Design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer

Demirci, Serpil; Hayal, Taha Bartu; Kıratlı, Binnur; Şişli, Hatice Burcu; Demirci, Selami; Şahın, Fikrettin; Doğan, Ayşegül

doi:10.1111/cbdd.13575

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…Interestingly, it was found that the treatment with this steroid oxime (50 µM, 24 h) induced a G 2 /M cell cycle arrest of LNCaP cells ( Figure 5 ). Also, LNCaP cells were not able to pass through to the S and G 2 /M phases treated by compound 5-FU, which is in agreement with literature for these cells [ 42 ].…”

Section: Resultssupporting

confidence: 90%

New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

et al. 2021

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The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and β-tubulin, which may account for the described effects.

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Section: Resultssupporting

confidence: 90%

New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

et al. 2021

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“…In order to determine the effect of USP7 suppression on the control of cell division, T47D and MCF7 cells were subjected to cell cycle analysis according to the protocol (Demirci et al, 2019). Briefly, cells were plated (3 × 10 5 cells/well) in 6-well tissue culture plates; after 24 h incubation, siRNA or p5091 was applied to the cells.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

Ubiquitin-specific protease 7 downregulation suppresses breast cancer in vitro

Hayal¹,

Doğan²,

Şişli³

et al. 2020

Turk J Biol

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Because breast cancer is complicated at the pathological, histological, clinical, and molecular levels, identification of new genetic targets against carcinogenic pathways is required to generate clinically relevant treatment options. In the current study, ubiquitin-specific protease 7 (USP7), which regulates various cellular pathways including Mdm2, p53, and NF–κB, was selected as a potential gene editing strategy for breast cancer in vitro. Anticancer activity of USP7 gene suppression has been evaluated through cell proliferation, gene expression, cell cycle, sphere dissemination, and cell migration analysis. Here, siRNA and shRNA strategies and an allosteric small-molecule inhibitor of USP7 were used to define potential anticancer activity against MCF7 and T47D human breast cancer cell lines. Both blockage of deubiquitination by p5091 and knockdown of USP7 reduced cell proliferation, cell migration, colony formation, and sphere dissemination for both MCF7 and T47D breast cancer cell lines. Restriction of USP7 activity strongly enhanced apoptotic gene expression and reduced metastatic ability of breast cancer cell lines. This study describes one potential molecular target for the suppression of breast cancer proliferation and metastasis. Identification of USP7 as a promising gene editing candidate might open up the possibility of new molecular drug research in targeting the ubiquitination pathway in cancer.

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“…The pharmacological properties of phenylpiperazines and their derivatives have been described by various researchers (Cohen et al 1982;Conrado et al 2010;Neves et al 2003;Hanano et al 2000). The design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer have been reported (Demirci et al, 2019). Many pharmaceutical compounds are derived from 1-phenyl-piperazine, including oxypertine (Archer et al, 1962), trazodone (Alhaider, 1992) and nefazodone.…”

Section: Chemical Contextmentioning

confidence: 99%

The structures of eleven (4-phenyl)piperazinium salts containing organic anions

et al. 2022

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Eleven (4-phenyl)piperazinium salts containing organic anions have been prepared and structurally characterized, namely, 4-phenylpiperazin-1-ium 4-fluorobenzoate monohydrate, C10H15N2 +·C7H4FO2 −·H2O, 1; 4-phenylpiperazin-1-ium 4-bromobenzoate monohydrate, C10H15N2 +·C7H4BrO2 −·H2O, 3; 4-phenylpiperazin-1-ium 4-iodobenzoate, C10H15N2 +·C7H4IO2 −, 4; 4-phenylpiperazin-1-ium 4-nitrobenzoate, C10H15N2 +·C7H4NO4 −, 5; 4-phenylpiperazin-1-ium 3,5-dinitrosalicylate, C10H15N2 +·C7H3N2O7 −, 6; 4-phenylpiperazin-1-ium 3,5-dinitrobenzoate, C10H15N2 +·C7H3N2O6 −, 7; 4-phenylpiperazin-1-ium picrate, C10H15N2 +·C6H2N3O7 −, 8; 4-phenylpiperazin-1-ium benzoate monohydrate, C10H15N2 +·C7H5O2 −·H2O, 9; 4-phenylpiperazin-1-ium p-toluenesulfonate, C10H15N2 +·C7H7O3S−, 10; 4-phenylpiperazin-1-ium tartarate monohydrate, C10H15N2 +·C4H5O6 −·H2O, 11; and 4-phenylpiperazin-1-ium fumarate, C10H15N2 +·C4H3O4 −, 12. Compounds 1 and 3–12 are all 1:1 salts with the acid proton transferred to the phenylpiperaizine basic N atom (the secondary amine) with the exception of 3 where there is disorder in the proton position with it being 68% attached to the base and 32% attached to the acid. Of the structures with similar stoichiometries only 3 and 9 are isomorphous. The 4-phenyl substituent in all cases occupies an equatorial position except for 12 where it is in an axial position. The crystal chosen for structure 7 was refined as a non-merohedral twin. There is disorder in 5, 6, 10 and 11. For both 5 and 6, a nitro group is disordered and was modeled with two equivalent orientations with occupancies of 0.62 (3)/0.38 (3) and 0.690 (11)/0.310 (11), respectively. For 6, 10 and 11, this disorder is associated with the phenyl ring of the phenylpiperazinium cation with occupancies of 0.687 (10)/0.313 (10), 0.51 (7)/0.49 (7) and 0.611 (13)/389 (13), respectively. For all salts, the packing is dominated by the N—H...O hydrogen bonds formed by the cation and anion. In addition, several structures contain C—H...π (1, 3, 4, 8, 9, 10, and 12) and aromatic π–π stacking interactions (6 and 8) and one structure (5) contains a –NO2...π interaction. For all structures, the Hirshfeld surface fingerprint plots show the expected prominent spikes as a result of the N—H...O and O—H...O hydrogen bonds.

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Design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer

Cited by 12 publications

References 42 publications

New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

Ubiquitin-specific protease 7 downregulation suppresses breast cancer in vitro

The structures of eleven (4-phenyl)piperazinium salts containing organic anions

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