Abstract:N-aryl-3,3-difluoroazetidin-2-ones featured by a latent electrophilic methylene quinoniminium function have been synthesized and evaluated as inhibitors of human leucocyte elastase. To promote hydrophobic interactions with the enzyme, to increase the rates of beta-lactam ring opening and of benzylic group departure, or to induce hydrosolubility, these compounds incorporate on their aromatic ring either an alkyl moiety, a methoxy substituent or a carboxylic group. Some of these beta-lactams proved to be good in… Show more
“…Reaction of the latter with an active site nucleophile (Nu) could then potentially inactivate the enzyme. This theme has been effective with other serine hydrolases. − …”
Section: Introductionmentioning
confidence: 97%
“…Competition between reaction with an active site nucleophile and diffusion of the quinone methide from the active site and subsequent hydrolysis (Nu = H 2 O) would be expected to limit the effectiveness of 2 as an inhibitor, and, in fact, molecules such as 2 were not efficient inhibitors of β-lactamases . If the quinone methide were tethered to the acyl group, however, one might expect greater efficiency, and, indeed, molecules incorporating this feature have effectively inhibited other serine hydrolases. − Consequently, we have constructed molecules analogous to 2 , but where the acyl group is tethered to the leaving group, and describe in this paper the interactions of one group of these molecules, dihydrobenzopyranones, with representative β-lactamases and a DD-peptidase. The specific molecules involved are the parent compounds 3a and 3b and two functionalized variants 4 and 5 .…”
Several 7-carboxy-3-amido-3,4-dihydro-2H-1-benzopyran-2-ones have been synthesized as potential beta-lactamase substrates and/or mechanism-based inhibitors. Substituted o-tyrosine precursors were prepared by the Sörensen method and then heated in vacuo to give the lactones. These compounds are cyclic analogues of aryl phenaceturates which are known to be beta-lactamase substrates. The goal of incorporating the scissile ester group into a lactone was to retain the leaving group tethered to the acyl moiety at the acyl-enzyme stage of turnover by serine beta-lactamases, in a manner similar to that during penicillin turnover. Further, in two cases, a functionalized methylene group para to the leaving group phenoxide oxygen was incorporated. These molecules possess a latent p-quinone methide electrophile which could, in principle, be unmasked during enzymic turnover and react with an active site nucleophile. All of these compounds were found to be substrates of class A and C beta-lactamases, the first delta-lactones with such activity. Generally, k(cat) values were smaller than for the analogous acyclic depsipeptides, which suggests that the tethered leaving group may obstruct the attack of water on the acyl-enzymes. Further exploration of this structural theme might lead to quite inert acyl-enzymes and thus to significant inhibitors. Despite the apparent advantage offered by the longer-lived acyl-enzymes, the functionalized compounds were no better as irreversible inhibitors than comparable acyclic compounds [Cabaret, D.; Liu, J.; Wakselman, M.; Pratt, R. F.; Xu, Y. Bioorg. Med. Chem. 1994, 2, 757-771]. Thus, even tethered quinone methides, at least when placed as dictated by the structures of the present compounds, were unable to efficiently trap a nucleophile at serine beta-lactamase active sites.
