Axial and Equatorial Cyclohexylacyl and Tetrahydropyranyl-2-acyl Radicals. An Experimental and Theoretical Study

DiLabio, Gino A.; Ku, Ingold; Roydhouse,; Jc, Walton

doi:10.1021/ol0481683

Cited by 16 publications

(4 citation statements)

References 26 publications

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“…The amine building block 11 was prepared in 12 steps from benzimidazole-5-carboxylic acid ( 12 ) as described in the literature (Scheme ). , Reductive amination using aldehydes 10a – g (Scheme ) and 10j , 10k , and 10l gave amines 13a – e , g , h , j . For trifluoroketone 10f , the product of the reductive amination was the corresponding alcohol 13h instead of ketone 13f .…”

Section: Resultsmentioning

confidence: 99%

Launching Spiking Ligands into a Protein–Protein Interface: A Promising Strategy To Destabilize and Break Interface Formation in a tRNA Modifying Enzyme

et al. 2013

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Apart from competitive active-site inhibition of protein function, perturbance of protein-protein interactions by small molecules in oligodomain enzymes opens new perspectives for innovative therapeutics. tRNA-guanine transglycosylase (TGT), a potential target to treat shigellosis, is active only as the homodimer. Consequently, disruption of the dimer interface by small molecules provides a novel inhibition mode. A special feature of this enzyme is the short distance between active site and rim of the dimer interface. This suggests design of expanded active-site inhibitors decorated with rigid, needle-type substituents to spike into potential hot spots of the interaction interface. Ligands with attached ethinyl-type substituents have been synthesized and characterized by Kd measurements, crystallography, noncovalent mass spectrometry, and computer simulations. In contrast to previously determined crystal structures with nonextended active-site inhibitors, a well-defined loop-helix motif, involved in several contacts across the dimer interface, falls apart and suggests enhanced flexibility once the spiking ligands are bound. Mass spectrometry indicates significant destabilization but not full disruption of the complexed TGT homodimer in solution. As directed interactions of the loop-helix motif obviously do not determine dimer stability, a structurally conserved hydrophobic patch composed of several aromatic amino acids is suggested as interaction hot spot. The residues of this patch reside on a structurally highly conserved helix-turn-helix motif, which remains unaffected by the bound spiking ligands. Nevertheless, it is shielded from solvent access by the loop-helix motif that becomes perturbed upon binding of the spiking ligands, which serves as a possible explanation for reduced interface stability.

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Section: Resultsmentioning

confidence: 99%

Launching Spiking Ligands into a Protein–Protein Interface: A Promising Strategy To Destabilize and Break Interface Formation in a tRNA Modifying Enzyme

et al. 2013

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“…Similarly, differences in the magnitudes of a H β can be used to distinguish conformers of other cycloalk(en)ylcarbinyl radicals (ring sizes up to C 15 ) . Equatorial and axial cyclohexylacyl radicals ( c -C 6 H 11 C • O) can be differentiated in a similar way . Cylohexylperoxyl radicals ( c -C 6 H 11 OO • ) are known to have a H β ≈ 5 G .…”

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confidence: 99%

Characterization of Equatorial and Axial Six-Membered-Ring Peroxyl Radicals

2007

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“…[26a] 22, [30] 23, [31] 24, [32] 25, [33] 26, [34] 27, [35] 28, [36] 31-d 1 , [37] 32, [38] 33, [18] 34, [19] and 1-d 1 .…”

Section: Methodsmentioning

confidence: 99%

Radical Reduction of Epoxides Using a Titanocene(III)/Water System: Synthesis of β‐Deuterated Alcohols and Their Use as Internal Standards in Food Analysis

et al. 2010

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We describe a comprehensive study into the Cp2TiCl‐mediated reductive epoxide ring opening using either water as a hydrogen source or deuterium oxide as a deuterium source. The remarkable chemical profile of this reaction allows access to alcohols with anti‐Markovnikov regiochemistry from different epoxides. The use of D2O as a deuterium source leads to an efficient synthesis of β‐deuterated alcohols, including a deuterated sample of tyrosol, a bioactive compound contained in the leaves of the olive, which was successfully applied as an internal standard in food analysis.

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Axial and Equatorial Cyclohexylacyl and Tetrahydropyranyl-2-acyl Radicals. An Experimental and Theoretical Study

Cited by 16 publications

References 26 publications

Launching Spiking Ligands into a Protein–Protein Interface: A Promising Strategy To Destabilize and Break Interface Formation in a tRNA Modifying Enzyme

Launching Spiking Ligands into a Protein–Protein Interface: A Promising Strategy To Destabilize and Break Interface Formation in a tRNA Modifying Enzyme

Characterization of Equatorial and Axial Six-Membered-Ring Peroxyl Radicals

Radical Reduction of Epoxides Using a Titanocene(III)/Water System: Synthesis of β‐Deuterated Alcohols and Their Use as Internal Standards in Food Analysis

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