Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

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Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents

Molecules ◽

10.3390/molecules24061066 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1066 ◽

Cited By ~ 10

Author(s):

Mohamed El-Naggar ◽

Hanan A. Sallam ◽

Safaa S. Shaban ◽

Salwa S. Abdel-Wahab ◽

Abd El-Galil E. Amr ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Anticancer Agents ◽

Human Cancer ◽

Docking Study ◽

Molecular Docking Study ◽

Reference Drug ◽

Human Cancer Cell Lines ◽

Dhfr Inhibitors

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 proved to be the most active DHFR inhibitors with an IC50 range of 0.04 ± 0.82–1.00 ± 0.85 µM, in comparison with Methotrexate (IC50 = 0.14 ± 1.38 µM). The highly potent DHFR inhibitors shared a similar molecular docking mode and made a critical hydrogen bond and arene‒arene interactions via Ser59 and Phe31 amino acid residues, respectively.

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Synthesis and Anticancer Activity Evaluation of Azepinobisindoles; the Isomeric Iheyamine A Derivatives

Oriental Journal Of Chemistry ◽

10.13005/ojc/350231 ◽

2019 ◽

Vol 35 (2) ◽

pp. 723-731

Author(s):

Weerachai Phutdhawong ◽

Sopita Rattanopas ◽

Jitnapa Sirirak ◽

Thongchai Taechowisan ◽

Waya S. Phutdhawong

Keyword(s):

Anticancer Activity ◽

Cell Line ◽

Cell Lines ◽

Human Cancer ◽

Docking Study ◽

Inhibitory Effect ◽

Molecular Docking Study ◽

Human Cancer Cell Lines ◽

Activity Evaluation ◽

Cancer Line

Azepinobisindole derivatives, the isomeric Iheyamine skeleton, was prepared and its anticancer activity evaluation were investigated against two human cancer cell lines, Hepatocellular carcinoma (HepG2) and human cervical cancer line (Hela) as well as the normal cell line (Vero cell line) using MTT assay. The anticancer activity results indicated that 2-methoxy-5-methyl-5H-azepino[2,3-b:4,5-bʹ]diindole was the most active derivative against tested cell lines. Additionally, molecular docking study in silico the possible inhibitory effect of cyclin-dependent kinase 2 (CDK2) by the azepinoindole revealed that all synthesized compounds fit well in the binding cavity of CDK2.

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Anticancer and molecular docking studies of some new pyrazole-1-carbothioamide nucleosides

Biointerface Research in Applied Chemistry ◽

10.33263/briac96.642648 ◽

2019 ◽

Vol 9 (6) ◽

pp. 4642-4648 ◽

Cited By ~ 3

Keyword(s):

Molecular Docking ◽

Human Cancer ◽

Docking Study ◽

Molecular Docking Study ◽

Reference Drug ◽

Human Cancer Cell Lines ◽

Chemical Structures ◽

Hct 116 ◽

Mcf 7

Eight pyrazole-1-carbothioamide nucleosides were synthesized through conensation of 3-(4-aminophenyl)-pyrazole-1-carbothioamide derivative 2 with four aldoses (arabinose, mannose, glucose and galactose) and acetylation of the produced nucleosides 3a-d with acetic anhydride in pyridine at room temperature to give their corresponding acetyl derivatives 4a-d. Their chemical structures were confirmed by spectroscopic and elemental analysis. The antiproliferative activity was screened against various human cancer cell lines (MCF-7, HepG2 and HCT-116) in vitro; compound 4b showed a significant IC50 values (8.5±0.72 for MCF-7, 9.4±0.84 for HepG2 and 11.7±0.89 µg/ml for HCT-116) which were close to the reference drug 5-fluorouracil (5-FU). Molecular docking study was utilized to illustrate the ability of the more active compounds 3b and 4b to inhibit thymidylate synthase and compare the results with an antimetabolite drug used in cancer chemotherapy "Raltitrexed".

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Synthesis, Anticancer Evaluation and Synergistic Effects with cisplatin of Novel Palladium Complexes: DNA, BSA Interactions and Molecular Docking Study

Medicinal Chemistry ◽

10.2174/1573406415666190128095732 ◽

2020 ◽

Vol 16 (1) ◽

pp. 78-92

Author(s):

Nenad Joksimović ◽

Nenad Janković ◽

Jelena Petronijević ◽

Dejan Baskić ◽

Suzana Popovic ◽

...

