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1.
ACS Med Chem Lett ; 14(7): 977-985, 2023 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-37465292

RESUMEN

The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.

2.
Chem Commun (Camb) ; 51(6): 1112-5, 2015 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-25461278

RESUMEN

3-Aryltetrahydrobenzisoxazoles prepared en route to the coleophomone natural products and analogues, were found to undergo a remarkable base-mediated rearrangement to 2-aryltetrahydrobenzoxazoles. The scope of this unprecedented, facile transformation was probed: a range of analogues was produced, a mechanism proposed, and an application demonstrated by synthesis of a known herbicidal compound.


Asunto(s)
Isoxazoles/química , Oxazoles/química , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular
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