- Peptide-Catalyzed Fragment Couplings that Form Axially Chiral Non-C2-Symmetric Biaryls
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We have demonstrated that small, modular, tetrameric peptides featuring the Lewis-basic residue β-dimethylaminoalanine (Dmaa) are capable of atroposelectively coupling naphthols and ester-bearing quinones to yield non-C2-symmetric BINOL-type scaffolds with good yields and enantioselectivity. The study culminates in the asymmetric synthesis of backbone-substituted scaffolds similar to 3,3′-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.) to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization, and a diastereoselective net arylation of the minimally modified nonsteroidal anti-inflammatory drug (NSAID) naproxen.
- Coombs, Gavin,Sak, Marcus H.,Miller, Scott J.
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supporting information
p. 2875 - 2880
(2020/01/24)
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- Structural studies of β-turn-containing peptide catalysts for atroposelective quinazolinone bromination
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We describe herein a crystallographic and NMR study of the secondary structural attributes of a β-turn-containing tetra-peptide, Boc-Dmaa-d-Pro-Acpc-Leu-NMe2, which was recently reported as a highly effective catalyst in the atroposelective bromination of 3-arylquinazolin-4(3H)-ones. Inquiries pertaining to the functional consequences of residue substitutions led to the discovery of a more selective catalyst, Boc-Dmaa-d-Pro-Acpc-Leu-OMe, the structure of which was also explored. This new lead catalyst was found to exhibit a type I′ β-turn secondary structure both in the solid state and in solution, a structure that was shown to be an accessible conformation of the previously reported catalyst, as well.
- Metrano,Abascal,Mercado,Paulson,Miller
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supporting information
p. 4816 - 4819
(2016/04/09)
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- Synthesis of a novel series of L-isoserine derivatives as aminopeptidase N inhibitors
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A series of novel L-isoserine derivatives were synthesised and evaluated for their ability to inhibit aminopeptidase N (APN)/CD13. In our preliminary biological results, some of these compounds possessed a potent inhibitory activity against the APN. Within this series, compound 14b not only showed similar enzyme inhibition (IC50 of 12.2μM) compared with the positive control bestatin (half maximal inhibitory concentration (IC 50) of 7.3μM), but also had a potent antiproliferative activity against human cancer cell lines cells.
- Yang, Kanghui,Fen, Jinghong,Fang, Hao,Zhang, Lei,Gong, Jianzhi,Xu, Wenfang
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experimental part
p. 302 - 310
(2012/07/02)
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- Antimicrobial toxicity studies of ionic liquids leading to a 'hit' MRSA selective antibacterial imidazolium salt
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Imidazolium salts can be classed as surfactants, detergents, ionic liquids, reagents, catalysts or solvents. A study of the toxicity and ecotoxicity of these salts yields valuable information for their use as pharmaceuticals as well as impact on the environment. Our approach to screen a series of chiral imidazolium salts for toxicity to bacteria and fungi, including clinical pathogen strains, has led to the identification of a 'hit' MRSA selective antimicrobial compound. Preliminary structure-activity-relationship (SAR) information (required position of l-phenylalanine and l-valine group) is also elucidated within this first generation of compounds. Conversely, most of the imidazolium salts were nontoxic (IC95 > 2 mM) to the 12 fungi strains and 8 bacteria strains screened, and we propose that they are suitable candidates for 'green chemistry' applications. Ecotoxicity studies (Biodegradation ISO 14593 'CO2 Headspace Test') of two bromide ionic liquids containing l-phenylalanine residues indicate that these ionic liquids passed the test (>60% in 28 days) and classed as readily biodegradable.
- Coleman, Deborah,Spulak, Marcel,Garcia, M. Teresa,Gathergood, Nicholas
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body text
p. 1350 - 1356
(2012/06/16)
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- Efficient synthesis of 2,5-diketopiperazines using microwave assisted heating
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In this study a general, efficient and environmentally benign solution phase synthesis of 2,5-diketopiperazines (DKPs) using microwave assisted heating in water is described. A series of 11 structurally different DKPs have been synthesized from dipeptide methyl esters. A range of common laboratory solvents have been tested as well as different reaction times and temperatures. Both classic thermal and microwave assisted heating have been investigated. Microwave assisted heating for 10 min using water as solvent proved, by far, to be the most efficient method of cyclization giving moderate to excellent yields (63-97%) of DKPs. In contrast to other published procedures, this method seems independent of the amino acid sequence.
