72776-05-7Relevant articles and documents
RETRACTED ARTICLE: Site-selective enzymatic C-H amidation for synthesis of diverse lactams
Cho, Inha,Jia, Zhi-Jun,Arnold, Frances H.
, p. 575 - 578 (2019/06/07)
A major challenge in carbon?hydrogen (C?H) bond functionalization is to have the catalyst control precisely where a reaction takes place. In this study, we report engineered cytochrome P450 enzymes that perform unprecedented enantioselective C?H amidation reactions and control the site selectivity to divergently construct b-, g-, and d-lactams, completely overruling the inherent reactivities of the C?H bonds. The enzymes, expressed in Escherichia coli cells, accomplish this abiological carbon?nitrogen bond formation via reactive iron-bound carbonyl nitrenes generated from nature-inspired acyl-protected hydroxamate precursors. This transformation is exceptionally efficient (up to 1,020,000 total turnovers) and selective (up to 25:1 regioselectivity and 97%, please refer to compound 2v enantiomeric excess), and can be performed easily on preparative scale.
The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain
Brown, Alan D.,Bagal, Sharan K.,Blackwell, Paul,Blakemore, David C.,Brown, Bruce,Bungay, Peter J.,Corless, Martin,Crawforth, James,Fengas, David,Fenwick, David R.,Gray, Victoria,Kemp, Mark,Klute, Wolfgang,Malet Sanz, Laia,Miller, Duncan,Murata, Yoshihisa,Payne, C. Elizabeth,Skerratt, Sarah,Stevens, Edward B.,Warmus, Joseph S.
, p. 230 - 239 (2018/12/11)
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives
Galletti, Paola,Soldati, Roberto,Pori, Matteo,Durso, Margherita,Tolomelli, Alessandra,Gentilucci, Luca,Dattoli, Samantha Deianira,Baiula, Monica,Spampinato, Santi,Giacomini, Daria
, p. 284 - 293 (2014/07/08)
The αvβ3 and α5β 1 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. We report here the design, synthesis and biological activity of some new β-lactam derivatives specifically designed to target integrins. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24 cells; in particular 1, expressed a higher affinity towards α5β1 integrin (EC50 of 12 nM) and 2 was more selective for integrin αvβ3 (EC 50 of 11 nM).
Cyclic dipeptides and azetidinone compounds and their use in treating CNS injury and neurodegenerative disorders
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Page/Page column 45, (2010/11/26)
The present invention provides 4-substituted-2-azetidinone compounds, bicyclic 2-5-diketopiperazine compounds, and pharmaceutical compositions thereof that are potent, safe and effective neuroprotective agents. Due to their strong central nervous system (CNS) activity, the compounds can be used to enhance memory and to treat a variety of neurological disorders. The compounds are particularly useful for treating neurological disorders caused by, or associated with, CNS trauma.
β-Lactam derivatives as enzyme inhibitors: N-substituted derivatives of (S)-4-oxoazetidine-2-carboxylate as inhibitors of elastase and papain
Achilles,Schneider,Schirmeister,Otto
, p. 798 - 802 (2007/10/03)
N-Alkyl and N-acyl substituted 4-oxoazetidine-2-carboxylates are synthesized and evaluated as inhibitors of the proteases porcine pancreatic elastase (PPE) and papain. The compounds are obtained by alkylation or acylation at the nitrogen of benzyl (S)-4-oxoazetidine-2-carboxylate, which is synthesized by a modified literature procedure. The enzymatic assays prove some derivatives to be effective inhibitors of PPE and/or papain. The N-BOC protected amino acid derivatives 10 and 13 inhibit PPE reversibly with K(I)-values in the micromolar range. On the other hand, papain is inactivated irreversibly by benzyl (S)-2-(benzyloxycarbonyl)azetidin-1-acetate (6).
Synthesis and biology of the rigidified glutamate analogue, trans-2-carboxyazetidine-3-acetic acid (t-CAA)
Kozikowski, Alan P.,Liao, Yi,Tueckmantel, Werner,Wang, Shaomeng,Pshenichkin, Sergey,Surin, Alexander,Thomsen, Christian,Wroblewski, Jarda T.
, p. 2559 - 2564 (2007/10/03)
Chemical approaches to the (-)- and (+)-trans-2-carboxyazetidine-3-acetic acids (-)-1 and (+)-1, and their homologues (-)-2 and (+)-2, compounds that represent rigidified analogues of glutamate (glu), are reported together with the complete biological characterization of (+)-1 (t-CAA) at the known glu recognition sites. t-CAA was found to be an inhibitor of Na+-dependent glu uptake and to act as a kainate receptor ligand.
Studies on the Alkylation of Dipeptide Substrates
Ager, David J.,Froen, Diane E.,Klix, Russell C.,Zhi, Benxin,McIntosh, John M.,Thangarasa, Rasiah
, p. 1975 - 1982 (2007/10/02)
Alkylation of anions derived from dipeptides with a glycine at the C-terminus have been investigated.A hydrocarbon sedition in the N-terminal residue does impart some asymmetric induction.The use of a chiral ester derivative provides the potential for double asymmetric induction and good selectivity.With an aspartyl residue at the N-terminus, problems were encountered due to competing side reactions.The use of an azetidione could circumvent some of these, but the observed induction was not high.
STEREOSPECIFIC SYNTHESIS OF DEALANYLALAHOPCIN
Baldwin, Jack E.,Adlington, Robert M.,Gollins, David W.,Schofield, Christopher J.
, p. 4733 - 4748 (2007/10/02)
The first synthesis of the novel α-amino acid dealanylalahopcin starting from (L)-aspartic acid is described.
A Stereoselective Approach to the δ-Lactone Fragment of the Lankacidin Antibiotics
Thomas, Eric J.,Williams, Andrew C.
, p. 992 - 994 (2007/10/02)
An approach to the synthesis of the lactone fragment of the lankacidin antibiotics is described which is based upon stereoselective modification of an L-aspartic acid derived β-lactam.
The Asymmetric Addition of the Sn(II) Enolates of Thioesters to α-Iminoesters. A Convenient Synthesis of Optically Active cis-Substituted β-Lactams.
Yamada, Tohru,Suzuki, Hiroshi,Mukaiyama, Teruaki
, p. 293 - 296 (2007/10/02)
The asymmetric addition of the Sn(II) enolates derived from thioesters to α-iminoesters having the chiral auxiliary on the nitrogen atom proceeds smoothly to afford syn-β-aminoacid derivatives, which are in turn converted to optically active cis-substituted β-lactams.
