- Structurally Diverse Acyl Bicyclobutanes: Valuable Strained Electrophiles
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Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted.
- Attard, Riley H.,Gardiner, Michael G.,Malins, Lara R.,Schwartz, Brett D.,Zhang, Meng Yao
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supporting information
p. 2808 - 2812
(2020/03/04)
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- Synthesis and cellular penetration properties of new phosphonium based cationic amphiphilic peptides
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A new category of phosphonium based cationic amphiphilic peptides has been developed and evaluated as potential antimicrobial peptides and cell penetrating peptides. The required building blocks were conveniently accessible from cysteine and could be applied in a solid phase peptide synthesis protocol for incorporation into peptide sequences. Evaluation of the antimicrobial properties and cellular toxicity of these phosphonium based peptides showed that these "soft" cationic side-chain containing peptides have poor antimicrobial properties and most of them were virtually non toxic (on HEK cells tested at 256 and 512 μM) and non-haemolytic (on horse erythrocytes tested at 512 μM), hinting at an interesting potential application as cell penetrating peptides. This possibility was evaluated using fluorescent peptide derivatives and showed that these phosphonium based peptide derivatives were capable of entering HEK cells and depending on the sequence confined to specific cellular areas.
- Silva Nigenda, Ezequiel,Postma, Tobias M.,Hezwani, Mohammed,Pirvan, Alin,Gannon, Susan,Smith, Carol-Anne,Riehle, Mathis,Liskamp, Rob M. J.
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supporting information
p. 982 - 987
(2018/06/27)
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- NOVEL COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, (formula 1) wherein R1,R2, R3, R4, R5, X, m and n are defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of such compounds in medicine.
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Page/Page column 51
(2016/02/26)
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- Protein ubiquitination: Via dehydroalanine: Development and insights into the diastereoselective 1,4-addition step
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We report a strategy for site-specific protein ubiquitination using dehydroalanine (Dha) chemistry for the preparation of ubiquitin conjugates bearing a very close mimic of the native isopeptide bond. Our approach relies on the selective formation of Dha followed by conjugation with hexapeptide bearing a thiol handle derived from the C-terminal of ubiquitin. Subsequently, the resulting synthetic intermediate undergoes native chemical ligation with the complementary part of the ubiquitin polypeptide. It has been proposed that the Michael addition step could result in the formation of a diastereomeric mixture as a result of unselective protonation of the enolate intermediate. It has also been proposed that the chiral protein environment may influence such an addition step. In the protein context these questions remain open and no experimental evidence was provided as to how such a protein environment affects the diastereoselectivity of the addition step. As was previously proposed for the conjugation step on protein bearing Dha, the isopeptide bond formation step in our study resulted in the construction of two protein diastereomers. To assign the ratio of these diastereomers, trypsinization coupled with high-pressure liquid chromatography analysis were performed. Moreover, the obtained peptide diastereomers were compared with identical synthetic peptides having defined stereogenic centers, which enabled the determination of the configuration of the isopeptide mimic in each diastereomer. Our study, which offers a new method for isopeptide bond formation and protein ubiquitination, gives insights into the parameters that affect the stereoselectivity of the addition step to Dha for chemical protein modifications.
- Meledin, Roman,Mali, Sachitanand M.,Singh, Sumeet K.,Brik, Ashraf
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supporting information
p. 4817 - 4823
(2016/06/13)
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- Polypeptide Immobilization
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The present invention provides a method, comprising (a) providing a reactant ligand attached to a substrate; (b) contacting the substrate with a fusion polypeptide, said fusion polypeptide comprising a capture polypeptide fused to a display polypeptide un
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Paragraph 0204
(2016/01/15)
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- AZAINDAZOLE COMPOUNDS AS CCR1 RECEPTOR ANTAGONISTS
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Disclosed are compounds of the formula (I), useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of CCR1 including autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Also disclosed are methods of making and methods of using same.
