N-arylated α-amino acids and pyrazolidin-3-ones are widely being used as chiral building blocks for pharmaceuticals and agrochemicals. Here we report a biocatalytic route for the asymmetric synthesis ...of various N-arylated aspartic acids applying ethylenediamine-N,N′-disuccinic acid lyase (EDDS lyase) as a biocatalyst. This enzyme shows a broad substrate scope, enabling the addition of a variety of arylamines to fumarate with high conversions, yielding the corresponding N-arylated aspartic acids in good isolated yields and with high enantiomeric excess (ee > 99%). Furthermore, we developed a chemoenzymatic method toward the synthetically challenging chiral 2-aryl-5-carboxylpyrazolidin-3-ones, using arylhydrazines as bis-nucleophilic donors in the EDDS lyase catalyzed hydroamination of fumarate followed by an acid-catalyzed intramolecular amidation, achieving good overall yields and high optical purity (ee > 99%). In addition, we successfully combined the EDDS lyase catalyzed hydroamination and acid-catalyzed cyclization steps in one pot, thus providing a simple chemoenzymatic cascade route for synthesis of enantiomerically pure pyrazolidin-3-ones. Hence, these biocatalytic methods provide convenient alternative routes to important chiral N-arylated aspartic acids and difficult 2-aryl-5-carboxylpyrazolidin-3-ones.
N-Substituted l-aspartic acids are important chiral building blocks for pharmaceuticals and food additives. Here we report the asymmetric synthesis of various N-arylalkyl-substituted l-aspartic acids ...using ethylenediamine-N,N'-disuccinic acid lyase (EDDS lyase) as a biocatalyst. This C-N lyase shows a broad non-natural amine substrate scope and outstanding enantioselectivity, allowing the efficient addition of structurally diverse arylalkylamines to fumarate to afford the corresponding N-arylalkyl-substituted l-aspartic acids in good isolated yield (up to 79%) and with excellent enantiopurity (>99% ee). These results further demonstrate that C-N lyases working in reverse constitute an extremely powerful synthetic tool to prepare difficult noncanonical amino acids.
Aspartic acid derivatives with branched N‐alkyl or N‐arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst ...to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N‐substituted aspartic acids, including N‐(3,3‐dimethylbutyl)‐l‐aspartic acid and N‐3‐(3‐hydroxy‐4‐methoxyphenyl)propyl‐l‐aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine‐N,N′‐disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C–N lyase (mutant D290M/Y320M) displayed a remarkable 1140‐fold increase in activity for the selective hydroamination of fumarate compared to that of the wild‐type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step‐economic synthesis of an important class of food additives.
Sweet! The enzyme ethylenediamine‐N,N′‐disuccinic acid lyase was optimized by structure‐guided mutagenesis for the enantioselective synthesis of challenging N‐substituted aspartic acids, which are important chiral precursors to artificial dipeptide sweeteners such as neotame and advantame. This redesigned C–N lyase displayed a remarkable 1140‐fold increase in activity for selective hydroamination of fumarate.
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Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel ...activity. Small-conductance calcium-activated potassium (SK/KCa) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance.
Aspartic acid derivatives with branched N‐alkyl or N‐arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst ...to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N‐substituted aspartic acids, including N‐(3,3‐dimethylbutyl)‐l‐aspartic acid and N‐3‐(3‐hydroxy‐4‐methoxyphenyl)propyl‐l‐aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine‐N,N′‐disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C–N lyase (mutant D290M/Y320M) displayed a remarkable 1140‐fold increase in activity for the selective hydroamination of fumarate compared to that of the wild‐type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step‐economic synthesis of an important class of food additives.
Süß! Das Enzym Ethylendiamin‐N,N′‐Dibernsteinsäure‐Lyase wurde durch strukturgelenkte Mutagenese für die enantioselektive Synthese von anspruchsvollen N‐substituierten Asparaginsäuren optimiert, die wichtige chirale Vorläufer für künstliche Dipeptid‐Süßstoffe wie Neotam und Advantam sind. Diese neu entwickelte C‐N‐Lyase zeigte einen bemerkenswerten 1140‐fachen Anstieg der Aktivität für die selektive Hydroaminierung von Fumarat.
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