3144-09-0Relevant articles and documents
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Boyer,Ellzey
, p. 127 (1958)
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Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL
Andrews, Charlotte L.,Cardozo, Joaquin M.,Chow, Alyssa S.,Crainic, Jennifer A.,Parsons, William H.,Rutland, Nicholas T.,Sheehan, Brendan K.
supporting information, (2021/08/04)
While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. A counterscreen against the bacterial rhomboid protease GlpG demonstrates that several of these compounds display selectivity for PARL over GlpG by as much as two orders of magnitude. Both the sulfonyl ester and sulfonamide scaffolds exhibit reversible binding and are able to engage PARL in mammalian cells. Collectively, our findings provide encouraging precedent for the development of PARL-selective inhibitors and establish N-[(arylsulfonyl)oxy]succinimides and N-arylsulfonylsuccinimides as new molecular scaffolds for inhibiting members of the rhomboid protease family.
Stoichiometric Nitroxyl Photorelease Using the (6-Hydroxy-2-naphthalenyl)methyl Phototrigger
Zhou, Yang,Cink, Ruth B.,Seed, Alexander J.,Simpson, M. Cather,Sampson, Paul,Brasch, Nicola E.
supporting information, p. 1054 - 1057 (2019/05/16)
The design and synthesis of a photoactivatable HNO donor incorporating the (6-hydroxynaphthalen-2-yl)methyl (6,2-HNM) photocage coupled to the trifluoromethanesulfonamidoxy analogue of the well-established HNO generator Piloty's acid is described. The photoactive HNO donor stoichiometrically generates HNO (~98%) at neutral pH conditions, and evidence for concerted C-O and N-S bond cleavage was obtained. The methanesulfonamidoxy analogue primarily undergoes undesired N-O bond cleavage.