Synthesis and Cytotoxic Activity of Latentiated Derivatives of 3-Methyleneoxindole

Kornet, Milton J.; Thio, Alan P.; Thorstenson, J. H.

doi:10.1002/jps.2600660732

Cited by 11 publications

(4 citation statements)

References 15 publications

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“…3-Alkyldioxindoles and their dehydration products, 3-methyleneoxindoles, are formed in the reactions of isatins with organoboron compounds, such as triallylboron 387 ; organomagnesium reagents 388,389 ; organozinc reagents 390,391 and organolithium reagents 392,393 , such as methyllithium 154 . These compounds are also obtained in aldolic and related condensations with acetone 394 or its oxime 395 ; aromatic 396,397 and heteroaromatic methylketones 398,399 ; cyclic alkylketones 400 ; acetates 401 ; propionates 402 ; acetoacetates 403 ; cyanoacetates 404 ; nitroalkanes 405 ; benzodiazepinones 406 ; imidazolinones 407 ; indoles 408 ; 2-methylquinolines 409 ; pyrazinones 410 ; thiazolidinediones [411][412][413][414][415] and xanthinones 416 In the reaction of isatins with some cyclic ketones, such as 4-hydroxy-2H-benzopyran-2-one 417 , the initial dioxindole formed reacts with a second equivalent of the ketone yielding a 3,3-disubstituted oxindole.…”

Section: Scheme 96mentioning

confidence: 99%

The chemistry of isatins: a review from 1975 to 1999

Silva¹,

Garden²,

Pinto³

2001

J. Braz. Chem. Soc.

846

447

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Isatinas (1H-indol-2,3-diona) são compostos de grande versatilidade sintética, podendo ser utilizados na obtenção de diversos sistemas heterociclos, como derivados indólicos e quinolínicos, o que as tornam importantes matérias-primas na síntese de fármacos. Isatinas também têm sido detectadas em tecidos de mamíferos, o que tem despertado o interesse em seu estudo como moduladores em diversos processos bioquímicos. Os avanços na aplicação de isatinas em síntese orgânica, bem como na compreensão de seus efeitos biológicos e farmacológicos nos últimos vinte e cinco anos encontram-se relatados nesta revisão e seus respectivos materiais suplementares.Isatins (1H-indole-2,3-dione) are synthetically versatile substrates, where they can be used for the synthesis of a large variety of heterocyclic compounds, such as indoles and quinolines, and as raw material for drug synthesis. Isatins have also been found in mammalian tissue and their function as a modulator of biochemical processes has been the subject of several discussions. The advances in the use of isatins for organic synthesis during the last twenty-five years, as well as a survey of its biological and pharmacological properties are reported in this review and in the accompanying supplementary information.

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Section: Scheme 96mentioning

confidence: 99%

The chemistry of isatins: a review from 1975 to 1999

Silva¹,

Garden²,

Pinto³

2001

J. Braz. Chem. Soc.

846

447

View full text Add to dashboard Cite

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“…The LCF was further purified by Sephedax LH-20 column chromatography (CC) and semi-preparative HPLC over a Si-60 column to yield three new compounds, coixspirolactam D ( 1 ), coixspirolactam E ( 2 ), and coixspiroenone ( 3 ), along with seven known lactams, coixspirolactam A ( 4 ), coixspirolactam B ( 5 ), coixspirolactam C ( 6 ), coixlactam ( 7 ), coixol ( 8 ), ethyl dioxindole-3-acetate ( 9 ), and isoindol-1-one ( 10 ), as well as two lignan derivatives, zhepiresionol ( 11 ) and ficusal ( 12 ) . Compounds 9 and 10 are the first isolates from natural resources.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative Lactams and Spiroenone from Adlay Bran in Human Breast Cancer Cell Lines

