50337-85-4Relevant articles and documents
Fluspirilene Analogs Activate the 20S Proteasome and Overcome Proteasome Impairment by Intrinsically Disordered Protein Oligomers
Fiolek, Taylor J.,Keel, Katarina L.,Tepe, Jetze J.
, p. 1438 - 1448 (2021/05/04)
Oligomerization of aggregation-prone intrinsically disordered proteins (IDPs), such as α-synuclein, amyloid β, and tau, has been shown to be associated with the pathogenesis of several neurodegenerative diseases, including Parkinson's and Alzheimer's disease. The proteasome is charged with regulating cellular levels of IDPs, but this degradation pathway can become dysregulated leading to their accumulation and subsequent aggregation. Although the pathogenesis of these neurodegenerative diseases is still under intense investigation, it has been shown that the oligomeric forms of IDPs, including α-synuclein and amyloid β, can impair proteasome function. This leads to additional accumulation of the IDPs, further promoting disease progression. Herein, we report the use of small molecule activators of the 20S subcomplex of the proteasome to restore impaired 20S proteasome activity and prevent IDP accumulation and oligomerization. We found that fluspirilene and its new synthetic analog (16) show strong 20S proteasome enhancement (doubling 20S proteolytic activity at μ2 μM, with maximum fold enhancement of μ1000%), overcome impaired proteasome function, and prevent the accumulation of pathogenic IDPs. These findings provide support for the use of 20S enhancers as a possible therapeutic strategy to combat neurodegenerative diseases.
Improved method for preparing penfuridol
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Paragraph 0048-0052; 0061-0063, (2020/06/09)
The invention discloses an improved method for preparing penfuridol, comprising the following steps: using 4, 4-bis (4-fluorophenyl) butyric acid as a starting material, carrying out reduction synthesis to synthesize an intermediate I [4, 4-bis (4-fluorophenyl)-1-butanol]; carrying out esterification with a sulfonyl chloride compound to synthesize an intermediate II [4, 4-bis (4-fluorophenyl)-1 (4-methyl-phenyl)-butyl sulfonate] or [4, 4-bis (4-fluorophenyl)-1-methyl-butyl sulfonate]; and condensing with pipradrol to obtain penfuridol. According to the preparation method, 4, 4-bis (4-fluorophenyl) butyric acid is used as a raw material, penfuridol is obtained through a reduction reaction, an esterification reaction and a condensation reaction, the total yield is 81.3%, the whole process isconvenient to operate and mild in reaction, the obtained product is high in yield and purity, and the preparation method is more economical and more suitable for industrial application. The technicalproblems that an existing method is low in yield and poor in purity are solved. The reaction general formula is as shown in the specification.
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.