- Tullberg, Marcus,Gr?tli, Morten,Luthman, Kristina
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p. 7484 - 7491
(2007/10/03)
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- Stereoselective synthesis of vinylogous peptides
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A trans or cis ethenyl group has been inserted between the α-carbon and the carboxyl group of α-aminoacids by Horner stereoselective olefination of α-aminoaldehydes. Numerous pure cis and trans vinylogous α-aminoacids have been obtained thus and coupled w
- Grison, Claude,Genève, Stéphane,Halbin, Etienne,Coutrot, Philippe
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p. 4903 - 4923
(2007/10/03)
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- Synthesis and Conformational Studies of Peptidomimetics Containing Furanoid Sugar Amino Acids and a Sugar Diacid
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Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-amino-2,5-anhydro-6-deoxy-D-gluconic acid (3, Gaa) and its mannonic (4, Maa), idonic (5, Iaa), and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthesized. The synthesis followed a novel reaction path in which an intramolecular 5-exo SN2 opening of the hexose-derived terminal aziridine ring in 2 by the γ-benzyloxy oxygen with concomitant debenzylation occurred during pyridinium dichromate oxidation of the primary δ-hydroxyl group to carboxyl function, leading to the formation of furanoid sugar amino acid frameworks in a single step. Incorporation of these furanoid sugar amino acids into Leu-enkephalin replacing its Gly-Gly portion gave analogues 8-11. Detailed structural analysis of these molecules by circular dichroism (CD) and various NMR techniques in combination with constrained molecular dynamics (MD) simulations revealed that two of these analogues, 8a and 10a, have folded conformations composed of an unusual nine-membered pseudo β-turn-like structure with a strong intramolecular H-bond between LeuNH → sugarC3-OH. This, in turn, brings the two aromatic rings of Tyr and Phe in close proximity, a prerequisite for biological activities of opioid peptides. The analgesic activities of 8a,b determined by mouse hot-plate and tail-clip methods were similar to that of Leu-enkephalin methyl ester. The syn disposition of the β-hydroxycarboxyl motif on the sugar rings appears to be the driving force to nucleate the observed turn structures in some of these molecules (8 and 10). Repetition of the motif on both sides of a furanose ring resulted in a novel molecular design of sugar diacid, 2,5-anhydro-D-idaric acid (7, Idac). Bidirectional elongation of the diacid moieties of 7 with identical peptide strands led to the formation of a C2-symmetric reverse-turn mimetic 12 which displayed a very ordered structure consisting of identical intramolecular H-bonds at two ends between LeuNH → sugar-OH, the same as in 8 and 10.
- Chakraborty,Ghosh,Jayaprakas,Sharma,Ravikanth,Diwan,Nagaraj,Kunwar
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p. 6441 - 6457
(2007/10/03)
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- 2-Benzoyl-2-ethoxycarbonylvinyl-l and 2-Benzoylamino-2-methoxy-carbonylvinyl-1 as N-Protecting Groups in Peptide Synthesis. Their Application in the Synthesis of Dehydropeptide Derivatives Containing N-Terminal 3-Heteroarylamino-2,3-dehydroalanine
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Ethyl 2-benzoyl-3-dimethylaminopropenoate (6) and methyl 2-benzoylamino-3-dimethylaminopropenoate (46) were used as reagents for the protection of the amino group with 2-benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxycarbonylvinyl groups in t
- Svete, Jurij,Aljaz-Rozic, Mateja,Stanovnik, Branko
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p. 177 - 193
(2007/10/03)
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- Selective Alkylation of Protected Peptide Derivatives by Phase-transfer Catalysis
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Schiff base dipeptide esters are selectively alkylated at the N-terminal α-carbon by phase-transfer catalysis to give both diastereomeric products.The reaction occurs with retention of configuration at the C-terminal α-carbon containing a non-glycine resi
- O'Donnell, M.J.,Burkholder, T.P.,Khau, V.V.,Roeske, R.W.,Tian, Z.
