Natural products containing a diazo group

Nawrat, Christopher C.; Moody, Christopher J.

doi:10.1039/c1np00031d

Cited by 86 publications

(67 citation statements)

References 102 publications

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“…16 Intrinsic antitumor and antibiotic activities endow some natural diazo compounds with potential clinical utility, but mechanisms of action in vivo are unclear. As the isolation and synthesis of diazo-containing natural products has been reviewed extensively elsewhere, 17,18 we summarize only key findings and recent advances. We focus, in particular, on the kinamycins and lomaiviticins, two classes of natural products with unusual structures and intriguing mechanisms of reactivity (Figures 1A and 1B).…”

Section: Natural Productsmentioning

confidence: 99%

Diazo Compounds: Versatile Tools for Chemical Biology

2016

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Diazo groups have broad and tunable reactivity. That and other attributes endow diazo compounds with the potential to be valuable reagents for chemical biologists. The presence of diazo groups in natural products underscores their metabolic stability and anticipates their utility in a biological context. The chemoselectivity of diazo groups, even in the presence of azido groups, presents many opportunities. Already, diazo compounds have served as chemical probes and elicited novel modifications of proteins and nucleic acids. Here, we review advances that have facilitated the chemical synthesis of diazo compounds, and we highlight applications of diazo compounds in the detection and modification of biomolecules.

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Section: Natural Productsmentioning

confidence: 99%

Diazo Compounds: Versatile Tools for Chemical Biology

2016

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“…(4)(5)(6)(7)(8)(9)(10)(11) are produced by certain strains of Salinispora and Streptomyces. The metabolites 1-4 contain a diazotetrahydrobenzo [b]fluorene (diazofluorene, gray box in 1), which comprises a diazocyclopentadiene fused to naphthoquinone and oxidized cyclohexenone rings (12)(13)(14)(15)(16)(17). Lomaiviticins A (1) and B (2) possess two diazofluorenes and C 2 -symmetric structures containing 2-4 deoxyglycoside residues.…”

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confidence: 99%

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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“…50,51 In addition, since diazotized peptides are the likely source of these alkylation adducts, 26,50 it is important to understand whether adducts bearing amides are also effectively repaired. Bacteria also produce diazo peptide natural products that may alkylate DNA, 52,53 adding additional impetus to understand the repair of amide adducts. Thus, we tested whether a DNA 9-mer modified with a cyclohexyl carboxymethylamide (see Table 2, entry 6), was a substrate for hAGT (see Fig.…”

Section: Resultsmentioning

confidence: 99%