Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

Fennell, Brandon D.; Warren, Julia; Chung, Kevin K.; Main, Hannah L.; Arend, A.; Tochowicz, A.; Götz, Marion G.

doi:10.3109/14756366.2011.651466

Cited by 14 publications

(7 citation statements)

References 56 publications

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“…ESI-HRMS (pos): m / z [M + H] + calcd for [C 32 H 39 N 4 O 4 S] + 575.2687, found 575.2682. The analytical data are consistent with those reported in the literature for both diastereomers …”

Section: Experimental Sectionsupporting

confidence: 90%

“…After purification via flash column chromatography (HP-Sphere C18, gradient from 10% to 90% MeCN, product elutes with 35% MeCN), the first batch of deprotected 4y resulted in 19.4 mg (33.8 μmol, 19%, colorless oil) of the title compund and the second batch of deprotected 4y afforded 63.9 mg (111 μmol, 62%, colorless oil) of the target compound (combined yield: 83.3 mg, 145 μmol, 81%) as a diastereomeric mixture (dr = 60:40, determined by 1 H NMR spectroscopy based on the integrals of CHCHCH). Using previously published NMR data, 66 (S)-(S)-7 (K11777) could be identified as the minor diastereomer. Repeated purification by flash column chromatography (HP-Sphere C18, gradient from 10% to 90% MeCN, product elutes with 35% MeCN) afforded 51.2 mg (89.1 μmol, 50%) of a diastereomeric mixture (dr = 60:40, A/B), with (S)-(S)-7 as major diastereomer A.…”

mentioning

confidence: 89%

“…This compound was prepared on the basis of procedures by Di Gioia 65 and Fennell. 66 A flame-dried Schlenk tube was charged with (9H-fluoren-9-yl)methyl ((2S)-1-oxo-3-phenyl-1-(((E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)a-mino)propan-2yl)carbamate (4y, 120 mg, 179 μmol, 1.00 equiv), 1-butyl-3methylimidazolium tetrafluoroborate ([Bmim][BF 4 ], 0.5 mL), and triethylamine (149 μL, 109 mg, 1.07 mmol, 6.00 equiv). The reaction mixture was stirred for 3 h at ambient temperature, followed by the addition of diethyl ether (2 mL).…”

mentioning

confidence: 99%

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Photoredox Alkenylation of Carboxylic Acids and Peptides: Synthesis of Covalent Enzyme Inhibitors

Kammer¹,

Lipp²,

Opatz³

2018

J. Org. Chem.

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The synthesis of vinyl sulfones and (α,β-unsaturated) nitriles from carboxylic acids was realized through oxidative decarboxylation with 1,4-dicyanoanthracene as an organic photoredox catalyst. Various types of C-radicals are generated and used to construct three different classes of potential covalent protease inhibitors. The procedure is functional group tolerant and applicable to natural products and druglike scaffolds. It may serve for the rapid construction of screening candidates as demonstrated by a three-step synthesis of the known protease inhibitor K11777.

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Section: Experimental Sectionsupporting

confidence: 90%

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confidence: 89%

mentioning

confidence: 99%

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Photoredox Alkenylation of Carboxylic Acids and Peptides: Synthesis of Covalent Enzyme Inhibitors

Kammer¹,

Lipp²,

Opatz³

2018

J. Org. Chem.

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“…1 H NMR and 13 C NMR chemical shifts (δ) are expressed in ppm, and coupling constants ( J ) are given in Hz. Compounds 5a – m , ,− 6a – d , 6f – j , ,,− and 10 were synthesized according to standard procedures and spectroscopic data are in agreement to those reported in literature.…”

Section: Methodsmentioning

confidence: 99%

Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis

et al. 2019

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This paper describes an optimization strategy of the highly active vinyl ketone 3 which was recognized as a strong inhibitor of rhodesain of Trypanosoma brucei rhodesiense, endowed with a k second value of 67 × 106 M–1 min–1 coupled with a high binding affinity (K i = 38 pM). We now report a new structure–activity relationship study based on structural variations on the P3, P2, and P1′ sites which led us to identify two potent lead compounds, i.e., vinyl ketones 4h and 4k. Vinyl ketone 4h showed an impressive potency toward rhodesain (k second = 8811 × 105) coupled to a good antiparasitic activity (EC50 = 3.6 μM), while vinyl ketone 4k proved to possess the highest binding affinity toward the trypanosomal protease (K i = 0.6 pM) and a submicromolar antiparasitic activity (EC50 = 0.67 μM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.

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“…Electrophiles that alkylate, acylate, phosphonylate or sulfonylate the active site cysteine irreversibly, include simple non-selective alkylating or acylating agents such as iodoacetate, N -ethylmaleimide, and diisopropyl fluorophosphate. Examples of electrophilic warheads used in selective and potent cysteine protease inhibitors include epoxysuccinates, vinylsulfones, allyl sulfones 54 . vinyl sulfonates, diazomethyl ketones and fluoro- or chloromethyl ketones 55 , 56 , 57 .…”

Section: Electrophilic Warheads For Cys Protease Inhibitorsmentioning

confidence: 99%

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Siklos

BenAissa

Thatcher

2015

Acta Pharmaceutica Sinica B

211

169

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Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.

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Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

Cited by 14 publications

References 56 publications

Photoredox Alkenylation of Carboxylic Acids and Peptides: Synthesis of Covalent Enzyme Inhibitors

Photoredox Alkenylation of Carboxylic Acids and Peptides: Synthesis of Covalent Enzyme Inhibitors

Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

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