process for the preparation of 1 from isobutyl (3S)-3-{methyl[(1S)-1-phenylethyl]-amino}butanoate (5c). The key steps in the synthetic sequence are an asymmetric Michael addition, which yields 5c, and a stereoselective alkylation, which yields (3S,4S)-3-allyl-1,4-dimethylazetidin-2-one (17).
Peptide based inhibitors of interleukin-8: Structural simplification and enhanced potency
Attwood, Michael R.,Conway, Elizabeth A.,Dunsdon, Rachel M.,Greening, John R.,Handa, Balraj K.,Jones, Philip S.,Jordan, Steven C.,Keech, Elizabeth,Wilson, Francis X.
, p. 429 - 432 (2007/10/03)
Important areas of a lead peptide inhibitor of IL-8 had been previously identified. Chemical modification led to the identification of key amide bonds which allowed the replacement of the central section of the peptide with modified amino acids and spacers. This approach led to inhibitors of lower molecular weight and of increased potency.
