Design, synthesis and biological evaluation of 7-(aryl)-2,3-dihydro-[1,4]dioxino[2,3- g ]quinoline derivatives as potential Hsp90 inhibitors and anticancer agents

Malayeri, Sina Omid; Abnous, Khalil; Arab, Atefeh; Akaberi, Maryam; Mehri, Soghra; Zarghi, Afshin; Ghodsi, Razieh

doi:10.1016/j.bmc.2016.12.050

Cited by 26 publications

(10 citation statements)

References 18 publications

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“…Doebner or pfitzinger reactions were used for the synthesis of target compounds 6 a – y (Scheme 1) and for the synthesis of compounds 9 a – e was used doebner reaction (Scheme 2). According to doebner reaction, benzo[h]quinoline carboxylic acids ( 9 a – e ) and some quinolone carboxylic acids were obtained using the condensation of substituted aldehyde, pyruvic acid and substituted aniline in EtOH under reflux [19–23] . According to pfitzinger reaction for the synthesis of some quinolone carboxylic acids, appropriate acetophenones and isatin in the presence of KOH were heated in EtOH (Scheme1) [24] …”

Section: Resultsmentioning

confidence: 99%

“…ChemistrySelect acids (9 a-e) and some quinolone carboxylic acids were obtained using the condensation of substituted aldehyde, pyruvic acid and substituted aniline in EtOH under reflux. [19][20][21][22][23] According to pfitzinger reaction for the synthesis of some quinolone carboxylic acids, appropriate acetophenones and isatin in the presence of KOH were heated in EtOH (Scheme1). [24] As shown in Scheme 3, the reaction between quinoline-4carboxylic acids (6 a-y) or benzo[h]quinoline carboxylic acids (9 a-e) with o-Phenylenediamine 10 led to the synthesis of quinoline benzamides 11 a-y and benzo[h]quinoline benzamides 12 a-e (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, Cytotoxicity, Pan‐HDAC Inhibitory Activity and Docking Study of N‐(2‐Aminophenyl)‐2‐arylquinoline‐4‐ and N‐(2‐Aminophenyl)‐2‐arylbenzo[h]quinoline‐4‐carboxamides**

et al. 2022

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A series of new N‐(2‐aminophenyl)‐2‐arylquinoline‐4‐carboxamide and N‐(2‐aminophenyl)‐2‐arylbenzo[h]quinoline‐4‐carboxamide derivatives were designed and synthesized. The cytotoxicity of the synthesized compounds was investigated on three cell lines A549, HT‐29 and HCT116. The synthesized compounds, despite simple structures, displayed moderate to good cytotoxicity. Pan‐HDAC inhibitory activity of the synthesized compounds was evaluated on two cell lines, HT‐29 and HCT116, which displayed inhibitory activity (%) of 9.77–50.39 % on HT‐29 and 7.1–53.64 % on HCT116 cell line at concentrations of 100 μM. The compounds 11 h, 11 k, 11 l, 11 m, 12 b, 12 c and 12 e with the best cytotoxicity (%) and Pan‐HDAC inhibitory activity (%) were selected to determine IC50 values. IC50 values were calculated from 18.5–43.5 μM on HCT116 compared to 15.9 μM for CI‐994 and 35.5–75.9 μM on HT‐29 compared to 33.65 μM for CI‐994. Pan‐HDAC inhibitory activity of these compounds was more than 100 μM on HCT116 cell line except for compound 12 e (85.75±7.49 μM). Docking study of selected compounds (11 h, 11 k, 11 l, 11 m, 12 b, 12 c and 12 e) was performed on HDAC isoforms that displayed the best docking scores on sirtuins.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis, Cytotoxicity, Pan‐HDAC Inhibitory Activity and Docking Study of N‐(2‐Aminophenyl)‐2‐arylquinoline‐4‐ and N‐(2‐Aminophenyl)‐2‐arylbenzo[h]quinoline‐4‐carboxamides**

et al. 2022

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“…Compounds were docked into the binding site of tubulin using MOE software. The top-score docking poses were selected for final ligand-target interaction analysis using the LigX module in MOE Software [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

Hadizadeh

Ghodsi

Mirzaei

et al. 2022

Computational and Mathematical Methods in Medicine

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Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner–Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

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“…The MTT‐based assay was performed by seeding 5,000 cancer cells per 180 µl RPMI complete culture medium in each well of 96‐well culture plates . The day after seeding, the culture medium was exchanged with medium containing standard antitumor agent's β‐lapachone and CA4 as well as different concentrations of novel synthesized compounds and RPMI control (contains no drug).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of novel benzo[c]acridine‐diones as potential anticancer agents and tubulin polymerization inhibitors

Behbahani

Tabeshpour

Mirzaei

et al. 2019

Archiv der Pharmazie

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A new series of novel benzo[c]acridine-diones possessing pharmacophoric elements of antitubulins with central dihydropyridine bridge were designed and synthesized as potential anticancer agents and tubulin polymerization inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against eight cancer cell lines including MCF-7, A2780, HeLa, HepG2, DU145, A549, PC3, and LNCAP cancer cells and normal cells (HUVEC) through 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, wherein β-lapachone and combretastatin A-4 were used as positive controls. Some of our compounds (4c and 4g) showed significant cytotoxic activity on cancer cells with IC 50 values in the range of 5.23-24.32 μM. None of the synthesized compounds showed significant cytotoxicity on normal HUVEC cells. Among all investigated derivatives, compound 4g showed promising greater antiproliferative activity against all tested cancer cells with the highest sensitivity observed for the PC3 cell line. Results from the flow cytometry analysis of PC3 and MCF-7 cancer cells treated with 4g showed an induced cell-cycle arrest at G2/M, and therefore induced apoptosis which occurred at low concentration of test compound, whereas annexin V-FITC/propidium iodide staining assay in the aforementioned cancer cell lines treated with 4g showed that 4g can cause necrosis in PC3 and MCF-7 cancer cells at higher concentration. Compound 4g proved to be an inhibitor of tubulin polymerization in a mode similar to that of colchicine and in a dose-dependent manner. Molecular docking studies of 4g into the colchicine-binding site of tubulin exhibited a possible mode of interaction between this compound and tubulin.

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Design, synthesis and biological evaluation of 7-(aryl)-2,3-dihydro-[1,4]dioxino[2,3- g ]quinoline derivatives as potential Hsp90 inhibitors and anticancer agents

Cited by 26 publications

References 18 publications

Synthesis, Cytotoxicity, Pan‐HDAC Inhibitory Activity and Docking Study of N‐(2‐Aminophenyl)‐2‐arylquinoline‐4‐ and N‐(2‐Aminophenyl)‐2‐arylbenzo[h]quinoline‐4‐carboxamides**

Synthesis, Cytotoxicity, Pan‐HDAC Inhibitory Activity and Docking Study of N‐(2‐Aminophenyl)‐2‐arylquinoline‐4‐ and N‐(2‐Aminophenyl)‐2‐arylbenzo[h]quinoline‐4‐carboxamides**

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

Synthesis and biological evaluation of novel benzo[c]acridine‐diones as potential anticancer agents and tubulin polymerization inhibitors

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