AT2433-A1, AT2433-A2, AT2433-B1, and AT2433-B2 novel antitumor antibiotic compounds produced by Actinomadura melliaura. Taxonomy, fermentation, isolation and biological properties.

Matson, James A.; Claridge, C. A.; Bush, James; Titus, Jeffery; Bradner, William T.; Doyle, Terrence W.; Horan, Ann C.; Patel, Mahesh

doi:10.7164/antibiotics.42.1547

Cited by 61 publications

(43 citation statements)

References 7 publications

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“…[1][2][3] The first class, exemplified by rebeccamycin from Saccharothrix aerocolonigenes (Scheme 1, 1), carry a single bglycoside, [4] or disaccharide as in AT2433 from Actinomadura melliaura (Scheme 1, 2), [5] the sugar constituents of which are critical for their potent topoisomerase I poisoning effects and ultimate antineoplastic effects. [6][7][8][9][10][11][12][13] The mechanism by which 1 inhibits topoisomerase I, by stabilization of the topoisomerase-DNA covalent complex, is reminiscent of that of the camptothecins.…”

Section: Introductionmentioning

confidence: 99%

“…To examine the dependence of RebM on metal divalent ions, EDTA (1 mm final concentration) or divalent metal (CaCl 2 , CoCl 2 , CuCl 2 , FeCl 2 , MgCl 2 , MnCl 2 , NiSO 4 , and ZnCl 2 , 1 mm final concentration) were added to the assay. Under the conditions adopted for kinetic determinations-RebM (100 nm) was used in the assay with fixed SAM (200 mm) and variable 19 (4, 6, 10, 15, and 20 mm) or with fixed 19 (20 mm) and variable SAM (5,10,20,50, and 100 mm)-the initial (first 5 min) velocity was linear. For structural elucidation, the preparative reaction of 19 with RebM was proportionately scaled up to 10 mL (50 mm 19, 100 mm SAM, 10 mm RebM) or 4 mL for 33/34.…”

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confidence: 99%

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RebG‐ and RebM‐Catalyzed Indolocarbazole Diversification

Zhang¹,

Albermann

Fu³

et al. 2006

ChemBioChem

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Rebeccamycin and staurosporine represent two broad classes of indolocarbazole glycoside natural products with antitumor properties. Based upon previous sequence annotation and in vivo studies, rebG encodes for the rebeccamycin N-glucosyltransferase, and rebM for the requisite 4'-O-methyltransferase. In the current study, an efficient in vivo biotransformation system for RebG was established in both Streptomyces lividans and Escherichia coli. Bioconversion experiments revealed RebG to glucosylate a set of indolocarbazole surrogates, the products of which could be further modified by in vitro RebM-catalyzed 4'-O-methylation. Both RebG and RebM displayed substrate promiscuity, and evidence for a remarkable lack of RebG regioselectivity in the presence of asymmetric substrates is also provided. In the context of the created indolocarbazole analogues, cytotoxicity assays also highlight the importance of 4'-O-methylation for their biological activity.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

RebG‐ and RebM‐Catalyzed Indolocarbazole Diversification

Zhang¹,

Albermann

Fu³

et al. 2006

ChemBioChem

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“…Morphological and cultural characters of the selected actinomycetes strain was studied by inoculating into sterile International Streptomycetes Project ISP 1,3-7,9 media (Matson et al, 1989;Ohshima et al, 1991). The media were sterilized and poured into sterile petridishes.…”

Section: Morphological Characterization Cultural Characterizationmentioning

confidence: 99%

Screening, isolation and purification of antibacterial agents from marine actinomycetes