Keyword(s):

Molecular Docking ◽

Human Cancer ◽

Synergistic Effects ◽

Spectroscopic Method ◽

Docking Study ◽

Palladium Complexes ◽

Molecular Docking Study ◽

Alkyl Aryl ◽

Human Cancer Cell Lines ◽

Low Concentrations

Background: In order to discover new agents for chemotherapy with improved properties compared to the existing agents and bearing in mind the fact that some Pd complexes possess better antitumor activity and exhibit less kidney toxicity compared to cisplatin, a series of novel square-planar palladium(II) complexes [Pd (L)2] (3a-f) with O,O bidentate ligands [L = ethyl 2- hydroxy-alkyl(aryl)-4-oxo-2-butenoate] were synthesized. Methods: All complexes were characterized by spectral (UV-Vis, IR, NMR, ESI-MS) and X-ray analysis and examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Fluorescence spectroscopic method was used for investigations of the interactions between CT-DNA or bovine serum albumin (BSA) and complex 3c. Viscosity measurements and molecular docking study were performed to confirm the mode of interactions between DNA and BSA and complex 3c. Results: Complexes that showed the best results, 3c, 3d, and 3e, were placed under further investigations. Selected complexes induced apoptosis and cell cycle arrest in HeLa and MDA-MB 231 cells. Low concentrations of 3c and 3e showed strong to moderate synergism with low concentrations of cisplatin. The interaction of 3d with cisplatin was antagonistic in all used concentrations, but low IC50 value indicates its usefulness as a single cytotoxic agent. It was also noted that the change of viscosity is more pronounced in DNA solution after addition of complex 3c. Conclusion: Obtained results indicate that the novel palladium(II) complexes have the potential to become candidates for treatment in anticancer therapy.

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Design, Synthesis, and Anticancer Activities of Novel 2-Amino-4-phenylthiazole Scaffold Containing Amide Moieties

Journal of Chemistry ◽

10.1155/2018/4301910 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Zhi-Hua Zhang ◽

Hong-Mei Wu ◽

Sai-Nan Deng ◽

Xiao-Yu Cai ◽

Yu Yao ◽

...

Keyword(s):

Cell Lines ◽

Antiproliferative Activity ◽

Human Cancer ◽

Structural Characteristics ◽

Docking Study ◽

Anticancer Activities ◽

Molecular Docking Study ◽

Human Cancer Cell Lines ◽

Biological Studies

Appropriately substituted 2-amino-4-phenylthiazole derivatives were designed and synthesized according to the structural characteristics of crizotinib. The obtained compounds were characterized using 1H NMR, 13C NMR, and HRMS. The target compounds 5a–o were evaluated for their in vitro antiproliferative activity against A549, HeLa, HT29, and Karpas299 human cancer cell lines. Based on results of biological studies, some of these compounds exhibited significant antiproliferative activity. Compound 5b possessed outstanding growth inhibitory effects on the four cell lines, especially for HT29 cell with IC50 value of 2.01 µM. Along with the biological assay data, a molecular docking study suggests that the target compounds were a potential inhibitor.

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BF3-OEt2 Catalyzed C3-Alkylation of Indole: Synthesis of Indolylsuccinimidesand Their Cytotoxicity Studies

Molecules ◽

10.3390/molecules26082202 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2202

Author(s):

Iqbal N. Shaikh ◽

Abdul Rahim ◽

Shaikh Faazil ◽

Syed Farooq Adil ◽

Mohamed E. Assal ◽

...

Keyword(s):

Cell Lines ◽

Human Cancer ◽

A549 Cells ◽

Docking Study ◽

Molecular Docking Study ◽

Human Cancer Cell Lines ◽

Cytotoxicity Studies ◽

Ic50 Value ◽

Hepg2 Cell Lines ◽

Ht 29

A simple and efficient BF3-OEt2 promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore, anti-proliferative activity of these conjugates was evaluated against HT-29 (Colorectal), Hepg2 (Liver) and A549 (Lung) human cancer cell lines. One of the compounds, 3w, having N,N-Dimethylatedindolylsuccinimide is a potent congener amongst the series with IC50 value 0.02 µM and 0.8 µM against HT-29 and Hepg2 cell lines, respectively, and compound 3i was most active amongst the series with IC50 value 1.5 µM against A549 cells. Molecular docking study and mechanism of reaction have briefly beendiscussed. This method is better than previous reports in view of yield and substrate scope including electron deficient indoles.

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Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

Molecules ◽

10.3390/molecules26133923 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3923

Author(s):

Adel A.-H. Abdel-Rahman ◽

Amira K. F. Shaban ◽

Ibrahim F. Nassar ◽

Dina S. EL-Kady ◽

Nasser S. M. Ismail ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Molecular Docking Study ◽

Human Cancer Cell Lines ◽

Hct 116 ◽

Mcf 7

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-−C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.

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Synthesis, cytotoxic activity, ADMET and molecular docking study of quinoline-based hybrid compounds of 1,5-benzothiazepines

New Journal of Chemistry ◽

10.1039/d0nj04295a ◽

2020 ◽

Vol 44 (47) ◽

pp. 20715-20725

Author(s):

Duong Ngoc Toan ◽

Nguyen Dinh Thanh ◽

Mai Xuan Truong ◽

Duong Nghia Bang ◽

Mai Thanh Nga ◽

...

Keyword(s):

Molecular Docking ◽

Cytotoxic Activity ◽

Cell Lines ◽

Docking Study ◽

Molecular Docking Study ◽

Unsaturated Ketones ◽

Hybrid Compounds

Some α,β-unsaturated ketones 4a–g of 3-acetyl-4-hydroxyquinolin-2(1H)-one were prepared and converted into a series of new hybrid compounds, quinoline-benzothiazepine 6a–g. Compounds 6d and 6g had the best activity against HepG2 and KB cell lines.

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