Synthesis and hydrolytic evaluation of acid-labile imine-linked cytotoxic isatin model systems

Matesic, Lidia; Locke, Julie M.; Vine, Kara L.; Ranson, Marie; Bremner, John B.; Skropeta, Danielle

doi:10.1016/j.bmc.2011.01.015

Cited by 21 publications

(17 citation statements)

References 39 publications

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“…Substituted indolin-2-ones have been identified as a versatile scaffold which exhibit diverse chemotherapeutic activities such as anticancer, antiviral and many others properties [1][2][3]. Among them, 1H-indole-2,3-dioxo-3-thiosemicarbazones have in general been reported to possess antitumour activities [3,4].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (Z)-4-benzyl-N'-(4-chloro-2-oxoindolin-3-ylidene)-piperazine-1-carbothiohydrazide, C20H20ClN5OS

Mao

Wan

et al. 2013

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialA mixture of the 4-chloroindoline-2,3-dione (0.18 g, 1.0 mmol) and 4-benzylpiperazine-1-carbothiohydrazide (0.25 g, 1.0 mmol) in absolute methanol (20 mL) was stirred at room temperature for 3 days. Thin layer chromatography (TLC) of the solution indicated the end of the reaction (R f = 0.40, dichloromethane/methanol = 95:5, v/v). The precipitates were collected by filtration and dried in air, which was purified by recrystallization from ethanol to give the title compound (yield 40%; m.p. 497-498 K). Yellow single crystals suitable for X-ray diffraction were grown from a mixture of dichloromethane and methanol (5:1, v/v) by slow evaporation at room temperature.

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Section: Discussionmentioning

confidence: 99%

Crystal structure of (Z)-4-benzyl-N'-(4-chloro-2-oxoindolin-3-ylidene)-piperazine-1-carbothiohydrazide, C20H20ClN5OS

Mao

Wan

et al. 2013

Zeitschrift Für Kristallographie - New Crystal Structures

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“…When the release was conducted in an aqueous solution at pH =7.4 with or without DTT, almost no DOX in the drugloaded micelles was released, which is consistent with the hydrolysis results of isatin-based aryl imine derivatives. 37 Obvious contribution of the reducing agent DTT to the drug release was not observed, because DOX is covalently bonded to the polymer chains via aromatic imine linkage, which is stable in the neutral aqueous solution. [36][37][38][39] However, when the release was performed in weak acidic solution, the influence of DTT on the release of DOX was observed; for example, when the release was conducted at pH =6.0 with and without DTT for 48 hours, different release rates were observed: 44 wt% (with DTT) and 34 wt% (without DTT) of DOX in micelles were released.…”

Section: In Vitro Dox Releasementioning

confidence: 99%

“…34,35 In recent years, the imine linkers have gained significant attention, because several studies indicate that the aromatic imines with extended π-π conjugation can significantly improve the stability of imine linkages in water. [36][37][38][39] Therefore, we speculated that investigation of pH-responsive behaviors of drug carriers, in which the drug is covalently attached to the polymer backbone in the hydrophobic cores via aromatic imine linkage, should be interesting, and would help to enable design of a pH-triggered drug delivery system. The imine linkage has been widely employed in the preparation of shell or core cross-linked (SCL or CCL) micelles for improvement of micellar integrity and drug encapsulation stability.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

Qiu

Pan

2015

IJN

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Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP) n s, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP) n s (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system.

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“…Previously reported N-alkylated 3-iminoisatins [133] (50a-e, Fig. (17)) have been found to be extremely cytotoxic, with two derivatives (50c and 50e) displaying nanomolar activity towards U937 lymphoma cells after a 24 h exposure [134].…”

Section: Gudipati Et Al Have Also Investigated Twelve 3-iminoisatinsmentioning

confidence: 99%

“…(26)) [170]. The bifunctional linker was selected on the basis of hydrolytic studies led by Matesic et al on a series of isatin-based imino acid derivatives [176]. The derivatives were functionalised at the C3 carbonyl group of 5,7-dibromo-N-(p-methoxybenzyl)isatin (7f) and were stable at physiological pH but readily cleaved at pH 4.5.…”

Section: Selectively Deliverable Conjugatesmentioning

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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Synthesis and hydrolytic evaluation of acid-labile imine-linked cytotoxic isatin model systems

Cited by 21 publications

References 39 publications

Crystal structure of (Z)-4-benzyl-N'-(4-chloro-2-oxoindolin-3-ylidene)-piperazine-1-carbothiohydrazide, C20H20ClN5OS

Crystal structure of (Z)-4-benzyl-N'-(4-chloro-2-oxoindolin-3-ylidene)-piperazine-1-carbothiohydrazide, C20H20ClN5OS

Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

Recent Highlights in the Development of Isatin-Based Anticancer Agents

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