Quinoline anticancer agents active on DNA and DNA-interacting proteins: From classical to emerging therapeutic targets

Lauria, Antonino; Monica, Gabriele La; Bono, Alessia; Martorana, Annamaria

doi:10.1016/j.ejmech.2021.113555

Cited by 57 publications

(38 citation statements)

References 181 publications

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“…Various natural products, bioactive drug molecules, pharmaceuticals, and agrochemicals incorporate quinoline pharmacophore [16][17][18]. Notable medicinal applications associated with the quinoline heterocycle include anticancer, anti-tubercular, antiproliferative, anti-malarial, antibacterial, anti-inflammatory, anti-protozoal, anti-fungal, anti-tumor, antioxidant, anti-HIV, anti-hypertensive, alkaline phosphatase inhibition and for the treatment of neurodegenerative disorders [19][20][21][22][23][24][25][26][27][28]. In parallel, thiosemicarbazones also display a wide plethora of biological properties ranging from anticancer, anti-bacterial, anti-tumor, anti-protozoal, anti-fungal, anti-leishmanial, and antiviral activities [29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

et al. 2021

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

et al. 2021

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“…Due to the steric and electron features, quinoline-based compounds are well-known DNA intercalating agents [ 63 ]. Therefore, the antiproliferative action of quinoline-related compounds can be related among others to intercalating between two adjacent base pairs of duplex DNA and inhibiting nucleic acid synthesis [ 64 ].…”

Section: Resultsmentioning

confidence: 99%

Glycoconjugation of Quinoline Derivatives Using the C-6 Position in Sugars as a Strategy for Improving the Selectivity and Cytotoxicity of Functionalized Compounds

et al. 2022

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Based on the Warburg effect and the increased demand for glucose by tumor cells, a targeted drug delivery strategy was developed. A series of new glycoconjugates with increased ability to interact with GLUT transporters, responsible for the transport of sugars to cancer cells, were synthesized. Glycoconjugation was performed using the C-6 position in the sugar unit, as the least involved in the formation of hydrogen bonds with various aminoacids residues of the transporter. The carbohydrate moiety was connected with the 8-hydroxyquinoline scaffold via a 1,2,3-triazole linker. For the obtained compounds, several in vitro biological tests were performed using HCT-116 and MCF-7 cancer cells as well as NHDF-Neo healthy cells. The highest cytotoxicity of both cancer cell lines in the MTT test was noted for glycoconjugates in which the triazole-quinoline was attached through the triazole nitrogen atom to the d-glucose unit directly to the carbon at the C-6 position. These compounds were more selective than the analogous glycoconjugates formed by the C-1 anomeric position of d-glucose. Experiments with an EDG inhibitor have shown that GLUTs can be involved in the transport of glycoconjugates. The results of apoptosis and cell cycle analyses by flow cytometry confirmed that the new type of glycoconjugates shows pro-apoptotic properties, without significantly affecting changes in the distribution of the cell cycle. Moreover, glycoconjugates were able to decrease the clonogenic potential of cancer cells, inhibit the migration capacity of cells and intercalate with DNA.

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“…Furthermore, some polycyclic heteroaromatic systems containing quinoline rings were encountered as potent DNA intercalators and/or topo II inhibitors. 49–60 In addition, the literature on cyclopenta[ b ]quinoline scaffolds reveals its potential as a potent DNA intercalator. 61 So, in this research we aimed to synthesize a novel series of 9 H -cyclopenta[ b ]quinoline derivatives sharing the same three common pharmacophoric features of DNA intercalators and topo II inhibitors, revealing their potential as antineoplastic agents.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, biological evaluation, and SAR studies of novel cyclopentaquinoline derivatives as DNA intercalators, topoisomerase II inhibitors, and apoptotic inducers

et al. 2022

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Quinoline anticancer agents active on DNA and DNA-interacting proteins: From classical to emerging therapeutic targets

Cited by 57 publications

References 181 publications

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Glycoconjugation of Quinoline Derivatives Using the C-6 Position in Sugars as a Strategy for Improving the Selectivity and Cytotoxicity of Functionalized Compounds

Design, synthesis, biological evaluation, and SAR studies of novel cyclopentaquinoline derivatives as DNA intercalators, topoisomerase II inhibitors, and apoptotic inducers

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