Short and Convergent Synthesis of Asterriquinone B1 and Demethylasterriquinone B1

Tatsuta, Kuniaki; Mukai, Hiroshi; Mitsumoto, Kazuki

doi:10.7164/antibiotics.54.105

Cited by 20 publications

(14 citation statements)

References 7 publications

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“…Preechinulin (5) [17][18][19][20][21] was synthesized starting from isoprenyl L-tryptophan derivative 15a (Chart 4). Deprotection of N-phthaloyl group in 15a [22][23][24] with hydrazine and coupling of the resulting amine with N-Boc-L-Ala gave 16a. Deprotection of N-Boc group in 16a and thermal cyclization afforded preechinulin (5).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Kuramochi

Ohnishi

Fujieda

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Peroxynitrite (ONOO), is a potent oxidant that can cause severe cell damage.1) Specifically, peroxynitrite promotes the oxidation of biomolecules such as lipids, proteins and nucleic acids, [2][3][4] as well as the nitration of tyrosine residues in proteins. 5,6) Furthermore, it has been suggested that peroxynitrite formation plays a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. [7][8][9] Neoechinulin A (1), an isoprenyl indole alkaloid, can protect neuronal PC12 cells from ONOO Ϫ -induced death. [10][11][12] We have previously shown that the biological effects, rather than scavenging activity against ONOO Ϫ , are likely to play a role in the cytoprotective action of neoechinulin A.12) However, the precise molecular mechanism remains elusive. To investigate the potential mechanism of action, we have designed and prepared a series of neoechinulin A analogues (2-6). We then examined the structure-activity relationships of these analogues in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against ONOO Ϫ derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells (Fig. 1). The results showed that: 1) the presence of the C-8/C-9 double bond is indispensable for anti-nitration and anti-oxidant activities as well as cytoprotective activity of neoechinulin A against ONOO Ϫ toxicity; 2) in conjunction with the C-8/C-9 double bond, the presence of an intact diketopiperazine moiety is essential for the anti-nitration activity but not for antioxidant or cytoprotective activity. Results and DiscussionCompound 2 was synthesized from 2-tert-butyl-1H-indole (7) 13) (Chart 1). Methoxy methyl (MOM) protection of 7, followed by the Vilsmeier reaction, gave aldehyde 9. A coupling reaction of the aldehyde 9 with diketopiperazine 10 using tBuOK in DMF afforded 11.14) Subsequent deprotection of protective groups provided the desired product 2. 15)Compound 3 was prepared by coupling of aldehyde 12 with N-Boc-Gly-OEt, followed by treatment of the resulting We synthesized a series of neoechinulin A derivatives and examined the structure-activity relationships in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against peroxynitrite from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells. Our results showed that the C-8/C-9 double bond, which constitutes a conjugate system with indole and diketopiperazine moieties of neoechinulin A is essential for anti-nitration and anti-oxidant activities as well as protection against SIN-1 cytotoxicity. The presence of an intact diketopiperazine moiety is an additional requirement for anti-nitration activity but not for the cytoprotective action. Our results suggest that the antioxidant activity or electrophilic nature of the C-8 carbon, both of which are afforded by the C-8/C-9 double bond, may play a role in the cytoprotective properties of this alkaloid.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Kuramochi

Ohnishi

Fujieda

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The reactionh as been successfully used as ak ey step in the total synthesis of the indole alkaloids gypsetin, [5] (+ +)-ambiguine H, [5] and asterriquinoneB1. [6] An alternative approachi st he Cope rearrangement reaction [Scheme 1, Eq. (2)].…”

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confidence: 99%

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

Chen

Fan

Zhang

et al. 2015

Chemistry A European J

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An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza-Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2-reverse prenylated indoles, such as indolines, indole-fused sultams and lactams, and the natural product bruceolline D.

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“…During a screen for insulin receptor agonists, either molecule was identified as hit, yet didemethylasterriquinone B1 being two orders of magnitude more active (Zhang et al, 1999). Access to asterriquinones relies either on synthetic chemistry (Liu et al, 1999;Tatsuta et al, 2001;Pirrung et al, 2005) or on a recently published chemoenzymatic route to DDAQ D (Schneider et al, 2007). With the imminent release of more fungal genomes, and those already available, the number of prenyltransferase genes should exceed a threshold to create a multi-enzyme collection to further diversify asterriquinones by prenylation in vitro.…”

Section: Heterologous Protein Expression and Enzyme Characterizationmentioning

confidence: 98%

The Aspergillus nidulans enzyme TdiB catalyzes prenyltransfer to the precursor of bioactive asterriquinones

Schneider

Weber

Hoffmeister

2008

Fungal Genetics and Biology

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Short and Convergent Synthesis of Asterriquinone B1 and Demethylasterriquinone B1

Cited by 20 publications

References 7 publications

Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

The Aspergillus nidulans enzyme TdiB catalyzes prenyltransfer to the precursor of bioactive asterriquinones

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