Regiocontrolled Synthesis of the Trimeric Quinone Framework of Conocurvone

Emadi, Ashkan; Harwood, John S.; Kohanim, Sahar; Stagliano, Kenneth W.

doi:10.1021/ol010272m

Cited by 36 publications

(38 citation statements)

References 15 publications

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“…In an effort to synthesize anti-retrovirals, Emadi et al previously reported the regiocontrolled synthesis of symmetrical and asymmetrical dimeric and trimeric naphthoquinones by using a novel method [4], [5]. Several of the dimeric naphthoquinones (binaphthoquinones) inhibited HIV-1 integrase with ID 50 (concentration of drug required to inhibit HIV-1 mediated cytopathogenicity in infected cells by 50%) ranging from 1 to 3.5 micromolar [6].…”

Section: Introductionmentioning

confidence: 99%

A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

et al. 2010

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BackgroundDimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhanced or suppressed growth in the presence of binaphthoquinones.Methodology/Principal findingsExposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growth with IC50s in the µM range. Drug sensitivity and resistance screens were performed by exposing arrays of a haploid yeast deletion mutant library to BiQs at concentrations near their IC50. Sensitivity screens identified yeast with deletions affecting mitochondrial function and cellular respiration as having increased sensitivity to BiQs. Corresponding to this, wild type yeast grown in the absence of a fermentable carbon source were particularly sensitive to BiQs, and treatment with BiQs was shown to disrupt the mitochondrial membrane potential and lead to the generation of reactive oxygen species (ROS). Furthermore, baseline ROS production in BiQ sensitive mutant strains was increased compared to wild type and could be further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydrogenase, NDE1, as critical to BiQ toxicity and over-expression of this gene resulted in increased ROS production and increased sensitivity of wild type yeast to BiQ.Conclusions/SignificanceIn yeast, binaphthoquinone cytotoxicity is likely mediated through NAD(P)H:quonine oxidoreductases leading to ROS production and dysfunctional mitochondria. Further studies are required to validate this mechanism in mammalian cells.

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Section: Introductionmentioning

confidence: 99%

A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

et al. 2010

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“…A high yielding one step synthesis of dimeric naphthoquinones 1–3 was described by us previously 8 and has been subsequently utilized by other research groups 9–10 to study the synthesis and biological properties of this unique class of compounds.…”

Section: Resultsmentioning

confidence: 99%

Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells

Emadi

Harwood

et al. 2011

Bioorganic & Medicinal Chemistry

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Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC50 = 15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.

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“…3 A special subgroup of these compounds is constituted by 2-hydroxynapthoquinones. 4,5 Natural 2-hydroxynaphthoquinones vary in structural complexity from the simple hydroxynaphthoquinones such as 2-hydroxy-1,4-naphthoquinone (lawsone, 1), the main component of a natural hair dye and a potent detector of latent finger marks on cloth or paper under infrared light, 6 to hydroxyphenylnaphthoquinones 3 or complex structures such as the trimeric hydroxynaphthoquinone conocurvone (2), a potential anti-HIV agent 7,8 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…Stagliano accomplished the arylation of lawsone and its derivatives through a Stille-type coupling reaction of their phenyliodonium ylides with arylstannates (Scheme 1). 7,8,26 Indolyl derivatives of lawsone have also been obtained from the coppercatalyzed reactions of its phenyliodonium ylide (8) with indoles. 27 Besides, a variety of aryl and heteroaryl derivatives of lawsone as well as the 3-styryl-lawsone have been attained through the Suzuki-type coupling of the same iodonium ylide with the appropriate aryl, heteroaryl and styryl boronates.…”

Section: Introductionmentioning

confidence: 99%

Styryl and functionalized aryl derivatives of lawsone through metal-free cross-coupling of its BF3-activated phenyliodonium ylide with cinnamaldehydes and arylaldehydes

et al. 2015

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Regiocontrolled Synthesis of the Trimeric Quinone Framework of Conocurvone

Cited by 36 publications

References 15 publications

A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells

Styryl and functionalized aryl derivatives of lawsone through metal-free cross-coupling of its BF3-activated phenyliodonium ylide with cinnamaldehydes and arylaldehydes

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