Attimarad¹,

Ediga

Karigar³

et al. 2012

Int Curr Pharm J

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As marine environmental conditions are extremely different from terrestrial ones, it is surmised that marine actinomycetes might produce novel bioactive compounds. Hence marine sediments, collected from the coastal areas of Gokharna and Muradeshwara of Karnataka state, were screened Seventeen isolates were obtained on starch-casein agar media by soil dilution technique. However, only six isolates namely ACT-A2, ACT-A3, ACT-A4, ACT-A5, ACT-A7 and ACT-A15 showed significant antibacterial activity against both gram-positive and gram-negative bacteria. Morphological, cultural and biochemical characterization indicated that the isolates belong to Streptomyces genus of Actinomycetes. Further studies were carried out with the most active ACT-A2. Optimization of media, temperature and pH by shake flask fermentation indicated starch-casein, 28°C and 7 to be suitable for ACT-A2. The production of antibiotics began after 24 h, reached maximum at 72 h and maintained at the same level up to 120 h. Ethyl acetate was used to extract antibacterial compounds from the culture filtrate. TLC was done on silica gel using ethyl acetate: methanol (6:4) and direct bioautography has shown the presence of two active substance, one with Rf 0.8 has more activity than the other with Rf 0.4. Further purification is done by column chromatography using a mixture of dicholoromethane and ethyl acetate. The findings from this investigation reveal that the strain ACT-A2 in order exhibited superior antimicrobial activities to other sediment isolates of actinomycetes.DOI: http://dx.doi.org/10.3329/icpj.v1i12.12448 International Current Pharmaceutical Journal 2012, 1(12): 394-402

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“…In both cases, the large heterocyclic ring system is substituted by a unique disaccharide consisting of a methoxyglucose and an aminosugar subunit, 2,4-dideoxy-4-methylamino-L-xylose. These two antibiotics were first isolated in 1989 (Golik et al, 1989;Matson et al, 1989) and their total synthesis was accomplished 10 years later (Chisholm et al, 1999;Chisholm and Van Vranken, 2000) but their mechanism of action remains largely unknown.…”

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DNA Binding and Topoisomerase I Poisoning Activities of Novel Disaccharide Indolocarbazoles

et al. 2002

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The antibiotics AT2433-A1 and AT2433-B1 are two indolocarbazole diglycosides related to the antitumor drug rebeccamycin known to stabilize topoisomerase I-DNA complexes. This structural analogy prompted us to explore the binding of four indolocarbazole diglycosides with DNA and their capacity to interfere with the DNA cleavage-reunion reaction catalyzed by topoisomerase I. The molecular basis of the drug interaction with double-stranded DNA and with purified chromatin, with particular emphasis on the role of the carbohydrate moiety, was investigated by means of complementary spectroscopic techniques, including surface plasmon resonance and electric linear dichroism. We compared the DNA binding properties, sequence recognition, and effects on topoisomerase I-mediated DNA relaxation and cleavage of AT2433-A1 bearing a 2,4-dideoxy-4-methylamino-L-xylose residue, its dechlorinated analog AT2433-B1, the diastereoisomer iso-AT2433-B1 with an inverted aminosugar residue, and compounds 5H-indolo [2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione, 12-␤-D-glucopyranosyl-12,13-dihydro-6-methyl (JDC-108) and 5H-indolo[2,3-a]pyrrolo[3, 4-c]carbazole-5,7(6H)-dione, 12-(6-O-␣-D-galacto-pyranosyl-␤-Dglucopyranosyl)-12,13-dihydro-6-methyl (JDC-277) with an uncharged mono-and disaccharide, respectively. The two antibiotics AT2433-A1 and AT2433-B1 proved to be highly cytotoxic to leukemia cells and this may be a consequence of their tight intercalative binding to DNA, preferentially into GC-rich sequences as inferred from DNase I footprinting studies and surface plasmon resonance measurements. Like the diastereoisomer iso-AT2433-B1, they have no inhibitory effect on topoisomerase I, in contrast to the uncharged diglycoside JDC-277, which stimulates DNA cleavage by the enzyme mainly at TG sites, as observed with camptothecin. Cytotoxicity measurements with CEM and CEM/C2 human leukemia cell lines sensitive and resistant to camptothecin, respectively, also suggested that topoisomerase I contributes, at least partially, to the mechanism of action of the neutral diglycoside JDC-277 but not to that of the cationic AT2433 compounds. Together, the results indicate that sequence-selective DNA interaction and topoisomerase I inhibition is controlled to a large extent by the stereochemistry of the diglycoside moiety.

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AT2433-A1, AT2433-A2, AT2433-B1, and AT2433-B2 novel antitumor antibiotic compounds produced by Actinomadura melliaura. Taxonomy, fermentation, isolation and biological properties.

Cited by 61 publications

References 7 publications

RebG‐ and RebM‐Catalyzed Indolocarbazole Diversification

RebG‐ and RebM‐Catalyzed Indolocarbazole Diversification

Screening, isolation and purification of antibacterial agents from marine actinomycetes

DNA Binding and Topoisomerase I Poisoning Activities of Novel Disaccharide Indolocarbazoles

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