Structure–activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines

Madonna, Sébastien; Béclin, Christophe; Laras, Younès; Moret, Vincent; Marcowycz, Aline; Lamoral-Theys, Delphine; Dubois, Jacques; Barthélémy-Requin, Magali; Lenglet, Gaëlle; Depauw, Sabine; Cresteil, Thierry; Aubert, Geneviève; Monnier, Valérie; Kiss, Róbert; David-Cordonnier, Marie-Hélène; Kraus, Jean‐Louis

doi:10.1016/j.ejmech.2009.11.006

Cited by 38 publications

(26 citation statements)

References 53 publications

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“…In parallel, inflammation and apoptotic genes were found to be induced. Concomitantly to this stress induction we also observed a clear signature of cell cycle inhibition, in accordance with the phenotype of treated cells (2).…”

Section: Introductionsupporting

confidence: 58%

“…In U87 cells, however, P53 exists in a non-mutated form and has been involved in the response of these cells to anti-cancer compounds, in particular the DNA alkylating agent Temozolomide, the main chemical arm against glioma (7,8), and also to nitrosoureas (9). Moreover, in our micro-array analyses of HQNBA-treated U87 cells we detected up-regulation of P53 and several genes of its signaling pathway (2).…”

Section: Introductionmentioning

confidence: 63%

“…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: 74%

“…More recently, we found that in different glioblastoma cell lines (U87, U373, Hs683, T989G) HQNBA derivatives efficiently blocked cell proliferation and migration in the absence of apopotosis (2). Taking advantage of the ability of U87 cells to survive these treatments, we analyzed the cellular response at the molecular level.…”

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: Introductionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 74%

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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“…15), are potent antitumor drugs. Their antiproliferative activities are strongly correlated with their ability to generate relatively stable and moderately reactive QM intermediates, which react with thiols but not with DNA, probably due to their low electrophilicity and, consequently, low reactivity with weak nucleophilicity [100].…”

Section: Drugs That Release Qms That React Preferentially With Proteimentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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Development of a FUT8 Inhibitor with Cellular Inhibitory Properties

Manabe,

Takebe,

Kasahara

et al. 2024

Angewandte Chemie

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Core fucosylation is catalyzed by α‐1,6‐fucosyltransferase (FUT8), which fucosylates the innermost GlcNAc of N‐glycans. Given the association of FUT8 with various diseases including cancer, selective FUT8 inhibitors applicable to in vivo or cell‐based systems are highly sought‐after. Here, we report the discovery of a compound that selectively inhibits FUT8 in cell‐based assays. High‐throughput screening revealed a FUT8‐inhibiting pharmacophore, and further structural optimization yielded an inhibitor with a KD of 49 nM. Notably, this binding occurs only in the presence of GDP (a product of the enzymatic reaction catalyzed by FUT8). Mechanistic studies suggested that this inhibitor generates a highly reactive naphthoquinone methide derivative at the binding site in FUT8, which subsequently reacts with FUT8. Furthermore, prodrug derivatization of this inhibitor improved its stability, enabling suppression of core fucose expression and subsequent EGFR and T‐cell signaling in cell‐based assays, paving the way for the development of drugs targeting core fucosylation.

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Structure–activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines

Cited by 38 publications

References 53 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

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Development of a FUT8 Inhibitor with Cellular Inhibitory Properties

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