ChemInform Abstract: SYNTHESIS OF β‐LACTAMS FROM SUBSTITUTED HYDROXAMIC ACIDS

Miller, Marvin J.; Mattingly, Phillip G.; Morrison, Marjorie A.; Kerwin, James F.

doi:10.1002/chin.198109216

Cited by 4 publications

(6 citation statements)

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“…Synthesis of (2R,3S)-2-tert-Butoxycarbonylamino-3-hydroxybutyric Acid (17b). 38 The same protocol applied to D-threonine (16b) gave 17b as a colorless oil. Yield: 95% (1.748 g).…”

Section: Discussionmentioning

confidence: 97%

“…The synthesis of threonine β-lactones 20a and 20b is reported in Scheme . The amino groups of l - and d -threonine were protected through treatment with di- tert -butyl dicarbonate in aqueous sodium bicarbonate to give 17a and 17b , respectively, by means of slight modification of a literature procedure . Cyclization to β-lactones 18a and 18b was accomplished through treatment of 17a and 17b , respectively, with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) by means of a literature procedure .…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Structure−Activity Relationships of N-(2-Oxo-3-oxetanyl)amides as N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors

et al. 2010

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The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-α, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a a series of β-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC50 = 420 nM; 7h, IC50 = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.

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“…Synthesis of (2R,3S)-2-tert-Butoxycarbonylamino-3-hydroxybutyric Acid (17b). 38 The same protocol applied to D-threonine (16b) gave 17b as a colorless oil. Yield: 95% (1.748 g).…”

Section: Discussionmentioning

confidence: 97%

Section: Chemistrymentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of N-(2-Oxo-3-oxetanyl)amides as N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors

et al. 2010

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“…(2R,3S)-2-tert-Butoxycarbonylamino-3-hydroxybutyric Acid (22b). 48 The yield, MS (EI), and 1 H NMR are given in ref 33.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…The synthesis of threonine β-lactones 23a , 23b , 24a , 24b , 24c , and 24d is illustrated in Scheme . The amino groups of l -, d -, l - allo -, and d - allo -threonine ( 20a–d , respectively) were protected with 12 or di- tert -butyl dicarbonate (Boc 2 O) in aqueous sodium bicarbonate to give 21a , 21b , 22a , 22b , 22c ,and 22d , respectively, employing a slightly modified literature procedure . Cyclization to β-lactones 23a,b and 24a–d was accomplished by treating the parent compounds 21a,b and 22a–d , respectively, with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) by means of a literature procedure …”

Section: Chemistrymentioning

confidence: 99%

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure−activity and structure−property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC 50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.

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“…18 The β-lactam containing inhibitor 78 was prepared as shown in Scheme 6 from O-benzyl hydroxamic acid 26 (synthesized from serine) by employing the procedure described by Miller. 19 The preparations of the unnatural amino acids adamantylglycine and β,β-dimethylaspartic acid are shown in Scheme 7. Thus oxazolidinone 29 was obtained from acid 27 using procedures described previously.…”

Section: Chemistrymentioning

confidence: 99%

Peptidomimetic Inhibitors of the Human Cytomegalovirus Protease

et al. 1997

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The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.

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ChemInform Abstract: SYNTHESIS OF β‐LACTAMS FROM SUBSTITUTED HYDROXAMIC ACIDS

Abstract: Durch Cyclisierung der Hydroxamsäurederivate (I) bzw. (III) (Darstellung beschrieben) nach den angegebenen Methoden werden die Lactame (II) bzw. (IV) erhalten (Modellversuche).

Cited by 4 publications

References 1 publication

Synthesis and Structure−Activity Relationships of N-(2-Oxo-3-oxetanyl)amides as N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors

Synthesis and Structure−Activity Relationships of N-(2-Oxo-3-oxetanyl)amides as N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

Peptidomimetic Inhibitors of the Human Cytomegalovirus Protease

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