Isolation and synthesis of 3,4-bis(indol-3-yl)pyrrole-2,5-dicarboxylic acid derivatives from the slime mould Lycogala epidendrum

Fröde, Rita; Hinze, Claudia; Josten, Ingrid; Schmidt, Bettina; Steffan, Bert; Steglich, Wölfgang

doi:10.1016/0040-4039(94)88320-3

Cited by 79 publications

(39 citation statements)

References 5 publications

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“…To a solution of L-Trp (100 mg, 490 µmol) in 25 mM HEPES (pH 7.5, 250 mL) were added the crude cell extracts, and the mixture was incubated at 24°C for 16 h. After the reaction had been quenched with trifluoroacetic acid (TFA, 250 µL), the mixture was lyophilized and filtered. Two rounds of reversed phase HPLC using a Beckman System Gold (Beckman Coulter) (0 f 100% acetonitrile in 0.1% TFA; Vydac C18 small pore column, 250 mm × 22 mm, 10 mL/min) afforded pure CPA (4), which displayed spectral properties consistent with those in the literature (19):…”

Section: Aminomentioning

confidence: 58%

Enzymatic Generation of the Chromopyrrolic Acid Scaffold of Rebeccamycin by the Tandem Action of RebO and RebD

2005

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During the biosynthesis of the fused six-ring indolocarbazole scaffolds of rebeccamycin and staurosporine, two molecules of L-tryptophan are processed to a pyrrole-containing five-ring intermediate known as chromopyrrolic acid. We report here the heterologous expression of RebO and RebD from the rebeccamycin biosynthetic pathway in Escherichia coli, and tandem action of these two enzymes to construct the dicarboxypyrrole ring of chromopyrrolic acid. Chromopyrrolic acid is oxidized by six electrons compared to the starting pair of L-tryptophan molecules. RebO is an L-tryptophan oxidase flavoprotein and RebD a heme protein dimer with both catalase and chromopyrrolic acid synthase activity. Both enzymes require dioxygen as a cosubstrate. RebD on its own is incompetent with L-tryptophan but will convert the imine of indole-3-pyruvate to chromopyrrolic acid. It displays a substrate preference for two molecules of indole-3-pyruvic acid imine, necessitating a net two-electron oxidation to give chromopyrrolic acid.Rebeccamycin 1 and staurosporine 2 ( Figure 1) are indolocarbazole antibiotics originally isolated from the actinomycetes LecheValieria aerocolonigenes and Streptomyces longisporoflaVus, respectively. Rebeccamycin is an inhibitor of DNA topoisomerase I, with a minimum inhibitory concentration of 1.75 µM (1). Staurosporine is one of the strongest inhibitors of protein kinases, displaying an IC 50 of 2.7 nM for protein kinase C (2) and IC 50 's in the range of 1-20 nM for most protein kinases. Because of the importance of both the protein kinases and DNA topoisomerases in cell growth and proliferation, these two compounds have been extensively studied as antitumor drug candidates. Analogues of both rebeccamycin and staurosporine have entered clinical trials for the treatment of neoplastic tumors (3, 4), renal cell cancer (5), and leukemia (6).The fused six-ring indolocarbazole scaffold in 1 and 2 is representative of a variety of natural products and derived from the dimerization of two molecules of L-tryptophan (LTrp) 1 via a complex set of oxidative transformations (7-10) (Scheme 1). Since this natural product scaffold is featured in molecules with an interesting range of biological activities, there has been substantial interest in understanding the enzymology of the oxidative dimerization and ring fusion from the starting pair of L-Trp substrates. Subsequent N-glycosylation of the aglycone through the anomeric carbon of a glucose moiety (in the case of rebeccamycin) and through both C 1 and C 5 of L-ristosamine, the deoxyhexose sugar of staurosporine, followed by the action of methyltransferases (11), leads to the active natural products (Scheme 1). In the case of staurosporine, the enzymatic generation of the N-C linkage between one indole nitrogen and C5 of the aminodeoxyhexose is of notable interest as a novel transformation (11,12).The biosynthetic gene clusters for rebeccamycin and staurosporine have been sequenced and functionally expressed in the heterologous host Escherichia coli, validatin...

