Benzoxazoles pevent misfolding: Benzoxazole‐based inhibitors of transthyretin (TTR) amyloid fibril formation are among the most effective found to date. They stabilize TTR against both acid‐mediated misfolding and urea denaturation by raising the activation barrier to tetramer dissociation, the rate‐limiting step for amyloid formation. The figure depicts the cocrystal structure of one of the better benzoxazole inhibitors bound to TTR.

Most chemical syntheses of thiazolines use serine residues, whereas nature employs cysteine residues. In a biomimetic approach, [(Ph3P+)2O](OTf−)2 was used to promote triphenylmethyl (Tr) deprotection and dehydrocyclization of simple cysteine N‐amides to give thiazolines in excellent chemical and optical yields (see scheme). This mild method was extended to the synthesis of, for example, thiazolines from cysteine‐containing dipeptides in high yield and without significant loss of chirality at the C2‐exomethine carbon atom. TF=trifluoromethanesulfonyl, Cbz=benzyloxycarbonyl

Fester Zusammenhalt: Wirkstoffe auf Benzoxazol‐Basis zählen zu den effektivsten Inhibitoren der Bildung von Amyloidfibrillen aus Transthyretin (TTR). Zum einen stabilisieren sie TTR gegen Fehlfaltungen infolge Säureeinwirkung, zum anderen vergrößern sie die Aktivierungsbarriere für die Dissoziation der TTR‐Tetramere, den geschwindigkeitsbestimmenden Schritt der Amyloidbildung. Unser Bild zeigt die Struktur eines Komplexes von TTR mit einem Benzoxazolinhibitor im Kristall.

Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.

The scope and limitations of TiCl(4)-mediated Delta(2)-thiazoline synthesis via tandem deprotection-dehydrocyclization of trityl-protected cysteine N-amides is presented. While chemical yields are acceptable (53-96%), the stereochemical outcomes vary on the basis of structural considerations and reaction conditions (22-99% ee). Racemization at the C(2)-exomethine position limits the utility of this method for the formation of a thiazoline within a peptide. Treatment of a tritylated Cys-Cys dipeptide with TiCl(4) afforded the corresponding thiazole-thiazoline heterocycle 12 (38% yield, 97% ee).

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Oxazole derivatives R 0220Design, Synthesis, and Evaluation of Oxazole Transthyretin Amyloidogenesis Inhibitors. -In order to identify novel transthyretin (TTR) inhibitors with enhanced potency and improved binding selectivity to TTR over other plasma proteins, oxazoles containing a carboxylic acid, an alkyl group and a halogenated aromatic pharmacophore are synthesized. Oxazoles (VII) are obtained in low to moderate overall yields via a diazo transfer reaction cf. (I)→(II), the in situ formed thioimidate (V) from a phosphazene intermediate, and reaction of (V) with acyl chlorides or anhydrides, followed by hydrolysis. Several compounds inhibit TTR amyloidogenesis in vitro and two bind TTR in human plasma with modest selectivity. In particular, (VIIa) and (VIIc) completely inhibit fibril formation and bind to TTR in the presence of other plasma proteins. -(RAZAVI, H.; POWERS, E. T.; PURKEY, H. E.; ADAMSKI-WERNER, S. L.; CHIANG, K. P.; DENDLE, M. T. A.; KELLY*, J. W.; Bioorg. Med. Chem. Lett. 15 (2005) 4, 1075-1078; Dep. Chem., Scripps Res. Inst.,