Irreversible enzyme inhibitors. CXV. Proteolytic enzymes. 5. Active-site-directed irreversible inhibitors of trypsin derived from p-(phenoxyalkoxy)benzamidines with a terminal sulfonyl fluoride

Baker, B. R.; Erickson, Edward H.

doi:10.1021/jm00308a011

Cited by 20 publications

(17 citation statements)

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“…This protease is therefore a key target for the development of antiinflammatory agents to combat these diseases. Alkyl and aryl sulfonyl fluorides have a long history as rather promiscuous covalent inhibitors of serine proteases (78)(79)(80)(81)(82)(83)(84)(85)(86)(87). In the late 1970s, the Powers group demonstrated the intrinsic reactivity differences across several serine proteases, including elastase, with 2-amido(peptido) benzenesulfonyl fluoride inhibitors (88,89).…”

Section: Significancementioning

confidence: 99%

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Zheng

Woehl

Kitamura

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

149

136

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Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.

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Section: Significancementioning

confidence: 99%

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Zheng

Woehl

Kitamura

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

149

136

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“…In view of these structural requirements, nonsteroidal ligands with two benzene rings seemed worthy of investigation. A model for such a ligand is p-(p'-aminophenoxypropoxy)benzamidine (Baker & Erickson, 1968). By linking this compound to CNBractivated Sepharose, Jameson & Elmore (1971 obtained an affinity adsorbent for the column separation of bovine a-and fl-trypsins.…”

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confidence: 99%

‘Affinity’ chromatography of steroid-transforming enzymes with a non-steroidal ligand

Renwick¹,

Chambers²,

Willcox³

1979

Biochemical Journal

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The chromatographic behaviour of an avian oestradiol-17 beta dehydrogenase, the 3(17) beta-hydroxy steroid dehydrogenase from Pseudomonas testosteroni and cortisone reductase from Streptomyces dehydrogenans was studied on columns of p-(phenoxypropoxy)aniline attached to CNBr-activated Sepharose. The ligand was effective in adsorbing the oestradiol dehydrogenase from a partially purified extract of chicken liver, and the cortisone reductase was perferentially retained when mixtures of the three dehydrogenases were applied to columns in 10mM-buffer. Under these conditions the 3(17)beta-hydroxy steroid dehydrogenase was eluted in the front, but was adsorbed in the presence of 3 M-KCl. beta-N-Acetylglucosaminidase present in the liver preparation was not retained by the ligand, whereas lactate dehydrogenase from rabbit muscle was adsorbed in a manner similar to the retention pattern found on affinity chromatography with 2',5'-ADP--Sepharose. The mean overall purification of the oestradiol dehydrogenase was 13-fold, with a mean recovery of 53%. p-(Phenoxypropoxy)aniline offers promise for the purification of steroid-transforming enzymes where elution with substrate or cofactor is not wanted. It is also suggested that the ligand may be of service in the purification of receptors of hormonal steroids.

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“…S-(2-Aminoethyl)-N-benzoyl-L-cysteine methyl ester hydrochloride was synthesized by the method of Elmore et al (1967) and 4-methylumbelliferyl p-(NNN-trimethylammonium)cinnamate chloride by the method of Jameson et al (1973). p-(p'-Aminophenoxypropoxy)benzamidine as the benzenesulphonate was prepared by a method based on that of Baker & Erickson (1968), but the yield of the intermediate p-hydroxybenzamidine (66%) was almost twice that reported by these workers. Dioxan (150ml for 0.1 mol of p-cyanophenol) replaced chloroform as solvent; reaction with ethanol-HCl was allowed to proceed for 10 days instead of 18 h; unchanged p-cyanophenol was removed by distillation under reduced pressure before reaction with NH3.…”

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confidence: 90%

“…223-224°C], and the latter was then converted into the benzenesulphonate, m.p. 183-186°C [Baker & Erickson (1968) quote m.p. 180-181°C; Partridge & Short (1947) quote m.p.…”

mentioning

confidence: 99%

“…187°C]. The remainder of the preparation of p-(p'-aminophenoxypropoxy)benzamidine benzenesulphonate was carried out as described by Baker & Erickson (1968) except that the hydrogenation of the p-nitro precursor was carried out in the presence of 10% palladium on charcoal at atmospheric pressure and the product was crystallized twice from acetonitrile by treatment with activated charcoal. The product had m.p.…”

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confidence: 99%

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Affinity chromatography of bovine trypsin. A rapid separation of bovine α- and β-trypsin

Jameson

Elmore

1974

Biochemical Journal

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Affinity adsorbents for bovine trypsin were prepared by covalently coupling p-(p'-amino-phenoxypropoxy)benzamidine to cellulose and to agarose. Trypsin binds to both adsorbents at pH6-8 and is released at low pH values or in the presence of n-butylamine hydrochloride. Pure beta-trypsin may be eluted from crude trypsin bound at pH8.0 to the cellulose adsorbent by stepwise elution with an acetate buffer, pH5.0. Both alpha- and beta-trypsin may be isolated by chromatography of crude trypsin on the agarose derivative in an acetate buffer, pH4.0. These two methods for purifying the trypsin are specific to the particular adsorbents. They are rapid and convenient in use. Both methods leave a mixture of the two enzymes bound to the adsorbent and release occurs only at low pH values. The effects of pH, composition and ionic strength of buffer and other variables on both purification methods are described. Affinity adsorbents of soya-bean trypsin inhibitor and of N-alpha-(N'-methyl-N'-sulphanilyl) sulphanilylagmatine bound to agarose were prepared, but were found to be of limited usefulness in the purification of trypsin.

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Irreversible enzyme inhibitors. CXV. Proteolytic enzymes. 5. Active-site-directed irreversible inhibitors of trypsin derived from p-(phenoxyalkoxy)benzamidines with a terminal sulfonyl fluoride

Cited by 20 publications

References 0 publications

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

‘Affinity’ chromatography of steroid-transforming enzymes with a non-steroidal ligand

Affinity chromatography of bovine trypsin. A rapid separation of bovine α- and β-trypsin

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