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

Significance DNA is a canonical target for chemotherapeutic intervention, and several DNA-reactive natural products are in clinical use. An understanding of the mode of DNA binding of these agents is an essential component of translational development. Here we show that (–)-lomaiviticin A (1), a naturally occurring DNA cleavage agent undergoing preclinical evaluation, binds DNA by an unusual mode of association involving insertion of two complex polycyclic arene fragments into the duplex, with concomitant disruption of base pairing. Additionally, our studies suggest that DNA binding activates the DNA cleavage activity of 1. This study provides a structural basis for the activity of 1 and for the development of synthetic DNA-damaging agents capable of recapitulating this mechanism of association and activation. (–)-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.