Mechanisms of toxicity of naphthoquinones to isolated hepatocytes

Miller, Marion G.; Rodgers, A.; Cohen, Gerald M.

doi:10.1016/0006-2952(86)90157-7

Cited by 118 publications

(49 citation statements)

References 24 publications

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“…Menadione (2-methyl-l,4-naphthoquinone) has long been known to be an inducer of the MPT in vitro; however, the mechanism by which menadione inhibits mitochondrial bioenergetics and causes lethal cell injury remains controversial because it possesses both redox cycling and arylating chemical reactivities (Gant et al, 1988;Henry and Wallace, 1996;Miller et al, 1986;O'Brien, 1991;Ross et al, 1986;Rossi et al, 1986). In isolated hepatic mitochondria, we found that substituted naphthoquinones induced a calcium-dependent depolarization of mitochondrial membrane potential that is inhibited by cyclosporine A .…”

Section: Quinone-induced Interference With Mitochondrial Calcium Regumentioning

confidence: 68%

Mitochondria-Mediated Cell Injury

et al. 1997

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Section: Quinone-induced Interference With Mitochondrial Calcium Regumentioning

confidence: 68%

Mitochondria-Mediated Cell Injury

et al. 1997

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“…These chemical properties of 1,4-naphthoquinones, such as plumbagin, may be the cause of their cytotoxicity and may influence their KAT-inhibitory activity. The toxicity also hampers their utility (5)(6)(7)(8). Therefore, we are interested in investigating the role of the chemical nature of plumbagin and other related 1,4-naphthoquinone analogs in KAT inhibition and cytotoxicity with the ultimate goal of synthesizing a non-toxic, reversible inhibitor.…”

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confidence: 99%

Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis

Vasudevarao

Mizar

Kumari

et al. 2014

Journal of Biological Chemistry

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Background: 1,4-Naphthoquinone analogs, such as plumbagin, are toxic compounds due to their redox cycling and thiolreactive properties. Results: The p300 inhibitor PTK1, a plumbagin derivative with greatly reduced toxicity, was synthesized and characterized. Conclusion: PTK1 is a reversible, non-competitive inhibitor of p300 KAT activity with reduced toxicity. Significance: These studies provide insight into naphthoquinone-mediated KAT inhibition and describe the synthesis of a therapeutically important, non-toxic inhibitor.

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“…These furonaphthoquinones have the potential to decrease glutathione (GSH) content, with an increase in glutathione disulfide (GSSG) formation. Naphthoquinone derivative-dependent de- 23) or redox cycle-generated reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide, which can be detoxified by glutathione peroxidase with concomitant formation of oxidized glutathione. 24) In conclusion, we have developed a direct one-pot cascade reaction via Sonogashira coupling and intramolecular cyclization for the synthesis of furonaphthoquinones.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Cytotoxicity on Human Leukemia Cells of Furonaphthoquinones Isolated from <i>Tabebuia</i> Plants

et al. 2013

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Furonaphthoquinones are promising skeletons for anticancer drug molecules. In particular, methoxylated furonaphthoquinones are characteristic constituents of Tabebuia plants. In this research, we synthesized the furonaphthoquinones by effective one-pot cascade reactions of 3-phenyliodonio-1,2,4-trioxo-1,2,3,4-tetrahydronaphthalenides with 3-butyn-2-ol in the presence of palladium and cuprous catalysts via Sonogashira coupling and intramolecular cyclization. Furthermore, we demonstrated that the synthetic furonaphthoquinones showed moderate cytotoxicity against human leukemia U937 and HL-60 cells. Our work highlights the importance of furonaphthoquinones as antileukemic agents.Key words furonaphthoquinone; Tabebuia plant; Sonogashira coupling; antileukemic activity Tabebuia plants belong to the Bignoniaceae family, which is commonly found in North and South America. The plants have been used for the treatment of cancer as folk medicines, Pau d'Arco, Ipé Roxo, Taheebo, and Lapacho. 1) In 1982, 2-(1-hydroxyethyl) naphtho [2,3-b] furan-4,9-dione FN0-ol and 2-acetylnaphtho[2,3-b] furan-4,9-dione FN0-one were isolated from Tabebuia cassinoides. Both these furonaphthoquinones showed significant activity against human oral epidermoid carcinoma KB cells.2) Subsequently, FN0-one was investigated as an anticancer agent in vitro, and it was found that this quinone shows moderate cytotoxicity against various cancer cell lines, including human oral squamous carcinoma HSC-2, HSC-3, HSC-4, human prostate carcinoma DU-145, human melanoma C8161, human lung adenocarcinoma A549, and human epithelial carcinoma HeLa cells.3-6) Previous phytochemical investigations of Tabebuia plants resulted in the isolation and characterization of a variety of furonaphthoquinones bearing a methoxy group in the benzene ring.7-9) Thus, these methoxylated furonaphthoquinones were confirmed to be characteristic constituents of Tabebuia plants.As described above, furonaphthoquinones are considered interesting natural compounds in biochemical and pharmacological fields. Herein, we report the detailed synthesis of these furonaphthoquinones and their antileukemic activity. Results and DiscussionSome of naturally occurring furonaphthoquinones bear a 1-hydroxyethyl group at the C2-position. Kobayashi et al. reported a synthesis method of furonaphthoquinones based on sequential coupling/ring closure reactions.10) However, the reaction with intact 3-butyn-2-ol was unsuccessful. Thus, we attempted to improve their method, with the aim of making it useful for the synthesis of a wide variety of the compounds having a hydroxy group. 2-(1-Hydroxyethyl)-furonaphthoquinones such as FN0-ol are envisaged to be formed through the in situ generation of iodonaphthoquinones from phenyliodonium ylides in the presence of cuprous oxide (Cu 2 O), followed by Sonogashira coupling with acetylene and subsequent intramolecular cyclization. The phenyliodonium ylide 3-phenyliodonio-1,2,4-trioxo-1,2,3,4-tetrahydronaphthalenide IY0, which would serve as a suitable precursor for the su...

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Mechanisms of toxicity of naphthoquinones to isolated hepatocytes

Cited by 118 publications

References 24 publications

Mitochondria-Mediated Cell Injury

Mitochondria-Mediated Cell Injury

Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis

Synthesis and Cytotoxicity on Human Leukemia Cells of Furonaphthoquinones Isolated from <i>Tabebuia</i> Plants

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