6078-95-1Relevant academic research and scientific papers
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.
Ring opening of methylenecyclopropanes with halides in liquid sulfur dioxide
Le?kovskis, Kristaps,Gulbe, Krista,Mishnev, Anatoly,Turks, Māris
supporting information, (2020/10/19)
Methylenecyclopropanes (MCP) undergo ring opening reactions with group I and II metal halides and ammonium halides in liquid SO2 to afford homoallylic halides, which are versatile reagents in organic synthesis. The developed reaction conditions are compatible with acid-labile substrates such as N-Boc-protected compounds. Liquid SO2 is a polar reaction medium with Lewis acid properties that solubilizes inorganic salts. The unique properties of SO2 were demonstrated by control experiments: 1) upon performing the reactions with the aforementioned salts in conventional solvents, the MCP ring opening was not observed either in the presence of catalytic amounts of H3PO4 (similar pKa to that of H2SO3), or in the absence of H3PO4; 2) a solution of SO2 in THF exhibited similar properties to that of liquid SO2.
Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity
Ashraf-Uz-Zaman, Md,Sajib, Md Sanaullah,Cucullo, Luca,Mikelis, Constantinos M.,German, Nadezhda A.
, p. 3652 - 3657 (2018/11/03)
Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.
Alkene Oxyamination Using Malonoyl Peroxides: Preparation of Pyrrolidines and Isoxazolidines
Alamillo-Ferrer, Carla,Curle, Jonathan M.,Davidson, Stuart C.,Lucas, Simon C. C.,Atkinson, Stephen J.,Campbell, Matthew,Kennedy, Alan R.,Tomkinson, Nicholas C. O.
, p. 6728 - 6740 (2018/06/26)
Treatment of homoallylic N-tosyl amines or allylic N-tosyl hydroxylamines with 1.5 equiv of a malonoyl peroxide provides a stereoselective method to access functionalized pyrrolidines and isoxazolidines. This metal free alkene oxyamination proceeds in 50-
Synthesis of Novel Quaternary Ammonium Salts and Their in Vitro Antileishmanial Activity and U-937 Cell Cytotoxicity
Duque-Benítez, Sandra M.,Ríos-Vásquez, Luz Amalia,Ocampo-Cardona, Rogelio,Cede?o, David L.,Jones, Marjorie A.,Vélez, Iván D.,Robledo, Sara M.
, (2016/05/24)
This work describes the synthesis of a series of quaternary ammonium salts and the assessment of their in vitro antileishmanial activity and cytotoxicity. A preliminary discussion on a structure-activity relationship of the compounds is also included. Three series of quaternary ammonium salts were prepared: (i) halomethylated quaternary ammonium salts (series I); (ii) non-halogenated quaternary ammonium salts (series II) and (iii) halomethylated choline analogs (series III). Assessments of their in vitro cytotoxicity in human promonocytic cells U-937 and antileishmanial activity in axenic amastigotes of L. (Viannia) panamensis (M/HOM/87/UA140-pIR-eGFP) were carried out using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) micromethod. Antileishmanial activity was also tested in intracellular amastigotes of L. (V) panamensis using flow cytometry. High toxicity for human U937 cells was found with most of the compounds, which exhibited Lethal Concentration 50 (LC50 ) values in the range of 9 to 46 μg/mL. Most of the compounds evidenced antileishmanial activity. In axenic amastigotes, the antileishmanial activity varied from 14 to 57 μg/mL, while in intracellular amastigotes their activity varied from 17 to 50 μg/mL. N-Chloromethyl-N,N-dimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (1a), N-iodomethyl-N,N-dimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (2a), N,N,N-trimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (3a) and N,N,N-trimethyl-N-(5,5-diphenylpent-4-en-1-yl)ammonium iodide (3b) turned out to be the most active compounds against intracellular amastigotes of L. (V) panamensis, with EC50 values varying between 24.7 for compound 3b and 38.4 μg/mL for compound 1a. Thus, these compounds represents new "hits" in the development of leishmanicidal drugs.
DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS
-
, (2011/12/02)
Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.
Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers
Chen, Gang,Xia, Hongguang,Cai, Yu,Ma, Dawei,Yuan, Junying,Yuan, Chengye
scheme or table, p. 234 - 239 (2011/02/26)
A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.
Studies on the mechanism, selectivity, and synthetic utility of lactone reduction using SmI2 and H2O
Parmar, Dixit,Duffy, Lorna A.,Sadasivam, Dhandapani V.,Matsubara, Hiroshi,Bradley, Paul A.,Flowers II, Robert A.,Procter, David J.
supporting information; experimental part, p. 15467 - 15473 (2010/02/16)
Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI2, activation of the lanthanide reagent by H2O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI2-H2O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI2-H2O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.
Ring-opening reaction of methylenecyclopropanes with LiCl, LiBr or NaI in acetic acid
Huang, Jin-Wen,Shi, Min
, p. 2057 - 2062 (2007/10/03)
The methylenecyclopropanes 1 react with LiCl, LiBr or NaI at 80°C to give the corresponding gem-disubstituted homoallylic halides 2 in good to excellent yields in acetic acid. In some cases, the ring-opening reaction can be completed within 5 min to give
A convenient one-pot synthesis of homoallylic halides and 1,3-butadienes
Wong, Ken-Tsung,Hung, Ying-Yueh
, p. 8033 - 8036 (2007/10/03)
An efficient one-pot synthetic pathway for the preparation of homoallylic halides by in situ generated MgBrCl-promoted ring opening of cyclopropylcarbinyl acetates has been established. An easily accessible one-pot synthetic protocol of 1,3-butadienes by the elimination of hydrogen halides from the resulting homoallylic halides in the presence of an excess amount of strong base has also been developed.
