<i>N</i>‐Cyano Sulfoximines: COX Inhibition, Anticancer Activity, Cellular Toxicity, and Mutagenicity

Park, Seong Jun; Baars, Hannah; Mersmann, Stefanie; Buschmann, Helmut; Baron, Jens Malte; Amann, Philipp M.; Czaja, Katharina; Hollert, Henner; Bluhm, Katharina; Redelstein, Regine; Bolm, Carsten

doi:10.1002/cmdc.201200403

Cited by 92 publications

(50 citation statements)

References 22 publications

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“…[20] Recently, we prepared a series of bioactive sulfoximines and demonstrated their potential applications in medicinal chemistry. [23] It was shown that the biological response significantly depended on the absolute configuration of the stereogenic sulfur atom. [23c] For obtaining those results, racemic compounds were prepared, which subsequently had to be resolved by HPLC using a chiral stationary phase.…”

Section: Methodsmentioning

confidence: 99%

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Enantioselective Nitrene Transfer to Sulfides Catalyzed by a Chiral Iron Complex

2013

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Sulfimides are nitrogen analogues of sulfoxides. [1] In organic synthesis, they serve as useful intermediates [1,2] and have been applied as efficient ligands for metal catalysts. [3] Because of their unique biological properties, [1a, 4] sulfimides have also gained considerable attention in agricultural science and medicinal chemistry. As sulfoxides, sulfimides are chiral and have a stereogenic center at the sulfur atom if they originate from unsymmetrically substituted sulfides. Although sulfimides can be easily synthesized by various means, [1,5] their preparation in enantioenriched form is still challenging. The most prominent strategies involve the use of chiral auxiliaries [3a, 6] or reagents. [7] All of those, however, require stoichiometric amounts of chiral compounds that are usually prepared by multi-step syntheses.The field of catalytic asymmetric sulfimidation is scarcely explored, and only very few catalyst systems have been documented. For example, Uemura, Taylor and their coworkers disclosed the use of chiral copper(I)/bis(oxazoline) catalysts. [8] However, only sterically hindered aryl benzyl sulfides gave satisfying results. Subsequently, Katsuki and coworkers introduced chiral manganese(III)/salen [9] and ruthenium(II)/salen [10] (or salalen) [11] complexes as asymmetric sulfimidation catalysts. Excellent results were achieved, but the synthesis of salen ligands proved cumbersome.Inspired by the early work of Bach [5a,b] and encouraged by our findings that simple iron(II) and iron(III) compounds could effectively catalyze non-asymmetric sulfide imidations, [5h-j] we decided to focus our search on chiral iron complexes for asymmetric versions of such reactions. Herein, we report that iron(III)/PyBOX combinations are highly effective catalysts for the aforementioned transformations. Noteworthy, this is the first iron-catalyzed enantioselective sulfimidation reported to date, despite many other breakthroughs in asymmetric iron catalysis. [12,13] The asymmetric imidation of thioanisole (1 a) with N-(ptolylsulfonyl)imino phenyliodinane (PhI=NTs) in acetonitrile was selected as the benchmark reaction for our preliminary screening. Various catalysts formed in situ from chiral ligands and iron(III) acetylacetonate ([Fe(acac) 3 ], 3 a) were tested.

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Section: Methodsmentioning

confidence: 99%

“…Comparing the optical rotations of 2 n and 4 n with the respective reported values proved that the oxidation had proceeded with retention of configuration. [23] It was shown that the biological response significantly depended on the absolute configuration of the stereogenic sulfur atom. was 93:7.…”

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Enantioselective Nitrene Transfer to Sulfides Catalyzed by a Chiral Iron Complex

2013

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“…Angeregt durch die Entdeckung des N-Cyansulfoximins Sulfoxaflor (14) als neuen Wirkstoffs für den Pflanzenschutz wurde ebenfalls die Bioaktivität des N-Cyansulfoximins 47 untersucht, wobei sich signifikante, selektive, COX-2-inhibitorische Eigenschaften herausstellten. [51] Dies lçste die Synthese einer Reihe von N-Cyansulfoximinanaloga anderer bekannter Sulfon-COX-2-Inhibitoren aus. Die Enantiomere von N-Cyansulfoximin 49, einem Analogon von DuP697 (48; DuPont Merck), wiesen auffällige Unterschiede auf: Ein Enantiomer von 49 stellte sich als potenter und selektiver COX-2-Inhibitor heraus, während das andere Enantiomer eine relativ schwache COX-1-und COX-2-Inhibition zeigte.…”

Section: Cox-2-inhibitorenunclassified

Sulfoximine: Eine vernachlässigte Chance in der medizinischen Chemie

Lücking

2013

Angewandte Chemie

121

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Innovation ist häufig als der Schlüssel zur Wirkstoff‐Findung beschrieben worden. Doch in der täglichen Routine neigen Medizinalchemiker dazu, nur das Instrumentarium der funktionellen Gruppen und Strukturelemente zu verwenden, das sie bereits kennen und lieben. Das Blockbuster‐Krebsmedikament Velcade (Bortezomib) wurde beispielsweise von mehr als 50 Unternehmen abgelehnt, vermutlich wegen seiner ungewöhnlichen Boronsäuregruppe (“Only a moron would put boron in a drug!”). Auch im Entwicklungsprozess des pan‐CDK‐Inhibitors BAY 1000394 sorgte der unkonventionelle Vorschlag, eine Sulfoximingruppe in die Leitstruktur einzuführen, zunächst für Spott und Stirnrunzeln, da Sulfoximine selten in der medizinischen Chemie verwendet worden sind. Jedoch war es gerade die Sulfoximingruppe, die es schließlich ermöglichte, die fundamentalen Probleme des Projekts zu überwinden, und so zur Identifizierung des klinischen pan‐CDK‐Inhibitors BAY 1000394 führte. Der vorliegende Kurzaufsatz gibt einen Überblick über eine weithin vernachlässigte Chance in der medizinischen Chemie – die Sulfoximingruppe.

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“…[7] Furthermore, the research group of Bolm has reported several bioactive sulfoximines with potent COX inhibitory activity, antiproliferative activity, cellular toxicity, and mutagenicity. [8][9][10] However, isosteric replacement in which the sulfur-bonded oxygen atom of sulfonamides (9) and acyl sulfonamides (4) is replaced by a nitrogen atom, that is, to respectively yield sulfonimidamides (12) and acyl sulfonimidamides (14), have been only sparsely applied in the area of drug design. For example, in the last decade, the research groups of Dodd and Malarcia have used sulfonimidamide-containing substances in organic synthesis, [11][12][13][14][15][16] and a few reports, including patent applications, have indicated the utility of the sulfonimidamide functional group in bioactive molecules.…”

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Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties

et al. 2015

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Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa , lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

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N‐Cyano Sulfoximines: COX Inhibition, Anticancer Activity, Cellular Toxicity, and Mutagenicity

Cited by 92 publications

References 22 publications

Enantioselective Nitrene Transfer to Sulfides Catalyzed by a Chiral Iron Complex

Enantioselective Nitrene Transfer to Sulfides Catalyzed by a Chiral Iron Complex

Sulfoximine: Eine vernachlässigte Chance in der medizinischen Chemie

Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties

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