Synthesis and Reactions of Oxazolones from L‐Tryptophan and α‐Haloacetic Anhydrides

Bergman, Jan; Lidgren, Göran; Gogoll, Adolf

doi:10.1002/bscb.19921010712

Cited by 13 publications

(8 citation statements)

References 53 publications

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“…The strong oxidant DDQ was used here as the reagent for dehydration and oxidative couplings and cyclization reactions, which we postulate to be the main reactions in the production of FICZ from I3P. In this context, it should be noted that in the equilibrium between tautomers 1a and 1b the enol form ( 1a ) predominates and that in earlier studies the presence of the keto tautomer 1b could not be detected by NMR . It was thought that dehydrogenation of 1a with DDQ might yield the hypothetic product 2 , which in turn should undergo decarboxylation to the likewise hypothetical aldehyde 3 (Scheme ).…”

Section: Resultsmentioning

confidence: 96%

“…In this context, it should be noted that in the equilibrium between tautomers 1a and 1b the enol form (1a) predominates and that in earlier studies the presence of the keto tautomer 1b could not be detected by NMR. 51 It was thought that dehydrogenation of 1a with DDQ might yield the hypothetic product 2, which in turn should undergo decarboxylation to the likewise hypothetical aldehyde 3 (Scheme 1).…”

Section: ■ Resultsmentioning

confidence: 99%

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Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ

Смирнова¹,

Wincent

Bergander

et al. 2015

Chem. Res. Toxicol.

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108

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Activation of the aryl hydrocarbon receptor (AhR), a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobiotic-free conditions is of considerable scientific interest. We have demonstrated previously that a photoproduct of tryptophan, 6-formylindolo[3,2-b]carbazole (FICZ), fulfills the criteria for an endogenous ligand for this receptor and proposed that this compound is the enigmatic mediator of the physiological functions of AhR. Here, we describe novel light-independent pathways by which FICZ can be formed. The oxidant H2O2 was shown to convert tryptophan to FICZ on its own in the absence of light. The enzymatic deamination of tryptamine yielded indole-3-acetaldehyde (I3A), which then rearranged to FICZ and its oxidation product, indolo[3,2-b]carbazole-6-carboxylic acid (CICZ). Indole-3-pyruvate (I3P) also produced I3A, FICZ, and CICZ. Malassezia yeast species, which constitute a part of the normal skin microbiota, produce a number of AhR activators from tryptophan. We identified both FICZ and CICZ among those products. Formation of FICZ from tryptophan or I3P produces a complex mixture of indole derivatives, some of which are CYP1A1 inhibitors. These can hinder the cellular clearance of FICZ and thereby increase its power as an AhR agonist. We present a general molecular mechanism involving dehydrogenations and oxidative coupling for the formation of FICZ in which I3A is the important precursor. In conclusion, our results suggest that FICZ is likely to be formed systemically.

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Section: Resultsmentioning

confidence: 96%

Section: ■ Resultsmentioning

confidence: 99%

Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ

Смирнова¹,

Wincent

Bergander

et al. 2015

Chem. Res. Toxicol.

Self Cite

108

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“…The canthin-6-one alkaloids have been synthesized via different approaches by many researchers [2,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75]. In order to use these methods to guide our review more clearly, we categorized classic and efficient synthetic methods according to their key reaction steps.…”

Section: Chemistrymentioning

confidence: 99%

Fruitful Decades for Canthin-6-ones from 1952 to 2015: Biosynthesis, Chemistry, and Biological Activities

Dai

Wang

et al. 2016

Molecules

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Abstract:In this review, more than 60 natural canthin-6-one alkaloids and their structures are considered. The biosynthesis, efficient and classic synthetic approaches, and biological activities of canthin-6-one alkaloids, from 1952 to 2015, are discussed. From an analysis of their structural properties and an investigation of the literature, possible future trends for canthin-6-one alkaloids are proposed. The information reported will be helpful in future research on canthin-6-one alkaloids.

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“…A similar reaction sequence was extended to valine, isoleucine and tryptophan amino acids. Oxozolone formation, hydrolysis to the corresponding pyruvic acid derivatives, [55][56][57] aldolization with formalin, in the presence of K2CO3 and subsequent lactonization led to the formation of isotetrones 13 -15 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation inMycobacterium smegmatis

Bag

Pal

Basu

et al. 2022

Preprint

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Hyperphosphorylated guanosine nucleotide (p)ppGpp, synthesized by Rel proteins, regulates the stringent response pathway responsible for biofilm growth and persister cell formation in the stationary phase of mycobacteria. The discovery of vitamin C as a potent inhibitor of Rel protein activities raises the prospect of such a tetrone lactone to prevent biofilm growth and persister cell formation. The closely related isotetrone lactone derivatives are identified in the present study as potent inhibitors of the above processes in a mycobacterium. Isotetrone lactone derivatives are synthesized from appropriate α-ketocarboxylic acids, derived from the a-amino acids. Aldol condensation with formaldehyde, followed by the lactone formation, completes synthesis of isotetrone derivatives, possessing varied substituents atC-4 carbon, in good yields. A series of biochemical evaluations of biofilm growth and persister cell formation inM. smegmatisis conducted. Among the derivatives, isotetrone possessing phenyl substituent atC-4 carbon completely inhibit the biofilm formation at 400 μg mL-1concentration, 84 h of post-exposure, followed by a moderate inhibition by the isotetrone possessingp-hydroxyphenyl substituent. Whereas, the latter isotetrone inhibits the growth of cells at 400 μg mL-1f.c. when monitored for 2 weeks, under PBS starvation condition. Isotetrones also potentiate the inhibition of antibiotic tolerant regrowth of cells by ciprofloxacin antibiotic (0.75 μg mL-1) and thus act as bio-enhancers. The combination is shown to significantly arrest the emergence of ciprofloxacin-resistant genetic mutants. The observations suggest that isotetrones in combination with ciprofloxacin are therapeutically superior when administered together. Systematic molecular dynamics studies show that isotetrone derivative binds to Rel protein more efficiently than vitamin C and the binding is aided by hydrogen bonding, van der Waals and electrostatic interactions at a binding site possessing serine, threonine, lysine and arginine residues. The present study establishes that the identified isotetrone derivatives (i) act as inhibitors ofM. smegmatisbiofilm growth and (ii) arrest the re-emergence of recalcitrant persister cells when administered together with ciprofloxacin antibiotic. Results of this study establish that isotetrones as new chemical entities that interfere with stringent response pathways in a mycobacterium under stress and permit overcoming the multidrug-resistant persister cell emergence in the bacterium.

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Synthesis and Reactions of Oxazolones from L‐Tryptophan and α‐Haloacetic Anhydrides

Cited by 13 publications

References 53 publications

Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ

Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ

Fruitful Decades for Canthin-6-ones from 1952 to 2015: Biosynthesis, Chemistry, and Biological Activities

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation inMycobacterium smegmatis

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