Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products

Kanizsai, Iván; Madácsi, Ramóna; Hackler, László; Gyuris, Márió; Szebeni, Gábor J.; Huzián, Orsolya; Puskás, László G.

doi:10.3390/molecules23081934

Cited by 12 publications

(14 citation statements)

References 48 publications

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“…Mitochondrial membrane potential (MMP) is affected by oxidative stress and may serve as a trigger for programmed cell death. Previously, we have shown that 8HQ analogs were able to normalize the mitochondrial membrane potential of U251 MG cells following oxidative stress in a dose dependent manner [16]. Here, we investigated whether Q134R and Q134S show any difference in their activity.…”

Section: Resultsmentioning

confidence: 94%

“…As previously reported, a formic acid-mediated three-component assembly of 8HQ ( 1 ), 4-(trifluoromethyl)benzaldehyde ( 2 ), and 4-methylpyrimidin-2-amine ( 3 ) gave access to racemic Q134 [16]. In order to prepare pure enantiomers, cinchona alkaloids were firstly tested in the Betti-3CR, giving no conversion.…”

Section: Resultsmentioning

confidence: 99%

“…RT cytoprotection assay was performed as previously described [14,16,25]. Briefly, RT-CES 96-well E-plate (BioTech Hungary, Budapest, Hungary) was coated with gelatin solution (0.2% in PBS, phosphate buffer saline) for 20 min at 37 °C, then gelatin was washed twice with PBS solution.…”

Section: Methodsmentioning

confidence: 99%

“…Systematic preparative efforts led to the analogue Q50, which was proven to be highly potent in improving cardiac functional recovery of ischemic/reperfused myocardium in rats [15]. Recently, a 48-membered Betti library was synthesized to screen for neuroprotective compounds by the utilization of formic acid mediated industrial-compatible coupling with sets of aromatic primary amines such as anilines, oxazoles, pyridines, and pyrimidines, with (hetero)aromatic aldehydes and 8-hydroxiquinoline derivatives [16]. To the best of our knowledge, the asymmetric Betti reaction incorporating 8-hydroxyquinoline has not been studied so far.…”

Section: Introductionmentioning

confidence: 99%

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Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent

Hackler¹,

Gyuris²,

Huzián³

et al. 2019

Molecules

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Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer’s disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent

Hackler¹,

Gyuris²,

Huzián³

et al. 2019

Molecules

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“…Mitochondrial membrane potential was measured as described previously in Reference [ 44 ]. Briefly, MV-4-11 cells (2 × 10 5 ) were plated in 24-well tissue culture plates (Corning Life Sciences, Corning, NY, USA) in RPMI 10% FCS and were treated in 500 μL media containing 40 nM or 200 nM DU385 compound.…”

Section: Methodsmentioning

confidence: 99%

Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations

Szebeni

Balog

Demjén³

et al. 2018

Molecules

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Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2-b]pyrazole-7-carboxamides have been tested for cytotoxic activity against five leukemia cell lines: Acute promyelocytic leukemia (HL-60), acute monocytic leukemia (THP-1), acute T-lymphoblastic leukemia (MOLT-4), biphenotypic B myelomonocytic leukemia (MV-4-11), and erythroleukemia (K-562) cells in vitro. Imidazo[1,2-b]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC50 values for the most effective lead compound DU385: 16.54 nM, 27.24 nM, and 32.25 nM on HL-60, MOLT-4, MV-4-11 cells, respectively. Human primary fibroblasts were much less sensitive in the applied concentration range. Both monolayer or spheroid cultures of murine 4T1 and human MCF7 breast cancer cells were less sensitive to treatment with 1.5–10.8 μM IC50 values. Flow cytometry confirmed the absence of necrosis and revealed 60% late apoptotic population for MV-4-11, and 50% early apoptotic population for HL-60. MOLT-4 cells showed only about 30% of total apoptotic population. Toxicogenomic study of DU385 on the most sensitive MV-4-11 cells revealed altered expression of sixteen genes as early (6 h), midterm (12 h), and late response (24 h) genes upon treatment. Changes in ALOX5AP, TXN, and SOD1 expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2-b]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations.

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A cytotoxic survey on 2‐amino‐1H‐imidazol based synthetic marine sponge alkaloid analogues

Gémes

Makra²,

Neuperger

et al. 2022

Drug Development Research

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Here, we describe the synthesis and biologic activity evaluation of 20 novel synthetic marine sponge alkaloid analogues with 2-amino-1H-imidazol (2-AI) core. Cytotoxicity was tested on murine 4T1 breast cancer, A549 human lung cancer, and HL-60 human myeloid leukemia cells by the resazurin assay. A total of 18 of 20 compounds showed cytotoxic effect on the cancer cell lines with different potential. Viability of healthy human fibroblasts and peripheral blood mononuclear cells upon treatment was less hampered compared to cancer cell lines supporting tumor cell specific cytotoxicity of our compounds. The most cytotoxic compounds resulted the following IC 50 values 28: 2.91 µM on HL-60 cells, and 29: 3.1 µM on 4T1 cells. The A549 cells were less sensitive to the treatments with IC 50 15 µM for both 28 and 29. Flow cytometry demonstrated the apoptotic effect of the most active seven compounds inducing phosphatidylserine exposure and sub-G1 fragmentation of nuclear DNA. Cell cycle arrest was also observed. Four compounds caused depolarization of the mitochondrial membrane potential as an early event of apoptosis. Two lead compounds inhibited tumor growth in vivo in the 4T1 triple negative breast cancer and A549 human lung adenocarcinoma xenograft models. Novel marine sponge alkaloid analogues are demonstrated as potential anticancer agents for further development.

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Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products

Cited by 12 publications

References 48 publications

Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent

Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent

Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations

A cytotoxic survey on 2‐amino‐1H‐imidazol based synthetic marine sponge alkaloid analogues

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