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. 2014 Aug 25;53(35):9325-8.
doi: 10.1002/anie.201404137. Epub 2014 Jul 9.

Analysis of diazofluorene DNA binding and damaging activity: DNA cleavage by a synthetic monomeric diazofluorene

Christina M Woo  1 , Nihar Ranjan, Dev P Arya, Seth B Herzon
Affiliations

Analysis of diazofluorene DNA binding and damaging activity: DNA cleavage by a synthetic monomeric diazofluorene

Christina M Woo et al. Angew Chem Int Ed Engl. .

Abstract

The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.

Keywords: DNA cleavage; DNA damage; cancer; natural products.

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Figures

Figure 1
Figure 1
Structures of (−)-lomaiviticins A–E (1–5) and kinamycins C, D, and F (6–8, respectively).
Figure 2
Figure 2
Structures of synthetic dimeric and monomeric diazofluorenes employed in this work.
Figure 3
Figure 3
FID assays of equimolar concentrations of diazofluorenes (0.88 µM) against thiazole orange (TO, 1.25 µM) using calf thymus DNA as substrate (0.88 µM in base pairs).
Figure 4
Figure 4
Linear dichroism spectra of (a) (−)-lomaiviticin aglycon (9) and (b) ethidium bromide at rbd 8. Buffer conditions: 10 mM sodium cacodylate, 0.5 mM EDTA, 100 mM KCl at pH 6.8 (T = 22–23 °C).
Figure 5
Figure 5
Agarose gel electrophoresis of the DNA cleavage of pBr322 DNA (800 ng) treated with diazofluorenes and DTT (5 mM) cofactor (24 h, 37 °C). Lane 1: pBr322 DNA. Lane 2: [6] = 500 µM. Lane 3: [9] = 500 µM. Lane 4: [9] = 250 µM. Lane 5: [9] = 125 µM. Lane 6: [10] = 500 µM. Lane 7: [10] = 250 µM. Lane 8: [10] = 125 µM. Lane 9: [11] = 500 µM. Lane 10: [11] = 250 µM. Lane 11: [11] = 125 µM. Form I = supercoiled DNA; Form II = nicked DNA; Form III = linearized DNA.
Figure 6
Figure 6
Agarose gel electrophoresis of the DNA cleavage of pBr322 DNA (800 ng) treated with diazofluorenes (24 h, 37 °C). Lane 1: pBr322. Lane 2: [6] = 500 µM. Lane 3: [6] = 250 µM. Lane 4: [9] = 500 µM. Lane 5: [9] = 250 µM. Lane 6: [11] = 500 µM. Lane 7: [11] = 250 µM. Lane 8: [10] = 500 µM. Lane 9: [10] = 250 µM. Form I = supercoiled DNA; Form II = nicked DNA; Form III = linearized DNA.
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References

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    1. Isolation of the kinamycins: Ito S, Matsuya T, Ōmura S, Otani M, Nakagawa A. J. Antibiot. 1970;23:315. Hata T, Ōmura S, Iwai Y, Nakagawa A, Otani M. J. Antibiot. 1971;24:353. Ōmura S, Nakagawa A, Yamada H, Hata T, Furusaki A, Watanabe T. Chem. Pharm. Bull. 1971;19:2428. Furusaki A, Matsui M, Watanabe T, Ōmura S, Nakagawa A, Hata T. Isr. J. Chem. 1972;10:173. Ōmura S, Nakagawa A, Yamada H, Hata T, Furusaki A. Chem. Pharm. Bull. 1973;21:931. Cone MC, Seaton PJ, Halley KA, Gould SJ. J. Antibiot. 1989;42:179. Seaton PJ, Gould SJ. J. Antibiot. 1989;42:189.

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    1. For the first evidence and proposals for generation of vinyl radicals from the diazofluorene, see: Laufer RS, Dmitrienko GI. J. Am. Chem. Soc. 2002;124:1854. Feldman KS, Eastman KJ. J. Am. Chem. Soc. 2005;127:15344. Feldman KS, Eastman KJ. J. Am. Chem. Soc. 2006;128:12562.

    1. Colis LC, Woo CM, Hegan DC, Li Z, Glazer PM, Herzon SB. Nat. Chem. 2014;6:504. - PMC - PubMed

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