Synergistic potentiation of (−)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821

Colis, Laureen; Herzon, Seth B.

doi:10.1016/j.bmcl.2016.04.090

Cited by 4 publications

(4 citation statements)

References 44 publications

(39 reference statements)

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“…We also found that the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-821 53 synergizes with (−)-lomaiviticin A (4). 54 Exposure of K562 cells to either 10 μM VE-821 or 500 pM (−)-lomaiviticin A (4) alone for up to 48 h was nonlethal. However, when treated with 10 μM VE-821 + 500 pM (−)-lomaiviticin A (4), the cells suffered 81% and 94% killing after 24 and 48 h, respectively.…”

Section: Translational Development Of (−)-Lomaiviticin a (4)mentioning

confidence: 99%

“…Sensitivity to (−)-lomaiviticin ( 4 ) conferred by deficiencies in ATM- and X-ray repair cross complementing 5 (KU80) are also consistent with the involvement of DNA damage and DSB formation. We also found that the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-821 synergizes with (−)-lomaiviticin A ( 4 ) . Exposure of K562 cells to either 10 μM VE-821 or 500 pM (−)-lomaiviticin A ( 4 ) alone for up to 48 h was nonlethal.…”

Section: The Dimeric Diazofluorene Is Required For Potent Cytotoxicitymentioning

confidence: 99%

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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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Section: Translational Development Of (−)-Lomaiviticin a (4)mentioning

confidence: 99%

Section: The Dimeric Diazofluorene Is Required For Potent Cytotoxicitymentioning

confidence: 99%

The Mechanism of Action of (−)-Lomaiviticin A

Herzon

2017

Acc. Chem. Res.

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“…The C 2 -symmetric bacterial metabolite (−)-lomaiviticin A ( 1 , Scheme 1) induces double-strand breaks (DSBs) in DNA 1 and is undergoing preclinical evaluation as a combination 2 and monotherapy 1e for the treatment of DNA DSB repair-deficient tumors. 3 1 binds DNA by a mode of association involving penetration of both diazotetrahydrobenzo[ b ]fluorene (diazofluorene) residues into the duplex.…”

mentioning

confidence: 99%

“…The C 2 -symmetric bacterial metabolite (–)-lomaiviticin A ( 1 , Scheme ) induces double-strand breaks (DSBs) in DNA and is undergoing preclinical evaluation as a combination and monotherapy for the treatment of DNA DSB repair-deficient tumors .…”

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confidence: 99%

Mechanism of Nucleophilic Activation of (−)-Lomaiviticin A

Xue

Herzon

2016

J. Am. Chem. Soc.

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(−)-Lomaiviticin A (1) is a C2-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage is initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate the formation of the vinyl radicals 1· and 2· from 1 by 1,7-addition of thiols to the diazofluorenes. These radicals can affect hydrogen atom abstraction from methanol and acetone. The first addition of thiol to 1 proceeds at a much greater rate than the second. The diazosulfide 5 formed en route to 1· has been detected at −50 °C and undergoes decomposition to 1· with a half-life of 110 min at −20 °C under air. These data, which constitute the first direct evidence for the generation of 1· and 2· from 1, provide insights into the mechanism of DNA cleavage by 1.

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