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Page/Page column 195
(2010/04/27)
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- One-pot synthesis of unsymmetrical disulfides using 1-chlorobenzotriazole as oxidant: Interception of the sulfenyl chloride intermediate
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A high-yielding and low temperature one-pot procedure is described for unsymmetrical disulfide synthesis from two different thiols using 1-chlorobenzotriazole (BtCl) as oxidant. The mechanism of the coupling involves in situ trapping of the sulfenyl chloride intermediate R1SCl by nucleophilic benzotriazole (BtH) to form R1SBt, which protects R1SCl from forming the homodimer R1SSR1. The methodology is applicable to all types of thiol (aliphatic, aromatic, heteroaromatic), with a variation developed for aliphatic-aliphatic couplings. Differentially N-protected cysteines couple to afford the unsymmetrical cystine derivatives in high yield (90%), which serves as a model for the one-pot intermolecular coupling of cysteine-containing peptides to form peptide disulfide heterodimers. Minimal exchange in aromatic-aromatic disulfide synthesis is noted on account of the mild conditions.
- Stellenboom, Nashia,Hunter, Roger,Caira, Mino R.
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experimental part
p. 3228 - 3241
(2010/06/13)
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- CATHEPSIN CYSTEINE PROTEASE INHIBITORS
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The present invention relates to novel compounds of the formula (I), wherein R'-R7, X, Y, D and n are as defined in the specification. These compounds are cysteine protease inhibitors which include but are not limited to inhibitors of cathepsms K, L, S an
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Page/Page column 52
(2008/12/04)
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- One-pot synthesis of N-protected β-chiral amino alcohols
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N-tert-butyloxycarbonyl-S-benzyl-cysteine, N-fluorenylmethyloxycarbonyl-alanine-, S-trityl-cysteine-, O-tert-butyl-serine- and O-tertbutyl-tyrosine were converted to the corresponding alcohols via sodium borohydride reduction of their in situ formed methy
- Somlai, Csaba,Peter, Antal,Forgo, Peter,Penke, Botond
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p. 1815 - 1820
(2007/10/03)
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- Total syntheses of lyngbyabellins A and B, potent cytotoxic lipopeptides from the marine cyanobacterium Lyngbya majuscula
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The first total syntheses of lyngbyabellins A and B, Lyngbya majuscula derived lipopeptides, are described. The functionalized thiazole carboxylic acid units were prepared by the oxidative dehydrogenation of the corresponding thiazolidines with chemical manganese dioxide. The asymmetric synthesis of the dichlorinated β-hydroxy acid by a chiral oxazaborolidinone mediated aldol reaction. Finally, fragment condensation followed by macrolactamization provided lyngbyabellin A. The total synthesis of lyngbyabellin B was accomplished by formation of the sensitive thiazoline ring after the macrolactamization.
- Yokokawa, Fumiaki,Sameshima, Hirofumi,Katagiri, Daichi,Aoyama, Toyohiko,Shioiri, Takayuki
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p. 9445 - 9458
(2007/10/03)
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- Total synthesis of lyngbyabellin A, a potent cytotoxic metabolite from the marine cyanobacterium Lyngbya majuscula
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The first total synthesis of lyngbyabellin A, a novel peptolide from the marine cyanobacterium Lyngbya majuscula, is described. Both functionalized thiazole carboxylic acid units were synthesized using our CMD (chemical manganese dioxide) oxidation from the corresponding thiazolidines. The asymmetric synthesis of the dichlorinated β-hydroxy acid was achieved by the chiral oxazaborolidinone mediated aldol reaction. Finally, fragment condensation followed by the macrolactamization provided lyngbyabellin A.
- Yokokawa, Fumiaki,Sameshima, Hirofumi,Shioiri, Takayuki
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p. 4171 - 4174
(2007/10/03)
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- Titanium(IV)-mediated tandem deprotection-cyclodehydration of protected cysteine N-amides: Biomimetic syntheses of thiazoline- and thiazole-containing heterocycles
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(matrix presented) The scope and limitations of TiCl4-mediated Δ2-thiazoline synthesis via tandem deprotection-dehydrocyclization of trityl-protected cysteine N-amides is presented. While chemical yields are acceptable (53-96%), the
- Raman, Prakash,Razavi, Hossein,Kelly, Jeffery W.
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p. 3289 - 3292
(2007/10/03)
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