An Investigation into the Cytotoxicity and Mode of Action of Some Novel <i>N</i>-Alkyl-Substituted Isatins

Vine, Kara L.; Locke, Julie M.; Ranson, Marie; Pyne, Stephen G.; Bremner, John B.

doi:10.1021/jm0704189

Cited by 134 publications

(102 citation statements)

References 31 publications

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“…The crystal structures of the resulting compounds MI-63 and MDM2 were recently reported by Popowicz et al [8]. Interestingly, the MI-63 binding pattern is mirrored as previously assumed [9][10][11]. As previously assumed, 6-chloro-2-indolinone occupies Trp pockets but the combination of neopentyl and substituted phenyl Mode and the previous hypothesis were reversed, suggesting that the conformation of the compound has been reversed, but the two states of MDM2 have a better inhibition.…”

Section: Introductionsupporting

confidence: 66%

“…Salicylaldehyde or substituted salicylaldehyde(1-2) and ethyl acetoacetate formed cyclization in the piperidine-catalyzed system to get acetyl coumarin compounds (6-7), And then reacted with isatin (3-5) and glycine or sarcosine [2 + 3] cyclization to form spiro intermediate (8)(9)(10)(11)(12)(13), Wherein the pyrrole 1'-methylated product (8)(9)(10) is directly reacted with the corresponding nitrogen-containing fragment to form (14-18); the remaining intermediates (11-13) are reacted with triphosgene and the corresponding amine to give the 4-methoxybenzyl protected intermediate (19)(20)(21)(22)(23)(24), which is present in the presence of trifluoromethanesulfonic acid deprotection to get 25-30, and finally reacts with the corresponding nitrogen-containing heterocycle and fragment to yield the target product 31-43.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

Liang¹,

Tong²,

Yu³

et al. 2017

Med chem

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A series of spiro-indolin-2-one derivatives were designed and synthesized as p53-MDM2 binding inhibitors. Though p53-MDM2 binding inhibitory and activities against p53 wild-type cell lines of most compounds were not that promising, some obtained structures showed moderate to strong inhibitory activities (IC 50 <0.08 µM) against p53 mutant cell lines (SW620), suggesting that these compounds may have different modes of action to p53 pathway, further studies on treatment of p53 mutant tumors are under investigation.cc

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Section: Introductionsupporting

confidence: 66%

Section: Chemistrymentioning

confidence: 99%

Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

Liang¹,

Tong²,

Yu³

et al. 2017

Med chem

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“…The method used was derived from Vine et al (2007). Cells (2.0 x 10 6 ) were treated with a solution containing 40 µg/mL PI, 100 µg/mL RNase A, and PBS (pH 7.4) at 37°C for 1 hour before the cell cycle analysis.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy

et al. 2015

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Tehei, M. (2015). Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy. Physics in Medicine and Biology, 60 (20), 7847-7859.Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy AbstractDespite the use of multimodal treatments incorporating surgery, chemotherapy and radiotherapy, local control of gliomas remains a major challenge. The potential of a new treatment approach called indirect radiochemo-beta therapy using the synergy created by combining methotrexate (MTX) with bromodeoxyuridine (BrUdR) under optimum energy x-ray irradiation is assessed. 9L rat gliosarcoma cells pre-treated with 0.01 μM MTX and/or 10 μM BrUdR were irradiated in vitro with 50 kVp, 125 kVp, 250 kVp, 6 MV and 10 MV xrays. The cytotoxicity was assessed using clonogenic survival as the radiobiological endpoint. The photon energy with maximum effect was determined using radiation sensitization enhancement factors at 10% clonogenic survival (SER10%). The cell cycle distribution was investigated using flow cytometric analysis with propidium iodide staining. Incorporation of BrUdR in the DNA was detected by the fluorescence of labelled anti-BrUdR antibodies. The radiation sensitization enhancement exhibits energy dependence with a maximum of 2.3 at 125 kVp for the combined drug treated cells. At this energy, the shape of the clonogenic survival curve of the pharmacological agents treated cells changes substantially. This change is interpreted as an increased lethality of the local radiation environment and is attributed to supplemented inhibition of DNA repair. Radiation induced chemo-beta therapy was demonstrated in vitro by the targeted activation of combined pharmacological agents with optimized energy tuning of x-ray beams on 9 L cells. Our results show that this is a highly effective form of chemo-radiation therapy. AbstractDespite the use of multimodal treatments incorporating surgery, chemotherapy and radiotherapy, local control of gliomas remains a major challenge. The potential of a new treatment approach called indirect radio-chemo-beta therapy using the synergy created by combining methotrexate (MTX) with bromodeoxyuridine (BrUdR) under optimum energy X-ray irradiation is assessed. 9L rat gliosarcoma cells pre-treated with 0.01 µM MTX and/or 10 µM BrUdR were irradiated in vitro with 50 kVp, 125 kVp, 250 kVp, 6 MV and 10 MV X-rays. The cytotoxicity was assessed using clonogenic survival as the radiobiological endpoint. The photon energy with maximum effect was determined using radiation sensitization enhancement factors at 10% clonogenic survival (SER 10% ). The cell cycle distribution was investigated using flow cytometric analysis with propidium iodide staining. Incorporation of BrUdR in the DNA was detected by the fluorescence of labeled antiBrUdR antibodies. The radiation sensitization enhancement exhibits energy dependence with a maximum of 2.3 at 125 kVp for the combined drug treated cells. At this energ...

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“…In 2007, Vine et al [49] synthesised a series of dibrominated N-substituted isatins (e.g. 6a-d and 7a-n, Fig.…”

Section: N-alkyl Substituted Isatin Derivativesmentioning

confidence: 99%

“…(5)). Given the increased potency of the halogenated isatins (see section 2.1) and the fact that N-methylation significantly enhanced the cytotoxicity of the parent compound (1) [39], these compounds were evaluated for their cytotoxicity against a panel cancer cell lines in vitro [49]. SAR studies indicated that the introduction of an aromatic ring with a one or three carbon atom linker at N1 increased the activity relative to that of the allyl (6a), 2´-methoxyethyl (6b) and 3´-methylbutyl (6c) Nsubstituted isatins.…”

Section: N-alkyl Substituted Isatin Derivativesmentioning

confidence: 99%

Recent Highlights in the Development of Isatin-Based Anticancer Agents

Vine¹,

Matesic²,

Locke³

et al. 2013

Advances in Anticancer Agents in Medicinal Chemistry

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Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and trisubstitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P-glycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships. Abstract:Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and tri-substitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, Pglycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships.

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An Investigation into the Cytotoxicity and Mode of Action of Some Novel N-Alkyl-Substituted Isatins

Cited by 134 publications

References 31 publications

Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy

Recent Highlights in the Development of Isatin-Based Anticancer Agents

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