c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo(2,1-b)quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2.The most potent compounds were 10c (11H-indeno[1,2b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (Kd) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific smallmolecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.
In the present work, the synthesis
of acetylated salicins, which
occur naturally in many Salicaceae species,
is reported. The preparation of 2-O-acetylsalicin,
2-O-acetylchlorosalicin, and 2-O-acetylethylsalicin from peracetylated bromosalicin with selective
acid-catalyzed deacetylation and one-pot nucleophilic substitution
of bromine as the key steps is described. The base-catalyzed O-2 →
O-6 acetyl migration afforded 6-O-acetylsalicin derivatives
in good yields. Thus, the first synthesis of 6-O-acetylsalicin
(fragilin) using acetyl group migration is reported as well as the
synthesis of 6-O-acetylchlorosalicin and 6-O-acetylethylsalicin. The NaOMe-catalyzed deacetylation
of acetylated glycosides gave salicin, chlorosalicin, and ethylsalicin
recently reported from Alangium chinense.
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