Novel, unifying mechanism for aromatic primary-amines (therapeutics, carcinogens and toxins): electron transfer, reactive oxygen species, oxidative stress and metabolites

Kovacic, Peter; Somanathan, Ratnasamy

doi:10.1039/c0md00233j

Cited by 23 publications

(17 citation statements)

References 56 publications

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“…86,87 Wang and Guengerich identified CYP-generated hydroxylamine and nitrenium species of 5F 203. 62 Our attempts to confirm the identity of the 5F 203 metabolites that contribute to increases in ROS production have been unsuccessful thus far.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

McLean¹,

Watkins²,

Campbell³

et al. 2015

Chem. Res. Toxicol.

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Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action.

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Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

McLean¹,

Watkins²,

Campbell³

et al. 2015

Chem. Res. Toxicol.

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“…62,63 However, the parent nitroso compounds ( 1 , Class B , C ; Table 4) and Diels-Alder cycloadducts ( 2 , Class A–C ; Table 4), which can undergo retro Diels-Alder reactions to generate a nitroso species, 64 had no significant antibacterial activity. Additionally, establishment of clear SAR trends suggested the existence of a discrete, conserved cellular target.…”

Section: Further Discussion and Perspectivementioning

confidence: 99%

N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

et al. 2011

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The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.

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“…The preponderance of bioactive substances or their metabolites incorporates ET functionalities, which, we believe, play an important role in physiological responses, examples of which include the following: quinones (or phenolic precursors), metal complexes (or complexors), nitroso and hydroxylamine metabolites from ArNO 2 and ArNH 2 [1], and conjugated imines (or iminium species). In vivo redox cycling of such entities with oxygen can occur, giving rise to OS through generation of ROS, for example, hydrogen peroxide, hydroperoxides, and superoxide.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Anesthetic Toxicity: Metabolism, Reactive Oxygen Species, Oxidative Stress, and Electron Transfer

Kovacic

Somanathan

2011

ISRN Anesthesiology

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There is much literature on the toxic effects of anesthetics. This paper deals with both the volatiles and locals. Adverse effects appear to be multifaceted, with the focus on radicals, oxidative stress (OS), and electron transfer (ET). ET functionalities involved are quinone, iminoquinone, conjugated iminium, and nitrone. The non-ET routes involving radicals and OS apparently pertain to haloalkanes and ethers. Beneficial effects of antioxidants, evidently countering OS, are reported. Knowledge at the molecular level should aid in devising strategies to combat the adverse effects.

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Novel, unifying mechanism for aromatic primary-amines (therapeutics, carcinogens and toxins): electron transfer, reactive oxygen species, oxidative stress and metabolites

Cited by 23 publications

References 56 publications

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

Mechanism of Anesthetic Toxicity: Metabolism, Reactive Oxygen Species, Oxidative Stress, and Electron Transfer

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