Syntheses and Biological Activities of Rebeccamycin Analogues. Introduction of a Halogenoacetyl Substituent

Moreau, Pascale; Anizon, Fabrice; Sancelme, Martine; Prudhomme, Michelle; Bailly, Christian; Sevère, Danièle; Riou, Jean‐François; Fabbro, Doriano; Meyer, Thomas; Aubertin, Anne-Marie

doi:10.1021/jm980396d

Cited by 51 publications

(49 citation statements)

References 27 publications

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“…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.…”

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confidence: 99%

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

2005

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“…Tryptophan dimers (or bisindoles) are a structurally and functionally diverse class of natural products (29). The best studied of these are the indolocarbazoles staurosporine and rebeccamycin, which are kinase and topoisomerase inhibitors, respectively (30,31). One very potent, but to date rarely encountered, and therefore underexplored, family of tryptophan dimers is the indolotryptolines.…”

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Yeast homologous recombination-based promoter engineering for the activation of silent natural product biosynthetic gene clusters

Montiel

Kang

Chang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Large-scale sequencing of prokaryotic (meta)genomic DNA suggests that most bacterial natural product gene clusters are not expressed under common laboratory culture conditions. Silent gene clusters represent a promising resource for natural product discovery and the development of a new generation of therapeutics. Unfortunately, the characterization of molecules encoded by these clusters is hampered owing to our inability to express these gene clusters in the laboratory. To address this bottleneck, we have developed a promoter-engineering platform to transcriptionally activate silent gene clusters in a model heterologous host. Our approach uses yeast homologous recombination, an auxotrophy complementation-based yeast selection system and sequence orthogonal promoter cassettes to exchange all native promoters in silent gene clusters with constitutively active promoters. As part of this platform, we constructed and validated a set of bidirectional promoter cassettes consisting of orthogonal promoter sequences, Streptomyces ribosome binding sites, and yeast selectable marker genes. Using these tools we demonstrate the ability to simultaneously insert multiple promoter cassettes into a gene cluster, thereby expediting the reengineering process. We apply this method to model active and silent gene clusters (rebeccamycin and tetarimycin) and to the silent, cryptic pseudogene-containing, environmental DNA-derived Lzr gene cluster. Complete promoter refactoring and targeted gene exchange in this "dead" cluster led to the discovery of potent indolotryptoline antiproliferative agents, lazarimides A and B. This potentially scalable and cost-effective promoter reengineering platform should streamline the discovery of natural products from silent natural product biosynthetic gene clusters.promoter engineering | indolotryptoline | environmental DNA

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“…Many of the biological effects of Violaceinare related to its ability to interfere with enzyme activities such as phosphatases [44]. Antimicrobial potential of Violacein may also come from its ability to act as a potent inhibitor of DNA topoisomerase [45] and protein kinases [46]. The three extracts of M. hexandra found effective against planktonic form of S. mutans were subjected to HPLC for generating their chromatographic fingerprint.…”

Section: Discussionmentioning

confidence: 99%

In vitro Antibacterial Activity of <i>Manilkara hexandra</i> (Sapotaceae) Seed Extracts and Violacein against Multidrug Resistant <i>Streptococcus mutans

Patel¹,

Ali²,

Nair³

et al. 2015

JNR

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Ipomoea reniformis Chaos is claimed in Indian traditional medical practice to be useful in the treatment of epilepsy and neurological disorders. In the present study, pretreatment effect of methanolic extract of Ipomoea reniformis on epilepsy and psychosis was evaluated in rodents using standard procedures. Besides evaluating epileptic and behavioral parameters, neurotransmitters such as Gamma-Amino Butyric Acid (GABA) in epilepsy and in psychosis dopamine, noradrenaline and serotonin contents in the rodent brain were estimated. The extract pretreatment reduced maximal electro shock; Isoniazid (INH) and Pentylenetetrazole (PTZ) induced seizures and also significantly inhibited the attenuation of brain GABA levels by INH and PTZ in mice. These results suggested that the observed beneficial effect in epilepsy may be by enhancing the GABAergic system. The test drug also inhibited the apomorphine induced climbing and stereotyped behavior and showed significantly reduced levels of brain dopamine, noradrenaline and serotonin which may be due to blocking of central dopaminergic, noradrenergic and serotonergic pathways or by enhancing the GABAergic system. The results obtained in present study suggest that the title plant possesses antiepileptic and antipsychotic activities in rodents.

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Syntheses and Biological Activities of Rebeccamycin Analogues. Introduction of a Halogenoacetyl Substituent

Cited by 51 publications

References 27 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

Yeast homologous recombination-based promoter engineering for the activation of silent natural product biosynthetic gene clusters

In vitro Antibacterial Activity of <i>Manilkara hexandra</i> (Sapotaceae) Seed Extracts and Violacein against Multidrug Resistant <i>Streptococcus mutans

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