Synthesis and antiproliferative activities of diversely substituted glycosyl-isoindigo derivatives

Sassatelli, Mathieu; Bouchikhi, Fadoua; Messaoudi, Samir; Anizon, Fabrice; Débiton, Eric; Barthomeuf, Chantal; Prudhomme, Michelle; Moreau, Pascale

doi:10.1016/j.ejmech.2005.10.004

Cited by 54 publications

(25 citation statements)

References 14 publications

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“…The antitumor properties of some of these compounds have been studied with respect to apoptosis and cell cycle arrest. Indirubin and several of its analogues exhibit their anticancer activity through modulating CDKs, which will arrest cell cycle progression leading to cell death by apoptosis [17,18,19,20,22,23,25,26,27,28]. Multiple indirubin derivatives have been shown to arrest cell cycle at G0/G1 phase at low micromolar concentrations (up to 1 µM), while higher concentrations, ≥ 5 µM, inhibit cell cycle at G2/M phase [23].…”

Section: Discussionmentioning

confidence: 99%

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The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Saleh

Aljada

El‐Abadelah

et al. 2015

Cell Physiol Biochem

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Background/Aims:The antileukemic potential of isoindigos make them desired candidates for understanding their mechanism of action. We have recently synthesized a novel group of pyridone-annelated isoindigos and identified the derivative 5'-Cl that is cytotoxic to various cancer cell lines. In the present study, we analyzed the effect of this compound on cell cycle of the promyelocytic leukemia cell line HL-60. Methods:HL-60 cells were treated with 5'-Cl and its effect on cell cycle stages were determined by flow cytometry. Expression of cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) were determined by Western blotting, and activation of CDKs was studied using kinase assays. Results:5'-Cl remarkably arrested cell cycle in HL-60 cells at the G0/G1 phase in a dose and time-dependent manner. Furthermore, 5'-Cl treatment significantly inhibited expression of D-cyclins, CDK2 and CDK4 and suppressed phosphorylation of the retinoblastoma protein Rb, whereas it increased the level of CKI p21. Molecular modelling experiments show that 5'-Cl may compete with ATP for binding to the catalytic subunit of CDK2 and CDK4 that could lead to inhibition of these enzymes. Indeed, 5'-Cl inhibited the kinase activity of CDK2 and CDK4 both in cell free systems and in treated cells. 5'-Cl also inhibited cell cycle progression in several other tumor cell lines. Conclusion:We demonstrate the potent inhibitory effects of 5'-Cl on HL-60 cells could be mediated by arresting cells in the G0/G1 phase.

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Section: Discussionmentioning

confidence: 99%

“…Several of these compounds have been shown to inhibit CDKs and glycogen-synthase kinase (GSK-3β) and induce apoptosis in leukemic cells with varying degrees of potency [17,18,19,20,22,23,25,26,27,28]. In spite of extensive investigations on the mode of action of isoindigos in various malignancies, comprehensive study is yet to be done.…”

Section: Introductionmentioning

confidence: 99%

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Saleh

Aljada

El‐Abadelah

et al. 2015

Cell Physiol Biochem

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“…Protected analogues are speculated to enhance cellular penetration and therefore, display superior biological activity compared to the corresponding non-protected compounds. Acetylated glycosyl-isoindigo derivatives prepared by Sassatelli et al displayed greater cytotoxicity against a panel of human solid tumour cell lines than the analogous benzylated compounds [142].…”

Section: Isoindigo and Derivativesmentioning

confidence: 99%

“…Glycosyl-isoindigo derivatives (60) have been prepared bearing benzyl or acetyl protecting groups on the sugar residue [142]. Protected analogues are speculated to enhance cellular penetration and therefore, display superior biological activity compared to the corresponding non-protected compounds.…”

Section: Isoindigo and 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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“…We have reported, in previous papers, the synthesis and biological activities of isoindigo derivatives (indirubin isomers possessing two indolin-2-one moieties) bearing a sugar residue attached to one of the aromatic nitrogens and diversely substituted on the aromatic rings at the 5-, 6-and/or 5′-positions [1], [2], [3] and [4]. 7′-Azaisoindigo analogues were also prepared to evaluate the influence of a 7-azaindolin-2-one moiety instead of an indolin-2-one part on the biological activities of these compounds [4].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, kinase inhibitory potencies and in vitro antiproliferative activity of isoindigo and 7′-azaisoindigo derivatives substituted by Sonogashira cross-coupling

Bouchikhi

Anizon

Moreau

2009

European Journal of Medicinal Chemistry

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In the course of structure-activity relationship studies we were interested in the synthesis of isoindigo and 7′-azaisoindigo derivatives substituted at the N-1 position by a 1-(2,3,4,6-tetra-O-acetyl-β-dglucopyranosyl), at the 5′-position by various chains introduced by Sonogashira cross-coupling and substituted or not at the 5-position by a bromine atom. To get an insight into the substitution pattern required for the best biological potencies, their kinase inhibitory potencies and their in vitro antiproliferative activities were evaluated. The derivatives were tested toward four protein kinases (CDK5/p25, GSK3, CK1, Dyrk1A) and their in vitro antiproliferative activity was tested against two human myeloid leukaemia cell lines (K562 and HL60).

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Synthesis and antiproliferative activities of diversely substituted glycosyl-isoindigo derivatives

Cited by 54 publications

References 14 publications

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Recent Highlights in the Development of Isatin-Based Anticancer Agents

Synthesis, kinase inhibitory potencies and in vitro antiproliferative activity of isoindigo and 7′-azaisoindigo derivatives substituted by Sonogashira cross-coupling

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