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Section: Aminomentioning

confidence: 58%

Enzymatic Generation of the Chromopyrrolic Acid Scaffold of Rebeccamycin by the Tandem Action of RebO and RebD

2005

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“…Thus, compound 2 was suggested to possess one indole and one 5-hydroxyindole moieties. As in case of compound 1, compound 2 bore a hydrogen atom on C-9 (d H 7.44, H-9), which was indicated by the HMBC correlations observed for H-9/C-8, H-9/C-9, and H-9/C-9Ј and the 1 H-1 H COSY cross peak between H-9 and NH-10 in acetone-d 6 solution. An NOE was observed between H-9 (d H 7.44) and H-4 (d H 7.64), thus suggesting that the indole ring without 5-OH group was attached on the adjacent position (C-8) to H-9 and the 5-hydroxyindole ring therefore present at the neighboring position (C-8Ј) to the methoxycarobonyl group.…”

Section: )mentioning

confidence: 95%

“…Cinereapyrrole B (2) had a molecular formula of C 22 6.63 (H-6Ј), and 7.19 (H-7Ј)], as possessed by compound 1, which was confirmed by the HMBC spectrum of 2 in acetone-d 6 observed for H-2Ј/C-3aЈ, H-2Ј/C-7aЈ, H-4Ј/C-3Ј, H-4Ј/C-6Ј, H-6Ј/C-4Ј, H-6Ј/C-7aЈ, H-7Ј/C-5Ј, H-7Ј/C-3aЈ, OH-5Ј/C-4Ј, OH-5Ј/C-5Ј, and OH-5Ј/C-6Ј. Thus, compound 2 was suggested to possess one indole and one 5-hydroxyindole moieties.…”

Section: )mentioning

confidence: 99%

New Bisindole Alkaloids Isolated from Myxomycetes Arcyria cinerea and Lycogala epidendrum

et al. 2005

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The myxomycetes (true slime molds) are an unusual group of primitive organisms that may be assigned to one of the lowest classes of eukaryotes.1) During our studies on search for bioactive natural products from myxomycetes, 2-4) we recently investigated a field-collected sample of fruit bodies of Arcyria cinerea and Lycogala epidendrum collected at Kochi prefecture. Here we describe isolation and structure elucidation of new bisindole alkaloids (1-5) along with seven known bisindoles (6-12), and their cytotoxic activity. Particularly, compound 12 was found to be cytotoxic against a panel of 39 human cancer cell lines. Results and DiscussionThe wild fruit bodies of Arcyria cinerea, collected in Kochi Prefecture, Japan, were extracted with 90% MeOH and 90% acetone. The combined extracts were separated by chromatographies on silica gel, ODS, and Sephadex LH-20 to give two new bisindole alkaloids, named cinereapyrrole A (1) and B (2), together with a known compound, arcyriarubin A (6), which was previously isolated from Arcyria denudata, 5) and Lycogala epedindrum. ], D Ϫ1.1 mmu). The UV spectrum of 1 showed absorption maximum at 283 nm, indicating the presence of conjugated system(s), while the IR absorption bands observed at 3396 and 1695 cm Ϫ1 implied the presence of hydroxy and conjugated carbonyl groups. The 1 H-NMR spectrum of 1 in CD 3 OD (Table 1) showed ten signals for nine aromatic protons and one methoxy group. The analysis of the 13 C-NMR (Table 2) and HMQC spectra of 1 clarified the presence of twenty two carbons including nine sp 2 methines, eleven sp 2 quaternary carbons, one methoxy (d C 51.3), and one carboxy or carboxy ester carbon (d C 163.6). By analysis of the suggested these carbons bore hydroxy groups. These NMR data were reminiscent of those of lycogarubin A (13), previously isolated from Lycogala epidendrum. 7) Lycogarubin A (13) was an symmetrical compound with one set of NMR signals, while NMR data of 1 implied that compound 1 was an unsymmetrical molecule. Another difference was the observation of an additional sp 2 proton observed at d H 7.29 (1H, s) in the 1 H-NMR of 1, which showed HMBC correlations to C-8, C-8Ј and C-9Ј. Thus, this additional hydrogen was placed on the C-9 position, while a methoxycarbonyl group was inferred to be attached on the C-9Ј position as in case of lycogarubin A (13); the methoxy protons at d H 3.65 (3H, s) showed an HMBC correlation to the ester carbonyl carbon (d C 163.6). An NOE correlation observed between H-9 and H-4 further confirmed the presence of a hydrogen atom at the C-9 position. The structure of cinereapyrrole A was therefore concluded as 1.Cinereapyrrole B (2) had a molecular formula of Two new bisindole alkaloids, named cinereapyrrole A (1) and B (2), were isolated from wild fruit bodies of Arcyria cinerea and three new bisindole alkaloids (3-5) were isolated from wild fruit bodies of Lycogala epidendrum. Seven known bisindoles (6-12) were concomitantly obtained from them. The structures of the new compounds were elucidated by spectral data. A...