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p. 2477 - 2488
(2007/10/02)
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- Activated ketone based inhibitors of human renin
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Application of the concept of activated ketones to the design of novel and potent transition-state analog inhibitors of the aspartyl protease renin is described. Three different classes of peptidic activated ketones were synthesized: 1,1,1-trifluoromethyl ketones, α-keto esters, and α-diketones. The corresponding alcohols were also evaluated as renin inhibitors in each series. While the trifluoromethyl alcohol 12 (I50 = 4000 nM) was equipotent to the simple methyl alcohol 7 (I50 = 3200 nM), the structurally similar α-hydroxy esters (32 and 30, I50's = 5.3 and 4.7 nM, respectively) and α- hydroxy ketones (41 and 42, I50 = 23 and 15 nM, respectively) were 150- 300-fold more active. The hydrating capability of the activated ketone functionality was important for intrinsic potency in the case of trifluoromethyl ketones, as illustrated by the significantly better activity of trifluoromethyl ketone 13 (I50 = 250 nM) compared to its alcohol analog 12 (I50 = 4000 nM). It was however unimportant for the α-keto ester (20 and 31, I50 = 15 and 4.1 nM, respectively) and α-diketone (43 and 44, I50 = 52 and 28 nM, respectively) based inhibitors, since their activity was essentially similar to that of the corresponding alcohols. These results collectively suggest that, whereas the trifluoromethyl ketones derive their renin inhibitory potency primarily from their ability to become hydrated, this is not a critical feature for the activity of α-dicarbonyl-based inhibitors. The α-keto ester and α-diketone based renin inhibitors benefit predominantly from the hydrophobic and/or H-bonding type binding interactions of the neighboring ester or acyl group itself, rather than the ability of this group to deactivate the adjacent ketone group and thereby make it susceptible to hydration.
- Patel,Rielly-Gauvin,Ryono,Free,Smith,Petrillo Jr.
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p. 2431 - 2447
(2007/10/02)
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- AMINO ACID 1,2-DIKETO DERIVATIVES AS RENIN INHIBITORS
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Compounds of the formula STR1 are disclosed. These compounds interevene in the conversion of angiotensin to angiotensin II by inhibiting renin and thus are useful as anti-hypertensive agents.
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- Synthesis and biological evaluation of phosphonamidate peptide inhibitors of enkephalinase and angiotensin-converting enzyme
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The effectiveness of phosphonamidate peptide analogues as inhibitors of rat kidney or human brain metallo-endopeptidase (enkephalinase, E.C. 3.4.24.11) and angiotensin-converting enzyme (ACE, 3.4.15.1) has been explored with a series of enkephalin analogu
- Elliott,Marks,Berg,Portoghese
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p. 1208 - 1216
(2007/10/02)
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- SYNTHESIS OF CHIRAL OLIGOPEPTIDES BY MEANS OF CATALYTIC ASYMMETRIC HYDROGENATION OF DEHYDROPEPTIDES
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Asymmetric hydrogenation of Ac-ΔTyr(Ac)-(S)-Ala-Gly-OMe (6), Ac-ΔTyr(Ac)-(R)-Ala-Gly-(S)-Phe-OMe (7), Ac-ΔPhe-NH-CH(R)-CH2-OCH2Ph (10), HCO-ΔPhe-(S)-Leu-OMe (16), X-AA-ΔPhe-AA'-OMe ( 5: X=tBOC, CBZ, CF3CO; AA, AA'= α-amino acid ), and t
- Ojima, Iwao,Yoda, Noriko,Yatabe, Momoko,Tanaka, Toshiyuki,Kogure, Tetsuo
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p. 1255 - 1268
(2007/10/02)
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- SYNTHESIS OF ENKEPHALIN ANALOGS VIA ASYMMETRIC HYDROGENATION OF DEHYDROPEPTIDE BUILDING BLOCKS
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1, D-Ala2, Leu5-OMe>Enkephalin and 1, D-Ala2, Leu5-OMe>Enkephalin were succesfully synthesized by the coupling of dipeptide units and tripeptide units which were readily obt
- Ojima, Iwao,Yoda, Noriko,Yatabe, Momoko
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p. 3917 - 3920
(2007/10/02)
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