- RETRACTED ARTICLE: Site-selective enzymatic C-H amidation for synthesis of diverse lactams
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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.
- Cho, Inha,Jia, Zhi-Jun,Arnold, Frances H.
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p. 575 - 578
(2019/06/07)
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- The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain
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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.
- 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.
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p. 230 - 239
(2018/12/11)
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- Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives
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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).
- Galletti, Paola,Soldati, Roberto,Pori, Matteo,Durso, Margherita,Tolomelli, Alessandra,Gentilucci, Luca,Dattoli, Samantha Deianira,Baiula, Monica,Spampinato, Santi,Giacomini, Daria
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p. 284 - 293
(2014/07/08)
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- Cyclic dipeptides and azetidinone compounds and their use in treating CNS injury and neurodegenerative disorders
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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.
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Page/Page column 45
(2010/11/26)
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- β-Lactam derivatives as enzyme inhibitors: N-substituted derivatives of (S)-4-oxoazetidine-2-carboxylate as inhibitors of elastase and papain
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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).
- Achilles,Schneider,Schirmeister,Otto
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p. 798 - 802
(2007/10/03)
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- Synthesis and biology of the rigidified glutamate analogue, trans-2-carboxyazetidine-3-acetic acid (t-CAA)
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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.
- Kozikowski, Alan P.,Liao, Yi,Tueckmantel, Werner,Wang, Shaomeng,Pshenichkin, Sergey,Surin, Alexander,Thomsen, Christian,Wroblewski, Jarda T.
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p. 2559 - 2564
(2007/10/03)
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- Studies on the Alkylation of Dipeptide Substrates
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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.
- Ager, David J.,Froen, Diane E.,Klix, Russell C.,Zhi, Benxin,McIntosh, John M.,Thangarasa, Rasiah
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p. 1975 - 1982
(2007/10/02)
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- STEREOSPECIFIC SYNTHESIS OF DEALANYLALAHOPCIN
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The first synthesis of the novel α-amino acid dealanylalahopcin starting from (L)-aspartic acid is described.
- Baldwin, Jack E.,Adlington, Robert M.,Gollins, David W.,Schofield, Christopher J.
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p. 4733 - 4748
(2007/10/02)
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- A Stereoselective Approach to the δ-Lactone Fragment of the Lankacidin Antibiotics
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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.
- Thomas, Eric J.,Williams, Andrew C.
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p. 992 - 994
(2007/10/02)
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- The Asymmetric Addition of the Sn(II) Enolates of Thioesters to α-Iminoesters. A Convenient Synthesis of Optically Active cis-Substituted β-Lactams.
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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.
- Yamada, Tohru,Suzuki, Hiroshi,Mukaiyama, Teruaki
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p. 293 - 296
(2007/10/02)
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- 3-[1-Hydroxyethyl]-4-carboxymethyl-azetidin-2-one
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In a process for the total synthesis of thienamycin from L-aspartic acid via intermediate III: STR1 there is disclosed a process for preparing III via STR2 wherein R is a protecting group.
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- Process for the preparation of 1-carbapenems and intermediates via silyl-substituted dithioacetals
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Disclosed is a process for the total synthesis of 1-carbapenem antibiotics (I) from L-aspartic acid via central intermediates II and III: STR1 wherein R is hydrogen, a pharmaceutically acceptable ester moiety or salt cation, or a readily removable blocking group; R6, R7 and R8 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl; R1' and Re are hydrogen, or a readily removable protecting group; Ra, Rb and Rc are selected from alkyl, aryl or aralkyl.
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- Process for the preparation of 1-carbapenems and intermediates via trithioorthoacetates
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Disclosed is a process for the total synthesis of 1-carbapenem antibiotics (I) from L-aspartic acid via intermediates II and III: STR1 wherein R is hydrogen, a pharmaceutically acceptable ester moiety or salt cation, or a readily removable blocking group; R6 and R7 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl; R1' is hydrogen or a protecting group; and Ra, Rb and Rc are independently selected from alkyl, aryl and aralkyl.
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- Process for preparing 7-(1-hydroxyethyl)-3-(2-aminoethylthio)-1-carbadethiaceph-3-em-3-carboxylic acid and intermediate therefor
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Disclosed is a process for preparing 7-(1-hydroxethyl)-3-(2-aminoethylthio)-1-carbadethiaceph-3-em-3-carboxylic acid and its pharmaceutically acceptable salts and esters (I) by total synthesis starting with L-aspartic acid and proceeding via intermediate II: STR1 R=blocking group
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- Process for the preparation of thienamycin and intermediates
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Disclosed is a process for the total synthesis of thienamycin from L-aspartic acid via intermediate III: STR1 R=H, blocking group or salt cation.
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- 4-Iodomethylazetidin-2-one
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Disclosed is a process for preparing 7-(1-hydroxethyl)-3-(2-aminoethylthio)-1-carbadethiaceph-3-em-3-carboxylic acid and its pharmaceutically acceptable salts and esters (I) by total synthesis starting with L-aspartic acid and proceeding via intermediates II and IIa (4-iodomethylazetidin-2-one): STR1
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