50972-25-3

Upstream product

• 824-72-6 P,P-dichlorophenylphosphine oxide 
• 100-51-6 benzyl alcohol 
• 65-85-0 benzoic acid 

Downstream Products

• 19236-61-4 dibenzyl phenylphosphonate 
• 200941-05-5 N-[benzyloxy(phenyl)phosphinyl]-L-glutamic acid dibenzyl ester 
• 14572-73-7 benzyl P-phenylphosphonamidate 
• 148533-52-2 (1R,2R,3S,5S)-methyl 3-(((benzyloxy)(phenyl)phosphoryl)oxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate 
• 1431753-57-9 4-((1R,2R,3S,5S)-3-((hydroxy(phenyl)phosphoryl)oxy)-2-(methoxycarbonyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid trifluoroacetate salt 
• 1431753-56-8 4-((1R,2R,3S,5S)-3-(((benzyloxy)(phenyl)phosphoryl)oxy)-2-(methoxycarbonyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-oxobutanoic acid trifluoroacetate salt 
• 148533-53-3 (1R,2R,3S,5S)-3-(Benzyloxy-phenyl-phosphinoyloxy)-8-(5-tert-butoxycarbonyl-pentyl)-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester 

Relevant academic research and scientific papers

Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors

NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion in mice.

Augmenting the efficacy of anti-cocaine catalytic antibodies through chimeric hapten design and combinatorial vaccination

Given the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy. In contrast, the resulting pool of antibodies from GNE/GNT co-administration demonstrated intermediate efficacy as compared to antibodies developed from either hapten alone. Overall, improved antibody catalytic efficiency appears necessary to achieve the synergistic benefits of combining cocaine hydrolysis with peripheral sequestration.

A New Covalent Inhibitor of Class C β-Lactamases Reveals Extended Active Site Specificity

O-Aryloxycarbonyl hydroxamates have previously been shown to efficiently inactivate class C β-lactamases by cross-linking serine and lysine residues in the active site. A new analogue of these inhibitors, d-(R)-O-(phenoxycarbonyl)-N-[(4-amino-4-carboxy-1-butyl)oxycarbonyl]hydroxylamine, designed to inactivate certain low-molecular mass dd-peptidases, has now been synthesized. Although the new molecule was found to be only a poor inactivator of the latter enzymes, it proved, unexpectedly, to be a very effective inactivator (ki = 3.5 × 104 M-1 s-1) of class C β-lactamases, more so than the original lead compound, O-phenoxycarbonyl-N-(benzyloxycarbonyl)hydroxylamine. Furthermore, the mechanism of inactivation is different. Mass spectrometry demonstrated that β-lactamase inactivation by the new molecule involved formation of an O-alkoxycarbonylhydroxamate with the nucleophilic active site serine residue. This acyl-enzyme did not cyclize to cross-link the active site as did that from the lead compound. Model building suggested that the rapid enzyme acylation by the new molecule may occur because of favorable interaction between the polar terminus of its side chain and elements of the Ω loop that abuts the active site, Arg 204 in particular. This interaction should be considered in the design of new covalent β-lactamase inhibitors. The initially formed acyl-enzyme partitions (ratio of ～1) between hydrolysis, which regenerates the active enzyme, and formation of an inert second acyl-enzyme. Structural modeling suggests that the latter intermediate arises from conformational movement of the acyl group away from the reaction center, probably enforced by the inflexibility of the acyl group. The new molecule is thus a mechanism-based inhibitor in which an inert complex is formed by noncovalent rearrangement. Phosphyl analogues of the new molecule were efficient inactivators of neither dd-peptidases nor β-lactamases.

Covalent inhibition of serine β-lactamases by novel hydroxamic acid derivatives

The effectiveness of β-lactam antibiotics is greatly limited by the ability of bacteria to produce β-lactamases. These enzymes catalyze the hydrolysis of β-lactams and thus loss of their antibiotic activity. The search for inhibitors of β-lactamases began soon after β-lactams were introduced into medical practice and continues today. Some time ago, we introduced a new class of covalent serine β-lactamase inhibitors, the O-aryloxycarbonyl hydroxamates, that inactivated these enzymes by a unique mechanism in which the active site became cross-linked. We describe in this paper some new variants of this class of inhibitor. First, we investigated compounds in which more polar hydroxamates were incorporated. These were generally not more active than the original compounds against representative class A and class C β-lactamases, but one of them, 1-(benzoyl)-O- (phenoxycarbonyl)-3-hydroxyurea, was significantly more stable in solution, thus revealing a useful platform for further design. Second, we describe a series of O-(arylphosphoryl) hydroxamates that are also irreversible inactivators of class A and class C β-lactamases, by phosphorylation of the enzyme, as revealed by mass spectra. These compounds did not, however, cross-link the enzyme active site. A striking feature of their structure-activity profile was that hydroxamate remained the leaving group on enzyme phosphorylation rather than aryloxide, even though the aryloxide was intrinsically the better leaving group, as indicated by pKa values and demonstrated by the products of hydrolysis in free solution. Model building suggested that this phenomenon arises from the relative affinity of the enzyme active site components for the two leaving groups. The results obtained for both groups of inhibitors are important for further optimization of these inhibitors.

Cocaine catalytic antibodies: The primary importance of linker effects

Current treatments for cocaine addiction are not effective. The development of a catalytic monoclonal antibody (mAb) provides a strategy for not only binding, but also degrading cocaine, which offers a broad-based therapy. Hapten design is the central element for programming antibody catalysis. The characteristics of the linker used in classic transition-state analogue phosphonate haptens were shown to be important for obtaining mAbs that hydrolyze the benzoate ester of cocaine.

Evaluation of phosphorus-containing inhibitors of γ-glutamyl hydrolase

Several putative, phosphorus-containing inhibitors of γ-glutamyl hydrolase were synthesized and evaluated for inhibitory activity. The phosphonamidoic acids were shown to be weak competitive inhibitors while both a phosphoramidate diester and a phosphonamidate ester were shown to be potent time-dependent inactivators, presumably through irreversible phosphorylation of an active site nucleophile.

Tetrazole-catalyzed synthesis of phosphonamidate esters

1H-Tetrazole selectively catalyzed sequential monoaddition of alcohol and amine to phosphonic dichlorides and provided phosphonamidate esters under mild conditions.

A convenient two-step one-pot synthesis of phosphonamidates

Phosphonamidates are formed in high yield from a one-pot sequential reaction of a phosphonyl dichloride with an alcohol and then an amine in the presence of catalytic 1H-tetrazole. Undesired disubstitution of the phoshphonyl dichloride by the alcohol or the amine is minimal due to the presence of tetrazole.