Dynemicin A, a novel antibiotic with the anthraquinone and 1,5-diyn-3-ene subunit.

Konishi, Masataka; Ohkuma, Hiroaki; Matsumoto, Kiyoshi; Tsuno, Takashi; Kamei, Hideo; Miyaki, Takeo; Oki, Taikan; Kawaguchi, Hiroshi; Vanduyne, Gregory D.; Clardy, Jon

doi:10.7164/antibiotics.42.1449

Cited by 310 publications

(173 citation statements)

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“…Most of actinomycetes producing enediyne antibiotics are also rare actinomycetes, such as Micromonospora strain which produce dynamicin and Actinomadura strain which produce maduropeptin. 45,46 The facts are supported by the appearance of PKSE gene with high frequency from rare actinomycetes ( Table 2). They are one of useful and attractive source of new bioactive compounds.…”

Section: Search For Novel Compound From Endophytic Actinomycetesmentioning

confidence: 74%

Endophytic actinomycetes: promising source of novel bioactive compounds

2017

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Endophytic actinomycetes associated with plant roots are a relatively untapped source of potential new bioactive compounds. This is becoming increasingly important, as the returns from discovery research on soil-dwelling microbes, have been continuously diminishing. We have isolated more than 1000 strains of actinomycetes from plant roots in our search for novel bioactive compounds, identified and assayed their bioactive metabolites, as well as investigated their biosynthetic genes for generating secondary metabolites. This has resulted in the discovery of several interesting compounds. Creation of plant root clone libraries enabled us to confirm that we had, indeed, isolated endophytes. In this paper, we introduce our approach to this promising line of research, incorporating data from other publications, and illustrate the potential that endophytic actinomycetes offer as a new source of novel lead compounds.

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Section: Search For Novel Compound From Endophytic Actinomycetesmentioning

confidence: 74%

Endophytic actinomycetes: promising source of novel bioactive compounds

2017

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“…The mass spectrum obtained by FIA-ESI-MS analysis of a mixture incubated at pH 8 revealed many ions containing dC 8 , most of which also contained up to three molecules of 1 per oligonucleotide ( Figure 1a). Although the wide range of adducts formed indicated that 1 readily bound the 2=-deoxycytidine-rich oligonucleotide under these conditions and provided confirmation that ESI-MS could be used to detect the incubation products, the resulting ions revealed little about the mode of binding.…”

Section: Resultsmentioning

confidence: 99%

“…Interactions Between 1 and dC 8 Armed with the previous results indicating that 2=-deoxycytidine-specific cleavage of the oligonucleotide-1 adduct was observed on heat treatment with piperidine [28,29], interactions between the enediyne and an all 2=-deoxycytidine oligonucleotide, dC 8 , were examined to determine whether or not the adducts could be isolated and studied. The mass spectrum obtained by FIA-ESI-MS analysis of a mixture incubated at pH 8 revealed many ions containing dC 8 , most of which also contained up to three molecules of 1 per oligonucleotide ( Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…ollowing the initial elucidation of the structure of the neocarzinostatin chromophore [1], much effort has been directed towards identifying additional natural enediynes and evaluating their activities [2][3][4][5]. Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10]. While these enediynes offer extremely high cytotoxic activities, their clinical use as anti-tumor agents has been limited due to their delayed activities and general toxicity [2][3][4][5].…”

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confidence: 99%

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Identification of the adduct between a 4-aza-3-ene-1,6-diyne and DNA using electrospray ionization mass spectrometry

Sherman

Pierce

Brodbelt

et al. 2006

J. Am. Soc. Mass Spectrom.

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The interactions between a novel enediyne [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium] (1) and various cytosine-containing oligonucleotides were studied using electrospray ionization mass spectrometry (ESI-MS) in a flow injection analysis mode useful for small volumes. This enediyne ligand, developed as a potential alternative to the highly cytotoxic natural enediynes, some of which have been successfully used as anti-tumor agents, has previously been shown to interact with DNA through frank strand scission as well as via the formation of adducts that lead to 2=-deoxycytidine-specific cleavage. Through ESI-MS, the structures of these adducts were examined and a sequence dependence of the 2=-deoxycytidine-specific cleavage was noted. Collisionally activated dissociation of the observed adducts confirmed the strength of the interactions between the enediyne and DNA and supports a direct linkage between the enediyne and the cytosine nucleobase, likely the result of a nucleophilic attack of the phenylethynyl group by the cytosine amine. , much effort has been directed towards identifying additional natural enediynes and evaluating their activities [2][3][4][5]. Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10]. While these enediynes offer extremely high cytotoxic activities, their clinical use as anti-tumor agents has been limited due to their delayed activities and general toxicity [2][3][4][5].To overcome the shortcomings of these natural enediynes, a range of synthetic analogs have been explored [3,11], each with the goal of improved properties for clinical use. While still capable of cleaving DNA like the natural products through cycloaromatization reactions and subsequent hydride abstraction by the diradical intermediate [2-4, 11, 12], these analogs offer potential advantages, such as more controlled activation of the compound in vivo [13][14][15][16][17][18][19][20][21][22][23] or increased selectivity for tumor cells [24 -30].To better evaluate the activities and properties of the many enediyne drug candidates as well as various other classes of drugs being developed, we present a technique for analyzing the interactions between these compounds and DNA using a flow injection analysis (FIA) mode coupled to an electrospray ionization mass spectrometer (ESI-MS). This analysis offers several key advantages over the traditional gel-based electrophoretic techniques. First, the dramatically better resolution of mass spectrometry versus polyacrylamide gel electrophoresis (PAGE) allows differentiation of similarly sized species, enabling the detection of very small molecules adducted to DNA. Second, while gel electrophoresis typically requires micrograms of sample, with our FIA method, a mass spectrum can easily be collected with nanograms, a sensitivity advantage of up to three orders of magnitude. Lastly, FIA-ESI-MS is easily adaptable to high-throughput analyses [31][32][33].In recent y...

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“…1 These moieties are found to be integral parts of highly potent antitumor, 2 and antifungal agents, 3 and first line components of antiretroviral therapy. 4 Terbinafine (Lamisil™) 3 is one example of an enyne derivative in clinical use.…”

Section: Introductionmentioning

confidence: 99%