Biomimetic syntheses of indole alkaloids. 11. Syntheses of .beta.-carboline and indoloazepine intermediates

Most studies of protein oxidation have typically focused on the reactivity of single amino acid side chains while ignoring the potential importance of adjacent sequences in directing the reaction pathway. We previously showed that hypochlorous acid (HOCl), a specific product of myeloperoxidase, inactivates matrilysin by modifying adjacent tryptophan and glycine (WG) residues in the catalytic domain. Here, we use model peptides that mimic the region of matrilysin involved in this reaction, VVWGTA, VVWATA and the library VVWXTA, to determine whether specific sequence motifs are targeted for chlorination or oxygenation by myeloperoxidase. Our results demonstrate that HOCl generated by myeloperoxidase or activated neutrophils converts the peptide VVWGTA to a chlorinated product, WG+32(Cl). Tandem mass spectrometry in concert with high resolution 1 H and two-dimensional NMR analysis revealed that the modification required crosslinking of the tryptophan to the amide of glycine followed by chlorination of the indole ring of tryptophan. In contrast, when glycine in the peptide was replaced with alanine, the major products were mono-and di-oxygenated tryptophan residues. When the peptide library VVWXTA (where X represents all 20 common amino acids) was exposed to HOCl, only WG produced a high yield of the chloroindolenine derivative. However, when glycine was replaced by other amino acids, oxygenated tryptophan derivatives were the major products. Our observations indicate that WG may represent a specific sequence motif in proteins that is targeted for chlorination by myeloperoxidase.

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“…The loss of NH resonance (Fig. 6B, Inset) suggests the formation of a chloroindolenine (46)(47)(48)(49)(50)(51).…”

Section: Nmr Analysis Indicates That M+32(cl) Is a Cross-linked Chlormentioning

confidence: 99%

Specific Sequence Motifs Direct the Oxygenation and Chlorination of Tryptophan by Myeloperoxidase

Wang

Kao

et al. 2006

Biochemistry

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“…5,6-Methylenedioxytryptamine (1216) condensed with methyl chloropyruvate to give tetrahydro-β-carboline (81%), which was transformed almost quantitatively to azepine 1217 using essentially Kuehne's protocol 99 (heating in pyridine followed by a reduction with NaBH 3 CN). A reaction of 1217 with the unsaturated ketone 1207 yielded an acrylate (69%), whose internal [4+2] cycloaddition in refluxing toluene was much more efficient (as compared to 1208) and provided anilino acrylate 1218 in a yield as high All attempts to cleave by ozonolysis double bond in indoline 1219 as well as in formamide 1220 met with no success, as did almost all other methods resulting in the formation of tarry products 98 , Scheme 41.…”

Section: Scheme 39mentioning

confidence: 99%

Recent developments in syntheses of the post-secodine indole alkaloids. Part III: Rearranged alkaloid types

Hájíček¹

2011

Collect. Czech. Chem. Commun.

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The third part of a planned review on developments in the field of total and formal total synthesis of the post-secodine indole alkaloids focuses on types of rearranged alkaloids, i.e. on the skeletons with altered connectivities next to the indol(e)ine moiety, especially with a new bond to N-1. It reviews the synthesis of melodane, goniomitine, chippiine/dippinine, lirofoline and tronocarpine alkaloids, as well as alkaloids of secoschizozygane/vallesamidine, schizozygane and isoschizozygane type. It covers the literature from approximately 1991 up to May 2011. A review with 115 references.

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“…Special attention is drawn to the fact that in an acidic medium the derivative 29 rearranges to the indoxyl derivative 30; in an alkaline medium processes leading to the formation of chloropyrimido[1,6-a]indole 31, the imidic ether 32, and oxindole 28 occur; the latter is also formed by treatment of the indole 31 with sodium methoxide (the formation of the imidic ether 32) followed by acid hydrolysis. It is worth mentioning that during an attempt at chromatographic purification of the N(2)-benzyl9b-chloroindolenine of type 24 on silica gel it underwent recyclization to the corresponding 2-benzyl-5-chloro-1,2,3,4-tetrahydropyrimido[1,6-a]indole [59]. …”

Section: Recyclizations With the Participation Of The Piperideine Ringmentioning

confidence: 99%

γ-Carbolines and their hydrogenated derivatives 3.* Hydrogenated derivatives of γ-carbolines: chemical and biological poperties (Review)

Alekseyev

Kurkin

Yurovskaya

2011

Chem Heterocycl Comp

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Biomimetic syntheses of indole alkaloids. 11. Syntheses of .beta.-carboline and indoloazepine intermediates

Abstract: The preparation and rearrangement of a-carbomethoxy-a-lchloromethylltetrahydro-d-carbolines (9a,b) provided methyl l,2,3,6-tetrahydroazepino[4,5-6]indole-5-carboxylates (10a,b) and derivatives, which serve as intermediates in a series of alkaloid syntheses.

Cited by 41 publications

References 3 publications

Specific Sequence Motifs Direct the Oxygenation and Chlorination of Tryptophan by Myeloperoxidase

Specific Sequence Motifs Direct the Oxygenation and Chlorination of Tryptophan by Myeloperoxidase

Recent developments in syntheses of the post-secodine indole alkaloids. Part III: Rearranged alkaloid types

γ-Carbolines and their hydrogenated derivatives 3.* Hydrogenated derivatives of γ-carbolines: chemical and biological poperties (Review)

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