PRELIMINARY COMMUNICATION The Novel Bis(benzoxazole) Cytotoxic Natural Product UK-1 Is a Magnesium Ion-Dependent DNA Binding Agent and Inhibitor of Human Topoisomerase II

Reynolds, Michael B.; DeLuca, Mark R.; Kerwin, Sean M.

doi:10.1006/bioo.1999.1138

Cited by 60 publications

(20 citation statements)

References 23 publications

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“…Previous studies by Reynolds et al and Kumar et al have implicated the role of divalent metal cation binding in the anticancer activities of UK-1 [41,42]. In these studies, both UK-1 and the anticancer analog 2 were observed to form monomeric 1:1 complexes with divalent metal cations in solution, in particular with the physiologically relevant cations Mg 2ϩ and Zn 2ϩ .…”

Section: Dna and Uk-1 Analogs With Metalsmentioning

confidence: 90%

“…In these studies, both UK-1 and the anticancer analog 2 were observed to form monomeric 1:1 complexes with divalent metal cations in solution, in particular with the physiologically relevant cations Mg 2ϩ and Zn 2ϩ . In addition, fluorescence and spectrophotometric experiments have shown that the double-stranded DNAbinding activity of UK-1 is ten-fold higher in the presence of Mg 2ϩ , thus indicating that DNA binding by UK-1 is metal mediated [41]. The metal-mediated binding of UK-1 to DNA has also been observed in our laboratory by ESI-MS, although the results demonstrate a clear preference for Ni 2ϩ , Co 2ϩ , and Zn 2ϩ -mediated binding, as opposed to Mg 2ϩ in which no detectable (DNA ϩ UK-1 ϩ Mg 2ϩ ) complexes were observed in the electrospray mass spectra [32].…”

Section: Dna and Uk-1 Analogs With Metalsmentioning

confidence: 99%

“…The bis(benzoxazole) natural product UK-1, a secondary metabolite isolated from Streptomyces, has been shown to possess a potent anticancer activity toward a variety of cancer and tumor-derived cells [41,42] (see Figure 1). In contrast, UK-1 was found to lack antibacterial activity against bacteria, yeast, and fungi.…”

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Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry

Oehlers

Mazzitelli

Brodbelt

et al. 2004

J. Am. Soc. Mass Spectrom.

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Electrospray ionization mass spectrometry is used to compare the metal ion binding and metal-mediated DNA binding of benzoxazole (1, 2, 3, 4) and benzimidazole (5) compounds and to elucidate the putative binding modes and stoichiometries. The observed metal versus non-metal-mediated DNA binding, as well as the specificity of DNA binding, is correlated with the biological activities of the analogs. The ESI-MS spectra for the antibacterial benzoxazole and benzimidazole analogs 4 and 5 demonstrated non-specific and non-metalmediated binding to DNA, with the appearance of DNA complexes containing multiple ligands. The anticancer analog 2 demonstrates a clear preference for metal-mediated DNA interactions, with an apparent selectivity for Ni 2ϩ -mediated binding over the more physiologically relevant Mg 2ϩ or Zn 2ϩ cations. Complexation between DNA and the biologically inactive analog 1 was not observed, either in the absence or presence of metal cations. (J Am Soc Mass Spectrom 2004, 15, 1593-1603

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Section: Dna and Uk-1 Analogs With Metalsmentioning

confidence: 90%

Section: Dna and Uk-1 Analogs With Metalsmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry

Oehlers

Mazzitelli

Brodbelt

et al. 2004

J. Am. Soc. Mass Spectrom.

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“…14 In the last decade efforts have been made to understand the selective cytotoxic activity of UK-1 (2) towards cancer cells versus bacteria and fungi, and for this purpose various synthetic derivates have been prepared ( Figure 5) and their biological activities evaluated and compared. [15][16][17] Reynolds et al 18 investigated the metal ion coordination by 2. It was shown that 2 bound divalent metal ions and DNA in a divalent metal ion-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Caboxamycin, a new antibiotic of the benzoxazole family produced by the deep-sea strain Streptomyces sp. NTK 937

et al. 2009

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Caboxamycin, a new benzoxazole antibiotic, was detected by HPLC-diode array screening in extracts of the marine strain Streptomyces sp. NTK 937, which was isolated from deep-sea sediment collected in the Canary Basin. The structure of caboxamycin was determined by mass spectrometry, NMR experiments and X-ray analysis. It showed inhibitory activity against Gram-positive bacteria, selected human tumor cell lines and the enzyme phosphodiesterase.

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“…UK-1 binds to double-stranded DNA in a metal ion-dependent fashion. One consequence of this interaction is inhibition of topoisomerase II [8]. Topoisomerase inhibitors arrest cells in S or G2 phase depending on time or concentration [9].…”

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confidence: 99%

Nataxazole, a New Benzoxazole Derivative with Antitumor Activity Produced by Streptomyces sp. Tü 6176†

et al. 2008

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The new benzoxazole derivative nataxazole was isolated from Streptomyces sp. (strain Tü 6176). Nataxazole is related in structure to the potent antitumor compounds UK-1 and AJI9561 and showed similar strong growth inhibitory activity against various human tumor cell lines.Keywords benzoxazole derivative, HPLC-diode array screening, antitumor activity, structure elucidation, Streptomyces Freshly isolated actinomycetes from soils collected in the environment of Natal, Rio Grande do Norte, Brasil, were grown in submerged culture in different media, and extracts prepared from mycelia and culture filtrates at various fermentation times were screened by HPLC-diode array analysis in combination with an in-house developed HPLC-UV-Vis database [2] to detect novel secondary metabolites. Strain Tü 6176 was found to be of special interest as it gave a mycelium extract that contained a dominant peak in the HPLC profile with a retention time of 14.8 minutes in standard reversed-phase gradient elution [2]. Its characteristic UV-visible spectrum (Fig. 1) differed from that of 867 reference compounds stored in the HPLC-UVVis database. Due to the collection site and its chemical structure (Fig. 2), the compound was named nataxazole (1).Strain Tü 6176 (RN-13.5) was isolated from a soil sample collected at Mata da Estrela, RN, Brazil. It was examined for a number of key properties known to be of value in streptomycete systematics. The presence of LLdiaminopimelic acid in the peptidoglycan [3] together with

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PRELIMINARY COMMUNICATION The Novel Bis(benzoxazole) Cytotoxic Natural Product UK-1 Is a Magnesium Ion-Dependent DNA Binding Agent and Inhibitor of Human Topoisomerase II

Cited by 60 publications

References 23 publications

Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry

Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry

Caboxamycin, a new antibiotic of the benzoxazole family produced by the deep-sea strain Streptomyces sp. NTK 937

Nataxazole, a New Benzoxazole Derivative with Antitumor Activity Produced by Streptomyces sp. Tü 6176†

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