65512-08-5Relevant articles and documents
A Non-Competitive Inhibitor of VCP/p97 and VPS4 Reveals Conserved Allosteric Circuits in Type I and II AAA ATPases
P?hler, Robert,Krahn, Jan H.,van den Boom, Johannes,Dobrynin, Grzegorz,Kaschani, Farnusch,Eggenweiler, Hans-Michael,Zenke, Frank T.,Kaiser, Markus,Meyer, Hemmo
supporting information, p. 1576 - 1580 (2018/01/22)
AAA ATPases have pivotal functions in diverse cellular processes essential for survival and proliferation. Revealing strategies for chemical inhibition of this class of enzymes is therefore of great interest for the development of novel chemotherapies or chemical tools. Here, we characterize the compound MSC1094308 as a reversible, allosteric inhibitor of the type II AAA ATPase human ubiquitin-directed unfoldase (VCP)/p97 and the type I AAA ATPase VPS4B. Subsequent proteomic, genetic and biochemical studies indicate that MSC1094308 binds to a previously characterized drugable hotspot of p97, thereby inhibiting the D2 ATPase activity. Our results furthermore indicate that a similar allosteric site exists in VPS4B, suggesting conserved allosteric circuits and drugable sites in both type I and II AAA ATPases. Our results may thus guide future chemical tool and drug discovery efforts for the biomedically relevant AAA ATPases.
Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties
Romeiro, Luiz A.S.,Da Silva Ferreira, Marcos,Da Silva, Leandro L.,Castro, Helena C.,Miranda, Ana L.P.,Silva, Cláudia L.M.,No?l, Franois,Nascimento, Jéssica B.,Araújo, Claudia V.,Tibiri?á, Eduardo,Barreiro, Eliezer J.,Fraga, Carlos A.M.
supporting information; experimental part, p. 3000 - 3012 (2011/07/08)
We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl) -4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [ 3H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (Ki = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (KB = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (KB = 0.017 nM).
Copper-catalyzed remote sp3 C-H chlorination of alkyl hydroperoxides
Kundu, Rituparna,Ball, Zachary T.
supporting information; experimental part, p. 2460 - 2463 (2010/07/05)
A copper-catalyzed methodology to functionalize remote sp3 C-H bonds in alkyl hydroperoxides is presented. The atom-transfer chlorination utilizes simple ammonium chloride salts as the chlorine source, and the internal redox process requires no external redox reagents.
