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The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer's disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new candidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small molecules that both remodel the AβO structure and localize a potent antioxidant that mimics the activity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold with nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and remolding along with assessments of bioactivity allow for the extraction of useful SAR information from screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate's bioactivity and its ability to reduce the fraction of antiparallel β-strand.

On the occasion of building fires, the risk of smoke, which adversely influences escape conditions, must be minimised. One way to reduce the risk is, for example, to pressurise the escape route in order to limit the infiltration of smoke. Careful determination of the design parameters of the pressurisation system is of great importance. This study will propose a new leakage area for single-leaf smoke control doors based on the analysis of the leakage area of the doors in the EN 12101-13 standard, estimating the leakage rate through closed doors. This value is half the currently recommended value, regardless of the opening direction. The determination of the leakage area is supported by measurements in pressurised smoke-free lobbies with single-leaf smoke control doors opening into and outwards from a pressurised space. The measurements are performed using the fans of the lobbies' pressurisation systems to provide the required air volume. The suitability of this method has also been tested using blower door assembly measurements. The newly proposed leakage area takes into account the increased air tightness of the smoke control doors, thereby ensuring that the optimum air volume to be supplied by the pressurisation system can be determined. The results of this research suggest an appropriate leakage area value for designers when using the calculation method proposed by the applicability of the investigated standard. [ABSTRACT FROM AUTHOR]

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Five- and six-membered cyclic nitroxide-based allylic phosphonate esters, α-ketophosphonate esters were obtained from the corresponding paramagnetic allyl bromides and acyl chlorides respectively via the Arbuzov reactions. The α-hydroxyphosphonate esters were accessed by Pudovik reactions from the corresponding paramagnetic ketones and aldehydes. The β-ketophosphonate esters were obtained from the appropriate 1-alkynylphosphonate esters via PdCl2-catalyzed hydration. The synthesis of an allylic phosphate ester and a paramagnetic geminal bisphosphonate was also reported. [ABSTRACT FROM AUTHOR]

The reaction of a diene nitroxide precursor with dichlorophenylphosphine in a McCormac procedure afforded pyrroline nitroxide condensed phospholen oxide. Lithiation of the protected 3-bromo-pyrroline nitroxide followed by treatment with chlorodiphenylphosphine after deprotection afforded (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)diphenylphosphine oxide, and after reduction, (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)diphenylphosphine was realized, which was also supported by X-ray single crystal diffraction measurements. This pyrroline diphenylphosphine derivative was converted to hexadecylphosphonium salt, which was more effective antineoplastic agent than its analogue MITO-CP. [ABSTRACT FROM AUTHOR]

Reactions of β-bromo-β,γ-unsaturated pyrroline nitroxide aldehyde ( 1) or nitrile ( 4) or their diamagnetic forms ( 5, 6) with 2-aminothiophenol or 2-mercaptobenzimidazole were evaluated. The reaction could be reproduced more easily with the application of O-acetyl derivatives of nitroxides to generate 2-substituted-benzothiazole, pyrrolo[3,4- b]benzo[1,5]tiazepine scaffolds with 2-aminothiophenol and benzimidazo[2,1- b]pyrrolo[3,4- e]-[1,3]thiazine scaffold with 2-mercaptobenzimidazole. [ABSTRACT FROM AUTHOR]