Lipoxygenases are lipid-peroxidizing enzymes that have been implicated in the pathogenesis of inflammatory diseases and lipoxygenase inhibitors may be developed as anti-inflammatory drugs. Structure comparison with known lipoxygenase inhibitors has suggested that (2Z)-2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester might inhibit the lipoxygenase pathway but we found that it exhibited only a low inhibitory potency for the pure 12/15-lipoxygenase (IC(50) = 0.7 mM). However, photoactivation, which induces a Z-to-E isomerization of the double bond, strongly augmented the inhibitory potency and an IC(50) value of 0.021 mM was determined for the pure E isomer. Similar isomer-specific differences were observed with the recombinant enzyme and its 12-lipoxygenating Ile418Ala mutant, as well as in intracellular lipoxygenase activity. Structure modeling of the enzyme/inhibitor complex suggested the molecular reasons for this isomer specificity. Since light-induced isomerization may proceed in the skin, such photoreactive compounds might be developed as potential drugs for inflammatory skin diseases.
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Efficient procedures for the preparation of the N-Bocprotected aldehydes 5a and 5b are described which are valuable precursors for the synthesis of hemithioindigo-based w-amino acids and peptides.Driven by the development of new experimental techniques, the investigation and modulation of fast processes of peptide and protein folding gain increasing interest. 1 In addition, the reversible photocontrol of the conformation and activity of biomolecules is intensively being explored. 2,3 In an attempt to develop modular and tunable photoswitches for these applications, we are exploring the synthesis of novel hemithioindigo-derived compounds. 4,5 Our design is based on significant light-induced end-toend distance changes and changes in the dipole moment. Recently, we have demonstrated that a hemithioindigobased a-amino acid can be applied as a light switch for the photomodulation of ionic current through modified gramicidin ion channels. 6 Based on this promising approach, the Boc-protected hemithioindigo-derived pseudo-w-amino acids 1a and 1b (Figure 1) are developed in our laboratories for their incorporation into cyclic peptides. Figure 1So far, these pseudo-amino acids have been synthesized and used as valuable building blocks in the synthesis of diand tripeptides via Boc-based peptide assembly in solution.For the synthesis of the hemithioindigo-based w-amino acids 1a and 1b, the Boc-protected aldehydes were prepared starting from 3-cyano-or 4-cyanobenzaldehyde. Protection of the aldehydes to give the dioxolanes 2a and 2b, 7,8 reduction to the benzylamines 3a and 3b, 7 Boc-protection to the carbamates 4a and 4b, and removal of the acetal protecting group provided the N-Boc-protected aldehydes 5a and 5b in excellent overall yields (Scheme 1). For the synthesis of the meta-substituted w-amino acid 1b, the aldehyde 5b and the literature-known thioindoxyl carboxylic acid chloride 6 were condensed using 1% sodium hydroxide/tert-butyl alcohol (Scheme 2) as previously described by us. 4 These conditions provided the hemithioindigo 1b in 70% isolated yield and >95% purity after purification by chromatography on Florisil. Scheme 1In Boc-based solution-phase peptide synthesis, trifluoroacetic acid in combination with scavengers (e.g., H 2 O, DMS, ethanedithiol, phenols, cresols, thiocresols, or thioanisols) is commonly used for deprotection strategies. However, we found treatment with hydrogen chloride in dioxane to be superior. Thus, Boc-deprotection of the dipeptide 7 4 (Scheme 3), derived from 1a 4 by EDC coupling, was carried out with 4 M hydrogen chloride in dioxane (r.t.) and gave the hydrochloride 8 quantitatively after evaporation of the solvent. Scheme 2
2‐Thiocyanatomethylen‐cycloalkanone‐(1) 2 wurden aus den entsprechenden 2‐Chlormethylen‐cycloalkanonen‐(1) 1 dargestellt. Bei der Umsetzung mit substituierten Phenylhydrazonen isolierten wir 2,4‐Dinitrophenylhydrazone (4b, 4c und 4e) bzw. 1,2,3‐Thiadiaziniumperchlorate (5a, 5a′) sowie substituierte Pyrazole (7e, 7f). Die Reaktion von 2 mit flüssigem Ammoniak führte sowohl zu Isothiazolen (8a, 8b) als auch Bis‐(2‐acyl‐vinyl)‐sulfiden (9c, 9f).
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