Sulfoximine: Eine vernachlässigte Chance in der medizinischen Chemie

Abstract

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.

Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates

“…Moreover,t he sulfoximine group has dual hydrogen-bond donor/acceptor functionality,b ut significantly decreased basicity. [6,17] The required sulfoximine building block 4 was synthesized in four steps from thiomorpholine. Thus, the amino group was first conveniently protected by reactionw ithb enzylc hloroformate (CbzCl).…”

“…Overall, these new resultsf urthers upport the earlier recommendation that the sulfoximine moiety be added to the medicinal chemist's toolbox, thus broadening the chemical repertoire in small-molecule drug discovery to tackle biological targets in an even more multifaceted manner. [6] Accordingly,f urther innovations in sulfoximines ynthetic methodology,a long with as ignificant increase in commercials ulfoximine building blocks, would help to accelerate the field of sulfoximines as pharmacophores in the life sciences.…”

“…[5] However,u ntil very recently,t he sulfoximine group has rarely been employed in drug discovery applications, even though it offers au nique combination of interesting properties, namely high chemicala nd metabolic stability, favorable physicochemical properties, hydrogen-bond acceptor/donor functionalities, and structurald iversity. [6] To date, there is no approved drug containing as ulfoximine group and the number of sulfoximine compounds evaluated in clinicalt rials has been very limited. A similar pictureh as emergedi nc rop protection applications; however, use of the sulfoximine insecticide sulfoxaflor wasa p-provedin2 013.…”

“…Even though the interestw as rather limited for many decades, research has been conducted in which the sulfoximine group was used in opportunistic approaches to replace as urprising variety of functional groups including alcohol, acid, amidine, sulfone, ands ulfonamide moieties. [6] Very recently,the physicochemical properties and behavior in selected in vitro assays of as et of small and fragment-like sulfoximines in comparisonw ith related sulfur-based analogues and amides has been reported. [17] To overcome the limitations of analyzing such small and fragment-like compounds,t hat study also contained am atched molecularp air analysis of sulfoximinesa nd relatedc ompounds from drug discovery projects at Boehringer Ingelheim.…”

Light‐Induced Ruthenium‐Catalyzed Nitrene Transfer Reactions: A Photochemical Approach towards N‐Acyl Sulfimides and Sulfoximines

“…[1,2] Some of those products showed relevant biological properties in crop protection [3] and medicinal chemistry. [4] Our interest has been focused on the application of such sulfur reagents in asymmetric catalysis. [5] For most synthetic approaches towards sulfimides and sulfoximines, sulfur imidations of sulfides and sulfoxides, respectively, are key transformations, and consequently several protocols have been developed.…”