“…Reaction of the latter with an active site nucleophile (Nu) could then potentially inactivate the enzyme. This theme has been effective with other serine hydrolases. − …”
Section: Introductionmentioning
confidence: 97%
“…Competition between reaction with an active site nucleophile and diffusion of the quinone methide from the active site and subsequent hydrolysis (Nu = H 2 O) would be expected to limit the effectiveness of 2 as an inhibitor, and, in fact, molecules such as 2 were not efficient inhibitors of β-lactamases . If the quinone methide were tethered to the acyl group, however, one might expect greater efficiency, and, indeed, molecules incorporating this feature have effectively inhibited other serine hydrolases. − Consequently, we have constructed molecules analogous to 2 , but where the acyl group is tethered to the leaving group, and describe in this paper the interactions of one group of these molecules, dihydrobenzopyranones, with representative β-lactamases and a DD-peptidase. The specific molecules involved are the parent compounds 3a and 3b and two functionalized variants 4 and 5 .…”
Several 7-carboxy-3-amido-3,4-dihydro-2H-1-benzopyran-2-ones have been synthesized as potential beta-lactamase substrates and/or mechanism-based inhibitors. Substituted o-tyrosine precursors were prepared by the Sörensen method and then heated in vacuo to give the lactones. These compounds are cyclic analogues of aryl phenaceturates which are known to be beta-lactamase substrates. The goal of incorporating the scissile ester group into a lactone was to retain the leaving group tethered to the acyl moiety at the acyl-enzyme stage of turnover by serine beta-lactamases, in a manner similar to that during penicillin turnover. Further, in two cases, a functionalized methylene group para to the leaving group phenoxide oxygen was incorporated. These molecules possess a latent p-quinone methide electrophile which could, in principle, be unmasked during enzymic turnover and react with an active site nucleophile. All of these compounds were found to be substrates of class A and C beta-lactamases, the first delta-lactones with such activity. Generally, k(cat) values were smaller than for the analogous acyclic depsipeptides, which suggests that the tethered leaving group may obstruct the attack of water on the acyl-enzymes. Further exploration of this structural theme might lead to quite inert acyl-enzymes and thus to significant inhibitors. Despite the apparent advantage offered by the longer-lived acyl-enzymes, the functionalized compounds were no better as irreversible inhibitors than comparable acyclic compounds [Cabaret, D.; Liu, J.; Wakselman, M.; Pratt, R. F.; Xu, Y. Bioorg. Med. Chem. 1994, 2, 757-771]. Thus, even tethered quinone methides, at least when placed as dictated by the structures of the present compounds, were unable to efficiently trap a nucleophile at serine beta-lactamase active sites.
“… 6 In fact, α,α-difluoro-β-lactams have been disclosed to be effective in the inhibition of human leukocyte elastase ( Scheme 1 ). 7 Several methods have been established to synthesize these compounds. 7–10 Among them, intramolecular ring closure of 3-functionalized-2,2-difluoroamides 8 ( Scheme 2A ) and [2 + 2] cyclization of halodifluoroacetates with imines 9 ( Scheme 2B ) were common methods.…”
Section: Introductionmentioning
confidence: 99%
“… 7 Several methods have been established to synthesize these compounds. 7–10 Among them, intramolecular ring closure of 3-functionalized-2,2-difluoroamides 8 ( Scheme 2A ) and [2 + 2] cyclization of halodifluoroacetates with imines 9 ( Scheme 2B ) were common methods. While the former often needs multistep synthesized substrates and excess sodium hydride or phosphine, 8 the latter requires excess zinc powder or organozinc reagent 9 and sometimes provides a mixture of the α,α-difluoro-β-amino ester and α,α-difluoro-β-lactam.…”
We have developed a novel copper-catalyzed cyclization of cyclopropenes/diazo compounds and bromodifluoroacetamides, efficiently synthesizing a series of α,α-difluoro-β-lactams in moderate to excellent yields under mild reaction conditions. This reaction represents...
“…β-Lactams expressed their importance in the synthesis of different fluorinated molecules such as sugar-βamino acid conjugates [15], amido esters [18], aminopropanes and heterocycles [17], as well as taxoids and β-amino acids [20]. Relevant bioactivities were reported for fluoro-taxoids [20] and some N-aryl-3,3-difluoroazetidin-2-ones [21].…”
Functionalized β-lactams and their derivatives have generated increasing interest in medicinal chemistry over the last decades. Because of their pharmacological potential the chemistry of fluorinated β-lactams and β-amino acids is considered to be an expanding research field. The stereocontrolled synthesis of various fluorine-containing acylic β-lactams has been accomplished from some readily available unsaturated bicyclic β-lactam isomers. The synthetic strategy was based on ring-opening metathesis of unsaturated bicyclic azetidinones followed by cross-metathesis with fluorine-containing olefins. The cross-metathesis transformations, performed under various conditions with the aim of studying chemodiscrimination of the olefin bonds, resulted in the corresponding functionalized β-lactam derivatives.
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