Indolocarbazole protein kinase C inhibitors from rebeccamycin

Fabre, Serge; Prudhomme, Michelle; Sancelme, Martine; Rapp, Maryse

doi:10.1016/s0968-0896(00)82003-9

Cited by 16 publications

(16 citation statements)

References 19 publications

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“…Prior to determining the effect of the drugs on topoisomerase I, it is important to ascertain that the introduction of the halogenoacetyl moiety does not reactivate the anti-PKC activity. In the past we have observed occasionally that modification of the indolocarbazole chromophore not only affects topoisomerase I inhibition but, in some cases, can have a significant effect on the unwanted PKC activity. , The inhibitory properties toward PKC-α were tested using protamine sulfate as previously described . The IC 50 values are reported in Table .…”

Section: Resultsmentioning

confidence: 99%

“…The lead compound in the series is the synthetic derivative NB-506 which is currently undergoing clinical trials. − The antitumor antibiotic rebeccamycin (Chart ) isolated from cultures of Saccharotrix aerocolonigenes , is structurally close to NB-506, and it is also similar to protein kinase C inhibitors such as bacterial metabolites staurosporine and K-252a. However, rebeccamycin has no effect on protein kinase C . Its antitumor activity correlates with its ability to inhibit topoisomerase I …”

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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In the course of structure-activity relationships on rebeccamycin analogues, a series of compounds bearing a halogenoacetyl substituent were synthesized with the expectation of increasing the interaction with DNA, possibly via covalent reaction with the double helix. Two rebeccamycin analogues bearing an acetyl instead of a bromoacetyl substituent were prepared to gain an insight into the role of the halogen atom. The new compounds show very little effect on protein kinase C and no covalent reaction with DNA was detected. However, the drugs behave as typical topoisomerase I poisons, and they are significantly more toxic toward P388 leukemia cells than to P388/CPT5 cells resistant to camptothecin. The introduction of a bromo- or chloro-acetyl substituent does not affect the capacity of the drug to interfere with topoisomerase I either in vitro or in cells. One of the bromoacetyl derivatives, compound 8, is the most cytotoxic rebeccamycin derivative among the hundred of derivatives we have synthesized to date. In addition, we determined the antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis, and against the Gram-negative bacterium Escherichia coli. The effect of the drugs on Candida albicans yeast growth and their anti-HIV-1 activities were also measured.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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“…NMR results for these compounds showed similarity to reported values. 21,22) Bioconversion experiments with 8 or 9 as an added sample were done to conˆrm which was the real intermediate, but neither compound was converted to rebeccamycin. Presumably, in the rebC disruptants, the other oxidase enzymes recognize the real intermediate of rebC disruptants as a substrate and produce 8 and 9.…”

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confidence: 99%

Characterization of the Biosynthetic Gene Cluster of Rebeccamycin fromLechevalieria aerocolonigenesATCC 39243

Onaka¹,

Taniguchi²,

Igarashi³

et al. 2003

Bioscience, Biotechnology, and Biochemistry

113

124

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The biosynthetic gene cluster for rebeccamycin, an indolocarbazole antibiotic, from Lechevalieria aerocolonigenes ATCC 39243 has 11 ORFs. To clarify their functions, mutants with rebG, rebD, rebC, rebP, rebM, rebR, rebH, rebT, or orfD2 disrupted were constructed, and the gene products were examined. rebP disruptants produced 11,11'-dichlorochromopyrrolic acid, found to be a biosynthetic intermediate by a bioconversion experiment. Other genes encoded N-glycosyltransferase (rebG), monooxygenase (rebC), methyltransferase (rebM), a transcriptional activator (rebR), and halogenase (rebH). rebT disruptants produced rebeccamycin as much as the wild strain, so rebT was probably not involved in rebeccamycin production. Biosynthetic genes of staurosporine, an another indolocarbazole antibiotic, were cloned from Streptomyces sp. TP-A0274. staO, staD, and staP were similar to rebO, rebD, and rebP, respectively, all of which are responsible for indolocarbazole biosynthesis, But a rebC homolog, encoding a putative enzyme oxidizing the C-7 site of pyrrole rings, was not found in the staurosporine biosynthetic gene cluster. These results suggest that indolocarbazole is constructed by oxidative decarboxylation of chromopyrrolic acid (11,11'-dichlorochromopyrrolic acid in rebeccamycin) generated from two molecules of tryptophan by coupling and that the oxidation state at the C-7 position depends on the additional enzyme(s) encoded by the biosynthetic genes.

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“…Trichomonas vaginalis lacks de novo purine and pyrimidine synthesis pathways ( Harris et al, 1988 ; Miller and Lindstead, 1983 ), hence nucleobase metabolites may out-compete and impair nucleotide scavenging pathways that are essential for T. vaginalis survival ( Wright et al, 2010 ; Zang et al, 2005 ). Staurosporine and its active analogues K252A and 7-oxostaurosporine are indolocarbazoles, and proposed as broad protein kinase inhibitors ( Akanishi et al, 1986 ; Fabre et al, 1994 ; Omura et al, 1977 ). Thiolutin and aureothricin are structural analogues, inhibit RNA polymerases to halt RNA synthesis in fungi ( Jimenez et al, 1973 ; Tipper, 1973 ), with a similar MOA described against other eukaryotic systems.…”

Section: Resultsmentioning

confidence: 99%

TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries

Lam

Vuong²,

Jex

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Trichomonas vaginalis is a neglected urogenital parasitic protist that causes 170 million cases of trichomoniasis annually, making it the most prevalent non-viral, sexually transmitted disease. Trichomoniasis treatment relies on nitroheterocyclics, such as metronidazole. However, with increasing drug-resistance, there is an urgent need for novel anti-trichomonals. Little progress has been made to translate anti-trichomonal research into commercialised therapeutics, and the absence of a standardised compound-screening platform is the immediate stumbling block for drug-discovery. Herein, we describe a simple, cost-effective growth assay for T. vaginalis and the related Tritrichomonas foetus . Tracking changes in pH were a valid indicator of trichomonad growth ( T. vaginalis and T. foetus ), allowing development of a miniaturised, chromogenic growth assay based on the phenol red indicator in 96- and 384-well microtiter plate formats. The outputs of this assay can be quantitatively and qualitatively assessed, with consistent dynamic ranges based on Z′ values of 0.741 and 0.870 across medium- and high-throughput formats, respectively. We applied this high-throughput format within the largest pure-compound microbial metabolite screen (812 compounds) for T. vaginalis and identified 43 hit compounds. We compared these identified compounds to mammalian cell lines, and highlighted extensive overlaps between anti-trichomonal and anti-tumour activity. Lastly, observing nanomolar inhibition of T. vaginalis by fumagillin, and noting this compound has reported activity in other protists, we performed in silico analyses of the interaction of fumagillin with its molecular target methionine aminopeptidase 2 for T. vaginalis , Giardia lamblia and Entamoeba histolytica , highlighting potential for fumagillin as a broad-spectrum anti-protistal against microaerophilic protists. Together, this new platform will accelerate drug-discovery efforts, underpin drug-resistance screening in trichomonads, and contributing to a growing body of evidence highlighting the potential of microbial natural products as novel anti-protistals.

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Indolocarbazole protein kinase C inhibitors from rebeccamycin

Cited by 16 publications

References 19 publications

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

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

Characterization of the Biosynthetic Gene Cluster of Rebeccamycin fromLechevalieria aerocolonigenesATCC 39243

TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries

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