New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S<sup>2</sup> Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation

Fustero, Santos; Rodrigo, Vanessa; Sánchez‐Roselló, María; Pozo, Carlos del; Timoneda, Joaquín; Frizler, Maxim; Sisay, Mihiret T.; Bajorath, Jürgen; Calle, Luis P.; Cañada, F. Javier; Jiménez‐Barbero, Jesús; Gütschow, Michael

doi:10.1002/chem.201100113

Cited by 14 publications

(6 citation statements)

References 21 publications

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“…The corresponding deprotected amino acids 48 further served as scaffolds for preparing selective inhibitors of cathepsins. 31 Scheme 10 Vinyl imines may act as surrogates of imino esters, since the double bond can be later oxidized to a carboxylic function. Liu and co-workers recently employed an aza-Henry (nitro-Mannich) reaction on chiral fluorinated sulfinylimines 49 to produce nitroamines 50 with complete diastereoselectivity, except in the case of R F = CF 2 H (dr = 72:28) 32 (Scheme 11).…”

Section: Methodsmentioning

confidence: 99%

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

2012

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This review article provides a comprehensive update on the development of new methods for the asymmetric synthesis of α-(trifluoromethyl)-α-amino acids, covering the literature from 2006 to mid-February 2012. Most of the methods discussed are based on asymmetric additions across the carbon-nitrogen double bond of the imines derived from esters of 3,3,3-trifluoropyruvic acid. Medium to high levels of stereocontrol can be achieved using phenylglycinol-derived chiral auxiliaries attached to the nitrogen of the corresponding imines. Among the enantioselective approaches, impressive results were achieved through the application of the Strecker reaction using chiral thioureas, as well as chiral Brønsted acids, as organocatalysts. 3 Catalytic Asymmetric Syntheses of α-(Trifluoromethyl)-αamino Acids 4 Miscellaneous 5 Conclusions

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Section: Methodsmentioning

confidence: 99%

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

2012

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“…The organic layers were combined and washed with brine, and the solvent was evaporated in vacuo. 6-(1,3-Dioxoisoindolin-2-yl)hexanoic acid (34): [92] The reaction was performed according to the general procedure with 6-aminohexanoic acid (5.25 g, 40 mmol) and phthalic anhydride (5.92 g, 40 mmol). (2) 938 mL, 1.374 g, 6mmol).…”

Section: Methodsmentioning

confidence: 99%

“…The introduction of fluorine into bioactive molecules is aw ell-established strategy in drug development. [32][33][34] In addition to potency, selectivity of enzyme inhibitors is crucial for their use as tools and therapeutics. The fluorine introduction can be used to modulate the acidity of adjacent moieties closed to fluorinea nd to adjust the compounds'l ipophilicity.M oreover,s pectroscopic, crystallographic, and computational studies indicate that the covalently bonded fluorine in organic molecules can act as ah ydrogen bond acceptor.…”

Section: Introductionmentioning

confidence: 99%

“…[29][30][31] Thus, pharmaceutical effectiveness, metabolic stability, and improved bioabsorption have been demonstrated for several fluorinated drugs relative to their nonfluorinated counterparts, and fluorophilic and fluorophobic environments within target proteins have been determined, as exemplified in the field of protease inhibitors. [32][33][34] In addition to potency, selectivity of enzyme inhibitors is crucial for their use as tools and therapeutics. To assess the selectivity of CEase inhibitors, we chose to investigate two serine hydrolases-monoacylglycerol lipase (MAGL;E C3 .1.1.23) [35] and fatty acid amide hydrolase (FAAH;E C3.5.1.99) [36][37][38] -which accept physiological substrates similar to those of CEase, that is, esters and amides of long-chain fatty acids, respectively, [39][40][41][42][43] and represent the major degrading enzymes in endocannabinoid metabolism.…”

Section: Introductionmentioning

confidence: 99%

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ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

et al. 2018

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Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (K ) of 1-19 μm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases-monoacylglycerol lipase and fatty acid amide hydrolase-were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.

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“…In the course of the determination of favorable (fluorophilic) and unfavorable (fluorophobic) environments within target proteins, inhibitors of serine and metalloproteases, [12] cysteine proteases, [13] and protein kinases [14] have been established.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural Characterization, and Antiangiogenic Activity of Polyfluorinated Benzamides

et al. 2018

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The introduction of fluorine into bioactive molecules is a matter of importance in medicinal chemistry. In this study, representatives of various chemical entities of fluoroaromatic compounds were synthesized. Depending on the reaction conditions, either tetrafluorophthalimides or ammonium tetrafluorophthalamates are accessible from tetrafluorophthalic anhydride and primary amines. Tetrafluorophthalamic acids undergo thermal decarboxylation to yield tetrafluorobenzamides. These could be successfully converted upon treatment with primary amines, in the course of an aromatic nucleophilic substitution, to 2,3,5-trifluorobenzamides with respective amino substituents at the 4-position. The five structure types were characterized by means of spectroscopic and crystallographic methods. The synthesized compounds were evaluated as inhibitors of angiogenesis by measuring microvessel outgrowth in a rat aortic ring assay. The biological activity was maintained throughout these different polyfluorinated chemotypes.

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New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S² Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation

Cited by 14 publications

References 21 publications

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

Synthesis, Structural Characterization, and Antiangiogenic Activity of Polyfluorinated Benzamides

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New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S2 Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation

Cited by 14 publications

References 21 publications

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

Synthesis, Structural Characterization, and Antiangiogenic Activity of Polyfluorinated Benzamides

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New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S² Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation