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. 2016 Dec 7;138(48):15559-15562.
doi: 10.1021/jacs.6b09657. Epub 2016 Nov 28.

Mechanism of Nucleophilic Activation of (-)-Lomaiviticin A

Mengzhao Xue  1 , Seth B Herzon  1   2
Affiliations

Mechanism of Nucleophilic Activation of (-)-Lomaiviticin A

Mengzhao Xue et al. J Am Chem Soc. .

Abstract

(-)-Lomaiviticin A (1) is a C2-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage is initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate the formation of the vinyl radicals 1· and 2· from 1 by 1,7-addition of thiols to the diazofluorenes. These radicals can affect hydrogen atom abstraction from methanol and acetone. The first addition of thiol to 1 proceeds at a much greater rate than the second. The diazosulfide 5 formed en route to 1· has been detected at -50 °C and undergoes decomposition to 1· with a half-life of 110 min at -20 °C under air. These data, which constitute the first direct evidence for the generation of 1· and 2· from 1, provide insights into the mechanism of DNA cleavage by 1.

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Figures

Figure 1
Figure 1
Aryl region of the 1H NMR spectra of 1, 2-d, and 3-d2. Conditions: 1 (1.22 mM), TEA (40 equiv), NACME (40 equiv), methanol-d4, air, 25 °C.
Figure 2
Figure 2
(A) Ionization of 2 or 2-d leads to ejection of the aminosugar residue and observation of the elimination products 4 or 4-d by HRMS analysis., (B) 1, 2: Selected region of the HRMS spectrum of 4, generated by hydrodediazotization of 1 in CH3OH or CH3OD, respectively. 3, 4: Selected region of the HRMS spectrum of 4-d, generated by hydrodediazotization of 1 in CD3OH or CD3OD, respectively. 5, 6: Predicted isotope distribution of 4 and 4-d, respectively.
Figure 3
Figure 3
Stereoview of DFT-minimized structure of 1 in water [B3LYP 6-31G(d)]. Hydrogen atoms are omitted for clarity.
Scheme 1
Scheme 1
Proposed Pathway for the Conversion of (−)-Lomaiviticin A (1) to (−)-Lomaiviticin C (2) and the Double Hydrodediazotization Product 3 via the Vinyl Radical Intermediates 1· and 2·
Scheme 2
Scheme 2
Postulated Pathway for the Formation of 1· and 2· via Nucleophilic Addition of Thiol
Scheme 3
Scheme 3
Generation and Decomposition of the Diazosulfide 5.a aSpectroscopic data shown corresponds to the major diazosulfide isomer. Reaction was run under air. 1H NMR data were acquired at −20 °C.
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References

    1. He H, Ding WD, Bernan VS, Richardson AD, Ireland CM, Greenstein M, Ellestad GA, Carter GT. J. Am. Chem. Soc. 2001;123:5362. - PubMed
    2. Woo CM, Beizer NE, Janso JE, Herzon SB. J. Am. Chem. Soc. 2012;134:15285. - PubMed
    3. Kersten RD, Lane AL, Nett M, Richter TKS, Duggan BM, Dorrestein PC, Moore BS. ChemBioChem. 2013;14:955. - PMC - PubMed
    4. Colis LC, Woo CM, Hegan DC, Li Z, Glazer PM, Herzon SB. Nat. Chem. 2014;6:504. - PMC - PubMed
    5. Colis LC, Hegan DC, Kaneko M, Glazer PM, Herzon SB. J. Am. Chem. Soc. 2015;137:5741. For a review, see. - PMC - PubMed
    6. Herzon SB, Woo CM. Nat. Prod. Rep. 2012;29:87. - PubMed
    1. Colis LC, Herzon SB. Bioorg. Med. Chem. Lett. 2016;26:3122. - PMC - PubMed
    1. Rajski SR, Williams RM. Chem. Rev. 1998;98:2723. For reviews of DNA-damaging natural products, see: - PubMed
    2. Wolkenberg SE, Boger DL. Chem. Rev. 2002;102:2477. - PubMed
    3. Tse WC, Boger DL. Chem. Biol. 2004;11:1607. - PubMed
    1. Woo CM, Li Z, Paulson EK, Herzon SB. Proc. Natl. Acad. Sci. U. S. A. 2016;113:2851. - PMC - PubMed
    1. Laufer RS, Dmitrienko GI. J. Am. Chem. Soc. 2002;124:1854. For the first proposals for the generation of sp2 radicals from the diazofluorene, see: - PubMed
    2. Feldman KS, Eastman KJ. J. Am. Chem. Soc. 2006;128:12562. - PMC - PubMed

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