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Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):2851-6. doi: 10.1073/pnas.1519846113. Epub 2016 Feb 29.

Structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A.

Author information

1
Department of Chemistry, Yale University, New Haven, CT 06520;
2
Department of Chemistry, Yale University, New Haven, CT 06520; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520 seth.herzon@yale.edu.

Abstract

(-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C2-symmetric structure that contains two unusual diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC)2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association.

KEYWORDS:

DNA; NMR; double-strand break; natural product

PMID:
26929332
PMCID:
PMC4801295
DOI:
10.1073/pnas.1519846113
[Indexed for MEDLINE]
Free PMC Article

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