Development of Enantioselective Synthetic Routes to (−)-Kinamycin F and (−)-Lomaiviticin Aglycon

Woo, Christina M.; Gholap, Shivajirao L.; Liang, Lu; Kaneko, Miho; Li, Zhenwu; Ravikumar, Ponneri C.; Herzon, Seth B.

doi:10.1021/ja307497h

Cited by 37 publications

(46 citation statements)

References 92 publications

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“…450–453 In these syntheses the predominant methods for diazo group installation has been Regitz diazo transfer to activated methines or oxidation of hydrazone intermediates accessed via condensation of hydrazine reagents with ketone precursors. Notably, the diazo group in the kinamycins has not been installed using a late-stage N–N bond formation such as the nitrous acid-based diazotization used to synthesize cremeomycin.…”

Section: N–n Bond Forming Enzymesmentioning

confidence: 99%

“…To date, no total synthesis of any lomaiviticin has been achieved, although the aglycone can be accessed in just eleven steps and 4 can be generated semi-synthetically from the more abundant metabolite 185 . 449,453,465,468,469 In these total synthesis and semi-synthesis efforts, the diazo groups are installed via Regitz diazo transfer onto an activated methine intermediate.…”

Section: N–n Bond Forming Enzymesmentioning

confidence: 99%

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Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

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Section: N–n Bond Forming Enzymesmentioning

confidence: 99%

Section: N–n Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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“…We adapted this chemistry to the synthesis of (–)-kinamycin F ( 3 ) 11 and the chain and ring isomers of lomaiviticin aglycon ( 21 and 22 , respectively). 12,11b (–)-Kinamycin F ( 3 ) was prepared in seven steps from ketone 15 and juglone 16 (Scheme 2A).…”

Section: Overview Of the Synthetic Strategymentioning

confidence: 99%

“…12,11b (–)-Kinamycin F ( 3 ) was prepared in seven steps from ketone 15 and juglone 16 (Scheme 2A). We pursued the oxidative coupling of two monomeric diazofluorenes to access lomaiviticin aglycon ( 21 / 22 , Scheme 2B).…”

Section: Overview Of the Synthetic Strategymentioning

confidence: 99%

The Mechanism of Action of (−)-Lomaiviticin A

Herzon

2017

Acc. Chem. Res.

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CONSPECTUS (–)-Lomaiviticin A (4) is a complex C2-symmetric bacterial metabolite that contains two diazofluorene functional groups. The diazofluorene consists of naphthoquinone, cyclo-pentadiene, and diazo substituents fused through a σ- and π-bonding network. Additionally, (–)-lomaiviticin A (4) is a potent cytotoxin, with half-maximal inhibitory potency (IC50) values in the low nanomolar range against many cancer cell lines. Because of limitations in supply, its mechanism of action had remained a “black box” since its isolation in the early 2000s. In this Account, I describe how studies directed toward the total synthesis of (–)-lomaiviticin A (4) provided a platform to elucidate the emergent properties of this metabolite and thereby connect chemical reactivity with cellular phenotype. We first developed a convergent strategy to prepare the diazofluorene (9 + 10 → 13). We then adapted this chemistry to the synthesis of lomaiviticin aglycon (21/22) and the natural monomeric diazofluorene (–)-kinamycin F (3). The key step in the lomaiviticin aglycon (21/22) synthesis involved the stereoselective oxidative coupling of two monomeric diazofluorenes (2 × 18→ 20) to establish the cojoining carbon–carbon bond of the target. As the absolute stereochemistry of the aglycon and carbohydrate residues of (–)-lomaiviticin A (4) were unknown, we developed a semisynthetic route to the metabolite that proceeds in one step and 42% yield by diazo transfer to the more abundant isolate (–)-lomaiviticin C (6). This allowed us to complete the stereochemical assignment of (–)-lomaiviticin A (4) and provided a renewable source of material. Using this material, we established that the remarkable cytotoxic effects of (–)-lomaiviticin A (4) derive from the induction of highly toxic double-strand breaks (DSBs) in DNA. At the molecular level, 1,7-nucleophilic additions to each electrophilic diazofluorene trigger homolytic decomposition pathways that produce sp2 radicals at the carbon atoms of each diazo group. These radicals abstract hydrogen atoms from the deoxyribose of DNA, a process known to initiate strand cleavage. NMR spectroscopy and molecular mechanics simulations were used to elucidate the mode of DNA binding. These studies showed that both diazofluorenes of (–)-lomaiviticin A (4) penetrate into the duplex. This mode of non-covalent binding places each diazo carbon atom in close proximity to each DNA strand. Throughout these studies, isolates containing one diazofluorene, such as (–)-lomaiviticin C (6) and (–)-kinamycin C (2), were used as controls. Consistent with our mechanistic model, these compounds do not induce DSBs in DNA and are several orders of magnitude less potent. Reactivity studies suggest that (–)-lomaiviticin A (4) is more electrophilic than simple monomeric diazofluorenes. We attribute this to through-space delocalization of the developing negative charge in the transition state for 1,7-addition. Consistent with this mechanism of action, (–)-lomaiviticin A (4) displays selective low-picomolar potencies toward DNA ...

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“…This binding site size is similar to that of well-known intercalators, such as ethidium bromide. Sequential additions of (À)-lomaiviticin aglycon (9) to DNA led to small changes in the CD signal at 303 nm and a small positive induced CD at 553 nm ( Figure S2 A). Sequential additions of (À)-lomaiviticin aglycon (9) to DNA led to small changes in the CD signal at 303 nm and a small positive induced CD at 553 nm ( Figure S2 A).…”

mentioning

confidence: 99%

Analysis of Diazofluorene DNA Binding and Damaging Activity: DNA Cleavage by a Synthetic Monomeric Diazofluorene

Woo¹,

Ranjan²,

Arya³

et al. 2014

Angewandte Chemie

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The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.Lomaiviticins A-E (1-5) [1] and kinamycins (6-8) [2] are com-

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Development of Enantioselective Synthetic Routes to (−)-Kinamycin F and (−)-Lomaiviticin Aglycon

Cited by 37 publications

References 92 publications

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

The Mechanism of Action of (−)-Lomaiviticin A

Analysis of Diazofluorene DNA Binding and Damaging Activity: DNA Cleavage by a Synthetic Monomeric Diazofluorene

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