- Synthesis and activity of pyrimidinylpropenamide antibiotics: The alkyl analogues of sparsomycin
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Facile syntheses of sparsomycin (3) and its four analogues (4-7) based on diastereoselective oxidation of sulfide, sulfenylation, and coupling of 6-methyluracylacryllic acid with monooxodithioacetal amine, are described. Studies on the biological activity of morphological reversion on src ts-NRK cells were also carried out.
- Nakajima, Noriyuki,Enomoto, Takeshi,Watanabe, Takehiro,Matsuura, Nobuyasu,Ubukata, Makoto
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- Symmetric benzidine derivatives as anti-HCV agents: Insight into the nature, stereochemistry of the capping amino acid and the size of the terminal capping carbamates
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Novel symmetric molecules, bearing a benzidine prolinamide core, two terminal carbamate caps of variable sizes and nature, including natural and unnatural amino acids were developed. Several terminal N-carbamate substituents of the core structure, ranging from linear methyl, ethyl and butyl groups to branching isobutyl group; and an aromatic substituent were also synthesized. Series 1 has hydrophobic AA residues, namely S and R phenylglycine and a terminal carbamate capping group, whereas Series 2 bears sulphur containing amino acids, specifically S and R methionine and the natural R methylcysteine. The novel compounds were tested for their inhibitory activity (EC50) and their cytotoxicity (CC50), using an HCV 1b (Con1) reporter replicon cell line. Compound 4 with the unnatural capping residue, bearing D-Phenylglycine amino acid residue and N-isobutyloxycarbonyl capping group, was the most active within the two series, with EC50 = 0.0067 nM. Moreover, it showed high SI50 > 14788524 and was not cytotoxic at the highest tested concentration (100 μΜ), indicating its safety profile. Compound 4 also inhibited HCV genotypes 2a, 3a and 4a. Compared to the clinically approved NS5A inhibitor Daclatasvir, compound 4 shows higher activity against genotypes 1b and 3a, as well as improved safety profile.
- Abadi, Ashraf H.,Abdel Karim, Shereen E.,Abdel-Halim, Mohammad,Ahmed, Nermin S.,Frakolaki, Efseveia,Vassilaki, Niki,Youssef, Youssef H.,Zoidis, Grigoris
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- α-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation
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Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine, and cysteine were successfully employed, as was an enantiomerically enriched α-OMTM-aldehyde derived from phenyllactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine.
- Hooper, Joel F.,Seo, Sangwon,Truscott, Fiona R.,Neuhaus, James D.,Willis, Michael C.
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supporting information
p. 1630 - 1634
(2016/02/20)
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- β-Lactones as a new class of cysteine proteinase inhibitors: inhibition of hepatitis A virus 3C proteinase by N-Cbz-serine β-Lactone
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Formula presented N-Benzyloxycarbonyl-L-serine β-lactone (1) is shown to irreversibly inactivate the 3C cysteine proteinase of hepatitis A virus (HAV) with kinact = 0.70 min-1, KI = 1.84 x 10-4 M and kinact/KI = 3800 M-1 min-1 at an enzyme concentration of 0.1 μM. Mass spectrometric and HMQC NMR studies using 13C-labeled 1 show that the active site cysteine (Cys-172) thiol of the HAV 3C proteinase attacks the β-position (i.e. C-4) of the oxetanone ring, thereby leading to ring opening and alkylation of the sulfur. In contrast, the enantiomer of this β-lactone, 2, is a reversible competitive inhibitor (Ki = 1.50 x 10-6 M) at similar enzyme concentrations. The β-lactone motif represents a new class of inhibitors of cysteine proteinases.
- Lall, Manjinder S.,Karvellas, Constantine,Vederas, John C.
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p. 803 - 806
(2008/02/12)
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