Identification of 8-Hydroxyquinoline Derivatives That Decrease Cystathionine Beta Synthase (CBS) Activity

Conan, Pierre; Léon, Alice; Gourdel, Mathilde; Rollet, Claire; Chaïr, Loubna; Caroff, Noéline; Goux, Nelig Le; Jossic-Corcos, Catherine Le; Sinane, Maha; Gentile, Lucile; Maillebouis, Louise; Martin, Jennifer; Vilaire, Marie; Corcos, Laurent; Mignen, Olivier; Croyal, Mikaël; Voisset, Cécile; Bihel, Frédéric; Friocourt, Gaëlle

doi:10.3390/ijms23126769

Cited by 3 publications

(15 citation statements)

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“…Several compounds identified in our drug screening point toward an important role of metal ion chelation in the regulation of CBS activity, as previously reported (Maréchal et al, 2019;Conan et al, 2022). Indeed, we previously showed that decreasing intracellular copper levels decreased the effects of CBS overexpression in yeast and H 2 S production in HepG2 cells (Conan et al, 2022). Here, the identification of several compounds involved in metal chelation [4-(2-Thiazolylazo)-resorcinol, 1-(2-Thiazolylazo)-2-naphtol, γ-thujaplicin, doxorubicin and daunorubicin hydrochloride, naphtoquinones.…”

Section: Role Of Metal Chelation In the Regulation Of Cbs Activitysupporting

confidence: 79%

Section: Role Of Metal Chelation In the Regulation Of Cbs Activitysupporting

confidence: 79%

“…Drug screening was performed as previously described ( Maréchal et al, 2019 ; Conan et al, 2022 ) using compounds obtained from the NIH from different sets: 166 FDA-approved Oncology Drugs (at a concentration of 10 mM in DMSO), 1,584 compounds of the NCI Diversity Set VI (at a concentration of 10 mM in DMSO), 811 compounds of the Mechanistic Set VI (at a concentration of 1 mM in DMSO) and 390 compounds of the Natural Products Set V (at a concentration of 10 mM in DMSO).…”

Section: Methodsmentioning

confidence: 99%

“…Determination of yeast cytosolic pH was performed as previously described ( Conan et al, 2022 ) using a pRS416- ADH plasmid containing a pH-sensitive ratiometric GFP variant named pHluorin (kindly obtained from S. Léon, IJM, Paris).…”

Section: Methodsmentioning

confidence: 99%

“…We recently developed a new screening method based on the budding yeast Saccharomyces cerevisiae which allows the identification of drugs or genes that interfere with the phenotypical consequences of CYS4 ( CBS homolog in yeast) overexpression. Using this method, we recently identified four molecules (disulfiram, chloroxine, clioquinol, and nitroxoline), all involved in metallic ion binding ( Maréchal et al, 2019 ; Conan et al, 2022 ), which effect on CBS activity has been validated in different cellular models ( Zuhra et al, 2020 ; Conan et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

et al. 2023

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Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeast-based pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS.

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Section: Role Of Metal Chelation In the Regulation Of Cbs Activitysupporting

confidence: 79%

Section: Role Of Metal Chelation In the Regulation Of Cbs Activitysupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

et al. 2023

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Chelation of Divalent Cations and Anti-Cancer Activityof 8-Hydroxystyrylquinoline Derivatives in Vitro

Virych,

Smokal,

Kharchenko

et al. 2023

BTSNUKSB

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Background. The search for new methods of cancer treatment and diagnosis are important. The disadvantages of chemotherapy drugs are the rapid acquisition of resistance and high toxicity. 8-hydroxyquinoline derivatives have a wide spectrum of biological activity and have the necessary properties for fluorescent cancer diagnosis. The aim of the study was to determine the chelation of calcium, magnesium and zinc cations by hydrophobic derivatives of 8-hydroxystyrylquinolines (8HQ) 2-(4-chlorostyryl)quinolin-8-ol (STQ-Cl) and 2-(4-nitrostyryl)quinolin-8-ol (STQ-NO2) in physiological solution, the stability of the complexes and the cytotoxicity of the compounds to prostate and breast cancer cell lines in vitro. Methods. 8HQ derivatives STQ-Cl and STQ-NO2 were used. Solutions of Ca2+, Mg2+, Zn2+ cations were prepared by the method of two-fold dilutions in 0.5-0.0078125 mM concentration range based on 0.9 % NaCl. Both individual solutions of each cation and a mixture in an equivalent molar ratio were used. The concentration of 8HQ derivatives were 0.05 mM. Optical absorption was registered in 200-700 nm wavelength range. Cytotoxicity was investigated on breast (MDA-MB-231) and prostate (DU-145) cancer cell lines. STQ-Cl and STQ-NO2 derivatives in DMSO were added to the incubation solution by four-fold dilutions (0.125–0.00003 mM). For luminescence studies, MDA-MB-231 and DU-145 cells were grown on coverslips. The final concentration of 8HQ derivatives were 5 mM. Cells were kept for 5, 10, 20 and 30 min. Luminescence was recorded under the same conditions for all samples, with an exposure time of 10 ms. Results. Mg2+ and Ca2+ (0.03125 mM) were contributed to reduce the intensity of optical absorption maxima of STQ-Cl by 1.6 and 1.3 times, respectively. The effect was most pronounced at 0.015625 mM Zn2+. Weak differences in the optical absorption of solutions were detected when STQ-NO2 was incubated with different concentrations of Mg2+ and Ca2+. The optical absorption intensity of the STQ-NO2 aqueous solution was increased at 0.015625 and 0.03125 mM Zn2+. The maximum cytotoxicity against MDA-MB-231 cells for STQ-Cl was about 80 %, and STQ-NO2 was 60 % at 0.04 mM Zn2+. DU-145 cells were more sensitive to STQ-NO2 (EC50 = 0.011 mM), but weakly sensitive to STQ-Cl (50 % at 0.125 mM). The maximum luminescence intensity was after 20 min of incubation with STQ-Cl and STQ-NO2 (5 mM) for both cells lines and was not change over time. Conclusions. The decrease of optical absorption maxima of STQ-Cl aqueous solutions in the presence of magnesium, calcium, and zinc cations was a consequence of aggregation processes. This phenomenon was probably the reason for the different cytotoxicity of STQ-Cl and STQ-NO2, as well as the presence of other mechanisms of action to cancer cells. Results was a consequence of different affinity of 8-hydroxyquinoline derivatives to magnesium, calcium and zinc cations, solubility in water, stability, aggregation of metal complexes and free compounds.

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Design, Synthesis, and Anticancer and Antibacterial Activities of Quinoline-5-Sulfonamides

Zieba,

Pindjakova,

Latocha

et al. 2024

Molecules

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A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a–f and 6a–f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a–h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a–d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a–f and 6a–f and 1,2,3-triazole derivatives 7a–h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a–f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.

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Identification of 8-Hydroxyquinoline Derivatives That Decrease Cystathionine Beta Synthase (CBS) Activity

Cited by 3 publications

References 64 publications

New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

Chelation of Divalent Cations and Anti-Cancer Activityof 8-Hydroxystyrylquinoline Derivatives in Vitro

Design, Synthesis, and Anticancer and Antibacterial Activities of Quinoline-5-Sulfonamides

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