Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors

Szymański, Paweł; Karpiński, Adam; Mikiciuk-Olasik, Elżbieta

doi:10.1016/j.ejmech.2011.04.038

Cited by 33 publications

(21 citation statements)

References 26 publications

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“…18 Recently, we have synthesized and evaluated new 16 tetrahydroacridine derivatives and 16 cyclopentaquinoline derivatives with hydrazinonicotinic acid or with fluorobenzoic acid moiety on growth inhibition of human non-small cell lung cancer A549 cells. [19][20][21][22][23] Non-small cell lung cancer accounts for more than 80% of all lung cancer cases. 1,24 The results of these studies showed that the most effective compounds were tetrahydroacridine and cyclopentaquinoline derivatives coupled with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain.…”

Section: Introductionmentioning

confidence: 99%

Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling

et al. 2017

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Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. We found that the most effective were tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain. The aim of this study was to determine the molecular mechanisms of compounds-induced cell cycle arrest and apoptosis in human lung adenocarcinoma cells. All compounds activated Ataxia telangiectasia mutated kinase and phosphorylated histone H2A.X at Ser139 indicating DNA damage. Treatment of cells with the compounds increased phosphorylation and accumulation of p53 that regulate cell cycle as well as apoptosis. All compounds induced G0/1 cell cycle arrest by phosphorylation of cyclin-dependent kinase 2 at Tyr15 resulting in attenuation of the kinase activity. In addition, cyclopentaquinoline derivatives induced expression of cyclin-dependent kinase 2 inhibitor, p21; however, tetrahydroacridine derivatives had no significant effect on p21. Moreover, all compounds decreased the mitochondrial membrane potential accompanied by increased expression of Bax and down-regulation of Bcl-2, suggesting activation of the mitochondrial pathway. All compounds also significantly attenuated the migration rates of lung cancer cells. Collectively, our findings suggest a central role of activation of DNA damage signaling in response to new acridine derivatives treatment to induce cell cycle arrest and apoptosis in cancer cells and provide support for their further development as potential drug candidates.

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Section: Introductionmentioning

confidence: 99%

Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling

et al. 2017

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“…11,12 Recent studies have demonstrated that homo-and hetero-dimers can improve the biological profile of tacrine and even overcome some of its side effects. 13 Afterwards, quite a number of tacrine derivatives, some of them as hybrid drugs, have been developed to improve its activity, as described in a recent review in this topic, 14 including tacrine-8-hydroxyquinoline hybrids, 15 mercapto-tacrine derivatives 16 , tacrine-fluorobenzoic acid hybrids 17 and tacrinemultialkoxybenzene hybrids. 18 Moreover, based on evidences that reduction of amyloid deposits lead to alleviation of the AD´s symptoms, 19,20 a considerable current effort has been directed towards the identification and the development of potential therapeutic agents able to reduce the soluble amyloid oligomers burden.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

Keri¹,

Quintanova²,

Marques³

et al. 2013

Bioorganic & Medicinal Chemistry

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“…Bis-(6-fl uoro)tacrines, synthesized by Hu et al were found to be more potent in inhibiting rat AChE than tacrine and the unsubstituted bistacrine [ 15 ] . Development of new therapies for AD is extremely important, thus in continuation of our previous study [ 16 ] , we present synthesis of a new series of amino derivatives of tetrahydroacridine coupled with fl uorobenzoic acid as potential multifunctional drugs. Fluorobenzoic acid, for the fi rst time coupled with tetrahydroacridine derivatives, possesses dual course of action.…”

Section: Synthesis Biological Activity and Molecular Modeling Of 4-fmentioning

confidence: 92%

“…However, these compounds exhibited IC 50 value similar to tacrine. In our previous study [ 16 ] , we described synthesis and biological evaluation of 3 derivatives of fl uorobenzoic acid and 1,2,3,4-tetrahydroacridin-9-ylamine with 2, 3 and 4 carbon atoms in the aliphatic chain. These 3 compounds were characterized, in comparison with tacrine, by 4-fold higher inhibitory activity towards AChE, suggesting that introduction of aliphatic chain was a good alteration.…”

mentioning

confidence: 99%

Synthesis, Biological Activity and Molecular Modeling of 4-Fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide Derivatives as Cholinesterase Inhibitors

Szymański

Markowicz

Bajda

et al. 2012

Arzneimittelforschung

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The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacridines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman's spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation.

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Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors

Cited by 33 publications

References 26 publications

Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling

Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling

Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

Synthesis, Biological Activity and Molecular Modeling of 4-Fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide Derivatives as Cholinesterase Inhibitors

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