Mechanisms of in Situ Activation for DNA-Targeting Antitumor Agents

Wolkenberg, S. E.; Boger, Dale L.

doi:10.1021/cr010046q

Cited by 333 publications

(242 citation statements)

References 288 publications

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“…Although detailed kinetic studies are needed to fully establish this point, this result suggests that 1 may become activated toward nucleophilic addition and DNA cleavage on binding to DNA. Such "shape-dependent catalysis" is reminiscent of the DNA-mediated activation of CC-1065 and duocarmycin elegantly elucidated by Boger and coworkers (45)(46)(47).…”

Section: Discussionmentioning

confidence: 96%

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

Woo

Paulson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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(-)-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 C 2 -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. (-)-Lomaiviticin A (1) possesses half-maximal inhibitory potencies (IC 50 s) in the low nanomolar-picomolar range against several cultured cancer cell lines (1, 2). (-)-Lomaiviticin C (3) and (-)-kinamycin C (4) are several orders of magnitude less potent, whereas (-)-lomaiviticin B (2) is ∼10-100-fold less potent. The cytotoxicity of 1 derives from the induction of double-strand breaks (DSBs) in DNA (18,19). K562 cells exposed to 5 nM of 1 for 30 min accumulated DSB levels that were comparable to 40 Gy of ionizing radiation. This DNA cleavage activity is not recapitulated by 3 or 4, suggesting both diazofluorenes of 1 are essential for cleavage activity. DNA DSBs are exceedingly cytotoxic (20), and these data provide an explanation for the remarkable potency of 1.The molecular mechanism of DNA DSB induction by (-)-lomaiviticin A (1) has been studied (18). Cell-free deuteriumlabeling experiments are consistent with a pathway comprising reductive activation of one diazofluorene (Fig. 1B) to generate the vinyl radical intermediate 1•, followed by hydrogen atom abstraction from the deoxyribose chain, a process known to lead to singlestrand breaks (SSBs) (21). Reductive activation of the remaining diazofluorene, followed by hydrogen atom abstraction, is believed to cleave the complementary DNA (cDNA) strand, leading to the observed DSB.However, the mode of interaction of (-)-lomaiviticin A (1) with DNA has not been elucidated. As C(sp 2 ) radicals are high-energy species, the mechanistic model outlined above pr...

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Section: Discussionmentioning

confidence: 96%

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

Woo

Paulson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A number of distinct chemical mechanisms have emerged for targeting DNA and RNA, but we will only consider the alkylating natural products here. The reader is referred to the reviews [51][52][53] for a comprehensive discussion of the different mechanisms such as non-covalent binders, 54 radical cleavage, 55 reactive oxygen species generation. 56 In the following section we will give an overview of different alkylation strategies that have evolved to target nucleic acids.…”

Section: Natural Products That Covalently Modify Nucleobasesmentioning

confidence: 99%

“…6, is representative of a small family of natural products that contain the dienone cyclopropane motif. 53 This motif is relatively stable until the molecule binds the minor groove of A-T rich strands of DNA. 57 Binding in the minor groove requires some rotation about the amide bond, disrupting conjugation of the vinylogous amide and increasing the electrophilicity of the dienone cyclopropane.…”

Section: Natural Products That Covalently Modify Nucleobasesmentioning

confidence: 99%

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

2016

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Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guaninecytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, - stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.

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“…Photodynamic therapy (PDT) takes advantage of light activation to achieve spatio-temporal selectivity for cancerous tissue, thus reducing the systemic toxicity to healthy cells [16][17][18][19]. PDT has recently emerged as an alternative, and, in some cases, a superior approach to conventional dermatological therapies and for the treatment of endoscopically accessible tumours [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Photochemistry and DNA photocleavage by a new unsupported dirhodium(II,II) complex

Burya

Turró

et al. 2013

Phil. Trans. R. Soc. A.

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One contribution of 18 to a Discussion Meeting Issue 'Photoactivatable metal complexes: from theory to applications in biotechnology and medicine' . The quantum yield for the photochemical transformation of 1 in H 2 O exceeds unity (Φ 550 nm = 1.38) indicative of dark reactions following the initial photoprocess. DNA photocleavage was observed for 1 (λ irr > 590 nm), whereas the complex is unreactive in the dark. This feature makes 1 a promising photodynamic therapy agent that does not operate via the production of singlet oxygen, 1 O 2 . Subject Areas: photochemistry Keywords

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Mechanisms of in Situ Activation for DNA-Targeting Antitumor Agents

Cited by 333 publications

References 288 publications

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

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

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

Photochemistry and DNA photocleavage by a new unsupported dirhodium(II,II) complex

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