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Concept: Thioester

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Abstract 1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti-inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction. 2. The present study used a model system estimating the reactivity of different synthetic chalcones and other α,β-unsaturated carbonyl compounds with thiols and compared the chemical reactivity with the biological activity, measured by HO-1 expression in human dermal fibroblasts. 3. Chemical reactivity with the thiol group of N-acetylcysteine was determined with 5,5'-dithiobis-(2-nitrobenzoic acid) and followed chemical principles of structure-reactivity relationship. Most reactive were sulforaphane, dimethylfumarate, chalcone 3 ((2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one) and chalcone 7 (1,3-diphenylprop-2-yn-1-one). This result demonstrates that α,β-unsaturated carbonyl derivatives react with thiols differently. All compounds were also biologically active; however, expression of HO-1 was not only related to the chemical reactivity but also to the lipophilicity of the molecules which likely affected transmembrane uptake. Most efficient inducers of HO-1 expression were BAP, 4-hydroxynonenal and chalcone 1 (4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile), chalcone 5 ((2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one) and chalcone 7.

Concepts: Thioester, Chemical reaction, Thiol, Cysteine, Organism, Glutathione

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C-S bond activation, cleavage and transformations by means of transition metal compounds have recently become more and more important in the petroleum industry and synthetic chemistry. Homogeneous transition metal compounds have been investigated in order to provide the fundamental insight into the C-S bond cleavage in problematic organosulfur compounds such as thiophene, benzo- and dibenzothiophene derivatives. Rendering transition-metal mediated reactions with organosulfur compounds catalytic may provide promising routes to deep hydrodesulfurization of petroleum feedstocks, and offer potentially useful synthetic protocols for cross-couplings and biomimetic organic synthesis. During the last few decades increasing work was documented on C-S bond activation and transformations by means of transition metal compounds. This review summarizes the recent advances in C-S bond cleavage via the insertion of transition metals into the inert C-S bonds of these problematic organosulfur compounds, and transition-metal mediated C-S bond transformations via C-S activation through cross-couplings of thioesters, ketene dithioacetals, sulfonyl chlorides, and other diverse organosulfur compounds.

Concepts: Thioester, Organosulfur compounds

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To address the difficulty in protecting a β-polycarbonyl compound, a method for the sequential protection of elongating carbonyl groups was demonstrated. The iterative chain elongation of a carboxylic acid with malonic acid half thioester followed by the protection of the resulting β-ketothioester was performed via the stepwise formation of an isoxazole ring using an O-protected oxime functionality. Yangonin and isosakuranetin were synthesized according to this procedure.

Concepts: Ketone, Thioester, Amide, Malic acid, Aldehyde, Malonic acid, Ester, Carboxylic acid

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3-Sulfanyl-oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan-3-ols, a mild and inexpensive Li catalyst enables chemoselective C-OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisosteres for thioesters due to their similar shape and electronic properties. Under the same conditions, various -activated secondary and tertiary alcohols are also successful. Derivatization of the oxetane sulfide linker provides further novel oxetane classes and building blocks. Comparisons of key physicochemical properties of the oxetane compounds to selected carbonyl and methylene analogues indicate that these motifs are suitable for incorporation into drug discovery efforts.

Concepts: Organosulfur compounds, Thioester, Chemical reaction, Thiol, Nitrogen, Alcohol, Sulfur, Functional groups

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An efficient N-linked glycosylation reaction between glycosylamines and p-nitrophenyl thioester peptides has been developed. The reaction conditions are mild and compatible with the C-terminal free carboxylic acid group and the unprotected N-linked sialyloligosaccharide. By means of this convergent strategy, a versatile N-glycopeptide fragment containing an N-terminal Thz and a C-terminal thioester was readily prepared, which is available for the synthesis of long glycopeptides and glycoproteins using the protocol of native chemical ligation.

Concepts: Chemical reaction, Chemical ligation, Thioester, Posttranslational modification, Peptide synthesis, Amino acid, Protein, Carboxylic acid

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N-Sulfanylethylcoumarinyl amide (SECmide) peptide, which was initially developed for use in the fluorescence-guided detection of promoters of N-S acyl transfer, was successfully applied to a facile and side reaction-free protocol for N-S acyl-transfer-mediated synthesis of peptide thioesters. Additionally, 4-mercaptobenzylphosphonic acid (MBPA) was proven to be a useful catalyst for the SECmide or N-sulfanylethylanilide (SEAlide)-mediated NCL reaction.

Concepts: Human Development Index, Organosulfur compounds, Thioesters, Thioester, Functional groups, Chemical reaction, Carboxylic acid, Carbonyl

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A number of captopril analogues were synthesised and tested as inhibitors of the metallo-β-lactamase IMP-1. Structure-activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.

Concepts: Acetic acid, Alcohol, Thioester, Carboxylic acids, Carboxylic acid, Carboxylate, Functional groups, Amino acid

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Elaiophylin is an unusual C2 -symmetric antibiotic macrodiolide produced on a bacterial modular polyketide synthase assembly line. To probe the mechanism and selectivity of diolide formation, we sought to reconstitute ring formation in vitro by using a non-natural substrate. Incubation of recombinant elaiophylin thioesterase/cyclase with a synthetic pentaketide analogue of the presumed monomeric polyketide precursor of elaiophylin, specifically its N-acetylcysteamine thioester, produced a novel 16-membered C2 -symmetric macrodiolide. A linear dimeric thioester is an intermediate in ring formation, which indicates iterative use of the thioesterase active site in ligation and subsequent cyclization. Furthermore, the elaiophylin thioesterase acts on a mixture of pentaketide and tetraketide thioesters to give both the symmetric decaketide diolide and the novel asymmetric hybrid nonaketide diolide. Such thioesterases have potential as tools for the in vitro construction of novel diolides.

Concepts: Polyketide, Thioester, Mixture, Polyketide synthase, In vitro, Assembly line, Novel, Enzyme

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A novel sulfa-Michael addition (SMA)-triggered tandem reaction was developed by combining a SMA reaction with a simultaneous rearomatization process utilizing a less reactive carbonyl group as an intramolecular electrophile partner, which provided a unique synthetic route to access various organosulfur compounds incorporating an N-aromatic heterocyclic motif and quaternary carbon centers.

Concepts: Functional group, Organosulfur compounds, Double bond, Carbon, Carbonyl, Thioester, Organic chemistry, Aldol reaction

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N(α) -Trifluoroacetyl-Cys-Leu-NH2 (TfaC-Leu-NH2 ) was incorporated into thioesters through its side-chain thiol group to develop a more reactive peptide-thioester than the commonly used peptide-3-mercaptopropionic acid (MPA)-thioester. The TfaC-thioester could be readily synthesized by solid-phase peptide synthesis (SPPS) with Boc chemistry using in situ neutralization protocols in sufficient yield without any side reaction associated with the use of TfaC. This thioester proved to display a much higher reactivity in the thiol-free native chemical ligation (NCL) reaction than the MPA-thioester, and to be comparable to the thioarylester, such as the 4-mercaptophenylacetic acid (MPAA)-thioester, in terms of the ligation rate. We were able to demonstrate the usefulness of the TfaC-thioester by using it to synthesize neuromedin S via a one-pot sequential NCL approach followed by desulfurization. This article is protected by copyright. All rights reserved.

Concepts: Organosulfur compounds, Thioester, Protein, Chemical reaction, Thiol, Amino acid, Chemical synthesis, Peptide synthesis