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“…We identified six natural compounds as inhibitors of Hes1 dimer formation ( Fig. 7) with the following IC 50 values: lindbladione (5), 18,19) IC 50 , 4.1 mM isolated from the myxomycetes Lindbladia tubulina; two bisindole alkaloids, lycogarubin B (6), 20) 16.5 mM and lycogaric acid A (7), 21) 6.0 mM isolated from the myxomycetes Lycogala epidendrum; demethyl-2Љ-epifraxamoside (8), 22) 7.8 mM isolated from Jasminum grandiflorum; and, two lignan glycosids, lyoniside (9), 23) 48.1 mM and nudiposide (10), 24) 9.6 mM isolated from Saraca asoca. Compounds 5 to 7 are natural products isolated by the Ishibashi group from myxomycetes (true slime molds), which are an unusual group of primitive organisms that can be assigned to one of the lowest classes of eukaryotes.…”

Section: )mentioning

confidence: 99%

Approaches to Neural Stem Cells and Cancer Cells Based on Natural Products

Arai

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have developed "protein-and cell-based screen methods" for the isolation of new natural products. By using VDR (vitamin D receptor) immobilized magnetic beads, two new natural products were isolated rapidly. To find inhibitors of Hes1 protein, which is one of the important transcriptional factors in neural stem cells, a Hes1 dimer plate assay was developed, and then first Hes1 dimer inhibitors were found from our natural products library. As a "cell-based screen method," a reporter gene assay for screening Hh (hedgehog) signaling inhibitors was constructed. New Hh signaling inhibitors were isolated from our natural extracts library. We evaluated their Hh inhibitory activity in Hh related protein synthesis and cytotoxicity against cancers, in which Hh signaling is aberrantly activated. In addition to the naturally made compounds library (extracts library), "small molecules based on natural products" were synthesized. The total synthesis of Melleumin A, B, which were isolated by our group, was achieved. From their synthetic derivatives, inhibitors of the Wnt signal, which has been reported to cause colon cancers, were discovered. Moreover, flavanone and chromone were selected as natural product scaffolds. Many flavonoids and chromones with diverse heterocyclic units were constructed using our efficient synthetic method.

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Isolation and synthesis of 3,4-bis(indol-3-yl)pyrrole-2,5-dicarboxylic acid derivatives from the slime mould Lycogala epidendrum

Cited by 79 publications

References 5 publications

Enzymatic Generation of the Chromopyrrolic Acid Scaffold of Rebeccamycin by the Tandem Action of RebO and RebD

Enzymatic Generation of the Chromopyrrolic Acid Scaffold of Rebeccamycin by the Tandem Action of RebO and RebD

New Bisindole Alkaloids Isolated from Myxomycetes Arcyria cinerea and Lycogala epidendrum

Approaches to Neural Stem Cells and Cancer Cells Based on Natural Products

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