Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure–activity relationship, and action mechanism studies

Moret, Vincent; Laras, Younès; Cresteil, Thierry; Aubert, Geneviève; Dou, Q. Ping; Chen, Di; Barthélémy-Requin, Magali; Béclin, Christophe; Peyrot, Vincent; Allegro, Diane; Rolland, Amandine; Angelis, Francesca De; Gatti, Evelina; Pierre, Philippe; Pasquini, Luca; Petrucci, Eleonora; Testa, Ugo; Kraus, J.L.

doi:10.1016/j.ejmech.2008.03.042

Cited by 48 publications

(38 citation statements)

References 16 publications

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“…However, in contrast to most pharmaceutical alkylating compounds, quinone methide is not sufficiently electrophile to react with DNA but is reactive enough to covalently bind adducts to strong nucleophiles such as thiol radicals (2). In addition, we demonstrated that these compounds can induce apoptotic cell death in several cancer cell lines (1,2).…”

Section: Introductionmentioning

confidence: 84%

“…For proliferation assay, the initial time-point was the time at which chemicals were added. Synthesis of HQNBA derivatives and related spectroscopic data have been previously reported (1,2).…”

Section: Methodsmentioning

confidence: 99%

“…We recently identified N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines (HQNBA) as a new anticancer family of compounds (1) and showed that these compounds act through the formation of a quinone methide intermediate with alkylating properties. However, in contrast to most pharmaceutical alkylating compounds, quinone methide is not sufficiently electrophile to react with DNA but is reactive enough to covalently bind adducts to strong nucleophiles such as thiol radicals (2).…”

Section: Introductionmentioning

confidence: 99%

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Alternative responses of primary tumor cells and glioblastoma cell lines to N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines: Cell death versus P53-independent senescence

Kraus¹,

Conti²,

Madonna³

et al. 2010

Int J Oncol

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Abstract. N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines (HQNBA) represent a new class of compounds showing anti-cancer activity. At the chemical level the compounds were shown to react preferentially with thiol radicals which may lead to unfolded cysteine containing proteins and subsequent ER-stress. At the molecular level, treatment of U87 cells with this class of derivatives induced an over-expression of stress genes, including P53 and numerous P53 target genes. By generating shRNA U87 cell clones impaired in P53 expression we found that P53 mediates neither proliferation arrest of treated U87 cells nor over-expression of potential P53 targets. Moreover, we discovered that a representative HQNBA derivative (JLK1486) induces strong but transient senescence in U87 cells in a P53-independent manner. We demonstrate that, in contrast to its effect on established glioblastoma cell lines, JLK1486 induces extensive death of primary glioblastoma cells. We provide evidence that both caspase 3, and 7 activation, and cathepsin B and D activities account for at least part of this cell death.

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Section: Introductionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alternative responses of primary tumor cells and glioblastoma cell lines to N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines: Cell death versus P53-independent senescence

Kraus¹,

Conti²,

Madonna³

et al. 2010

Int J Oncol

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“…The compounds exert potent in vitro antiproliferative effects at concentrations ranging from 0.005 to 5 lM on a panel of tumor cell lines including adenocarcinoma, glioma and melanoma (Moret et al, 2009;Madonna et al, 2010). Among them, JLK1486 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Among them, JLK1486 ( Fig. 1) was found the most representative analogue which exerts a potent antitumor activity on various glioma cell lines (Hs683, T98G, and U373) at nanomolar range (Moret et al, 2009;Madonna et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Blood–brain barrier permeability and transport studies of JLK1486: a new antiglioblastoma drug

Barthélémy-Requin

Nugier²,

Madonna³

et al. 2011

Med Chem Res

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The knowledge of the brain permeation properties of drugs acting at the brain level is particularly important in the early phase of development and before clinical development. JLK1486 is a new anticancer drug recently reported, which in vitro evaluation on glioma cell lines is particularly promising. We reported here the HPLC analysis of cerebrospinal fluid (CSF) samples of rat injected by JLK1486. Only 0.23% of the total JLK1486 injected was found in CSF, indicating that only small amount of the drug cross the BBB, while theoretical calculations predict for this drug a high capacity of permeation. A possible hypothesis is the rapid metabolism of JLK1486 into conjugate metabolites. Relative to the possible interaction between JLK1486 and P-glycoprotein (P-gp), an ATPase assay was performed allowing to conclude that JLK1486 drug is not a good substrate for P-gp ATPase. In vivo experiments on transgenic mice brain xenografted by glioblastoma cells actually underway are required in order to confirm the in vivo antiproliferative properties of JLK1486 on glioblastoma.

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Synthesis, characterization and biological evaluation of a cobalt(II) complex with 5‐chloro‐8‐hydroxyquinoline as anticancer agent

Zhang

Meng

Liu

et al. 2016

Applied Organom Chemis

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A new cobalt(II) complex (1) of 5‐chloro‐8‐hydroxyquinoline was prepared and structurally characterized using infrared spectroscopy, electrospray ionization mass spectrometry, elemental analysis, single‐crystal X‐ray diffraction as well as powder X‐ray diffraction. Its biological activities including DNA binding and anticancer activity were investigated. The DNA binding study of complex 1 suggested that it interacted with calf thymus DNA mainly via an intercalative binding mode. The in vitro anticancer activity of complex 1 was screened against a series of tumor cell lines as well as the normal liver cell line HL‐7702 using MTT assay. complex 1 showed much higher cytotoxicity than corresponding metal salt and ligand towards the five tested tumor cell lines, in which T‐24 was the most sensitive tumor cell line towards 1, with IC50 value of 7.04 ± 0.06 μM. complex 1 was found to greatly induce cell cycle arrest in T‐24 cells at S phase, and consequently to induce cell apoptosis in a dose‐dependent mode suggested by cell apoptosis analysis via Hoechst 33258 and acridine orange/ethidium bromide staining assays. The cell apoptosis mechanism of 1 was studied targeting the mitochondrion‐mediated pathway, since the apoptotic mechanism in the T‐24 cells treated by 1 was investigated by reactive oxygen species (ROS) detection, intracellular calcium concentration measurement and caspase‐9/3 activity assay. The results suggested that the cell apoptosis induced by 1 was closely related to the loss of mitochondrial membrane potential, ROS production and enhancement of intracellular [Ca2+], which would trigger the caspase‐9/3 activation via a mitochondrial dysfunction pathway. Copyright © 2016 John Wiley & Sons, Ltd.

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Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure–activity relationship, and action mechanism studies

Cited by 48 publications

References 16 publications

Alternative responses of primary tumor cells and glioblastoma cell lines to N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines: Cell death versus P53-independent senescence

Alternative responses of primary tumor cells and glioblastoma cell lines to N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines: Cell death versus P53-independent senescence

Blood–brain barrier permeability and transport studies of JLK1486: a new antiglioblastoma drug

Synthesis, characterization and biological evaluation of a cobalt(II) complex with 5‐chloro‐8‐hydroxyquinoline as anticancer agent

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