Chung

Hsu

Lin

et al. 2011

J. Agric. Food Chem.

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Two new lactams, coixspirolactam D (1) and coixspirolactam E (2), and a new spiroenone, coixspiroenone (3), together with seven known compounds, coixspirolactam A (4), coixspirolactam B (5), coixspirolactam C (6), coixlactam (7), coixol (8), ethyl dioxindole-3-acetate (9), and isoindol-1-one (10), and two neolignans, zhepiresionol (11) and ficusal (12), were isolated from the bioactive subfraction of adlay bran ethanolic extract (ABE). Compounds 9 and 10 are the first isolates from natural resources. The structures of new compounds were identified by spectroscopic methods, including infrared (IR) spectrum, 1D and 2D nuclear magnetic resonance (NMR), and mass spectrum (MS). All of the isolated compounds were tested for antiproliferative effects on MCF-7, MDA-MB-231, and T-47D cells. Results showed that compounds 1, 3, 4, 6, and 7 at 50 μM significantly inhibited MCF-7 cell proliferation by 30.2, 19.2, 21.0, 13.5, and 32.4%, respectively; compounds 2, 4, and 7 significantly inhibited T-47D cells at 50 μM by 20.7, 24.8, and 28.9%; and compounds 1, 2, and 12 significantly inhibited MDA-MB-231 cells at 50 μM by 47.4, 25.3, and 69.3%, respectively. In conclusion, ABE has antiproliferative activities, and this effect is partially related to the presence of lactams and spiroenone.

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“…The alcohol (6) and aldehyde (7) may also be formed via the peroxyl radical (4), but most interest in respect of the biological activity of IAA in plants has focused on a subsequent degradation product, 3-methylene-2-oxindole (8) (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Our interest in the IAA/HRP combination arose from the possible application of IAA as a prodrug in cancer therapy, with HRP generating a cytotoxin (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Reactivity toward Thiols and Cytotoxicity of 3-Methylene-2-oxindoles, Cytotoxins from Indole-3-acetic Acids, on Activation by Peroxidases

Folkes

Rossiter

Wardman

2002

Chem. Res. Toxicol.

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Oxidation of indole-3-acetic acid and its derivatives by peroxidases such as that from horseradish produces many products, including 3-methylene-2-oxindoles. These have long been associated with biological activity, but their reactivity has not been characterized. We have previously demonstrated the potential value of substituted indole acetic acids and horseradish peroxidase as the basis for targeted cancer therapy, since the compounds are of low cytotoxicity until oxidized, when high cytotoxicity is observed; the combination of prodrug and enzyme depletes intracellular thiols. In this study, 3-methylene-2-oxindole and derivatives substituted in the 4-, 5-, or 6-position with methyl, F, or Cl have been synthesized and their reactivity toward representative thiol nucleophiles (glutathione, cysteine, and a cysteinyl peptide) measured using stopped-flow kinetic spectrophotometry. Rate constants were in the range approximately 2 x 10(3) to 2 x 10(4) M(-)(1) s(-)(1) at pH 7.4, 25 degrees C, implying a lifetime of a few tens of milliseconds for these methylene oxindoles in the cellular environment and diffusion distances of a few micrometers. As expected, halogen substitution decreased the rate of production of the methylene oxindoles on treatment of horseradish peroxidase. The cytotoxicities of the compounds were measured using Chinese hamster V79 fibroblast-like cells in vitro. The halogen-substituted derivatives were much more cytotoxic than the 5-methyl analogue or the parent (unsubstituted) compound, consistent with the trends in rate constant for reaction with the thiols. The results show that the cytotoxic response in the prodrug (indole acetic acid) and enzyme (horseradish peroxidase) system reflects the reactivity of methylene oxindoles toward nucleophiles much more than the rate of generation of the oxindoles, and helps explain the possible advantages of 5-fluoroindole-3-acetic acid compared to IAA as a lead compound for investigation in targeted cancer therapy.

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Synthesis and Cytotoxic Activity of Latentiated Derivatives of 3-Methyleneoxindole

Cited by 11 publications

References 15 publications

The chemistry of isatins: a review from 1975 to 1999

The chemistry of isatins: a review from 1975 to 1999

Antiproliferative Lactams and Spiroenone from Adlay Bran in Human Breast Cancer Cell Lines

Reactivity toward Thiols and Cytotoxicity of 3-Methylene-2-oxindoles, Cytotoxins from Indole-3-acetic Acids, on Activation by Peroxidases

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