Synthesis, characterization and in vitro anti-neoplastic activity of gypsogenin derivatives

Emirdağ-Öztürk, Safiye; Babahan, İlknur; Özmen, Ali

doi:10.1016/j.bioorg.2013.12.001

Cited by 17 publications

(8 citation statements)

References 31 publications

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“…The 13 C NMR spectrum of LH 2 showed oxime carbon (HNC=NOH) and (HC=NOH) peaks at 137.06 and 137.06 ppm, whereas hydrazone imine (MeC=NNH) was seen at 165.45 ppm, as shown in our previous studies [30–32] . Aromatic carbons were between 126.34 and 107.05 ppm, whereas the carbons of methyl groups for indole were observed at 51.27 ppm.…”

Section: Resultssupporting

confidence: 78%

“…3‐Methoxy‐indole‐hydrazone glyoxime (LH 2 ) was synthesized from the starting materials (antiglyoximehydrazine [GH 2 ] and 3‐methoxy indole) using glacial acetic acid as the catalyst. The starting material antichloroglyoxime was explained in our previous work [30–32] . A cooled (5 °C) solution of 3‐methoxy indole (1 mmol) in ethanol was added dropwise into a cooled solution containing (1 mmol) GH 2 and 3–5 drops of CH 3 COOH with constant stirring.…”

Section: Methodsmentioning

confidence: 99%

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A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF₂⁺ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

Babahan

Özmen

Aksel

et al. 2020

Applied Organom Chemis

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In this study, a novel bidentate ligand containing oxime, hydrazone, and indole moieties and its BF2+‐bridged transition metal complexes [Ni(II), Cu(II), and Co(II)] were synthesized and their cytotoxic activities against prostate and breast cancer cells were investigated. The vic‐dioxime ligand bearing indole–hydrazone side groups was synthesized by reacting antiglyoximehydrazine (GH2) with 3‐methoxy indole. The ligand forms mononuclear complexes with a metal‐to‐ligand ratio of 1:2 with M = Co(II)(H2O)2, Ni(II), and Cu(II). These metal complexes were then reacted with BF3(C2H5)2O to obtain BF2+‐bridged transition metal complexes. The Co(II) complex of the ligand is proposed to be octahedral with water molecules as axial ligands, whereas the Ni(II) and Cu(II) complexes are proposed to be square planar. Spectral studies showed that the ligand bonded to the metal ion in a neutral bidentate fashion through the azomethine nitrogen atom and the imine oxime group. Structural assignments are supported by a combination of 1H nuclear magnetic resonance (NMR), 13C NMR, Fourier‐transform infrared, LC/MS, elemental analyses, and magnetic susceptibility testing. For determining the cytotoxic effects of the novel anticancer products, cancer cells were cultured. The antiproliferative effects were determined using the MCF‐7 breast cancer and PC‐3 prostate cancer cell lines. The antiproliferative effects of the products were analyzed and their apoptotic or necrotic effects were determined with the Hoechst/propidium iodide double staining method in both cancer cell lines. Paclitaxel was used as the positive control (1 μm). The results indicated that the newly synthesized compounds are effective on both cell lines between concentrations of 5 and 40 μm and show their effects by apoptotic mechanisms. Besides, these products were found to be more effective on the MCF‐7 cell line. The cytotoxic efficiency of the newly synthesized products was more than that of paclitaxel (depending on concentration), which is a chemotherapeutic agent used in cancer therapy.

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Section: Resultssupporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF₂⁺ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

Babahan

Özmen

Aksel

et al. 2020

Applied Organom Chemis

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“…17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eurasian continent. Previous studies have demonstrated anti-cancer activities of gypsogenin derivatives 1c, 1e and 1f ( Fig.…”

mentioning

confidence: 99%

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

Çiftçi

Öztürk

Ali

et al. 2018

Biological & Pharmaceutical Bulletin

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SummaryThe discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC 50 value of 9.3 µM. In contrast, the IC 50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC 50 =8.7 μM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppresses signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors. KeywordsGypsogenin, Abelson tyrosine-protein kinase 1, chronic myelogenous leukemia Biological and Pharmaceutical Bulletin Advance PublicationCancer is a worldwide health problem, and despite intensive research efforts over the last several decades, an effective cure has not been identified. 1)However, the recent discovery of molecular targeted drugs against cancer at the end of the 20 th century has led to promising results. 1,2) Imatinib (Fig. 1), which targets the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL), [3][4][5][6] was discovered based on the findings that chronic myelogenous leukemia (CML) is caused by a chromosomal translocation that results in the constitutively expressed and active BCR-ABL. 7,8) While imatinib can be initially effective in treating CML, some patients have shown drug resistance to imatinib. [9][10][11] Several new generation drugs with a different binding mode to Abelson kinase (ABL) have thus been developed. 6,[12][13][14][15][16] These drugs are artificial heterocyclic compounds, however, if widely distributed natural products and/or their derivatives show the inhibitory activity against BCR-ABL, it would be more convenient to get.Pentacyclic triterpenoids, a category of natural compounds, can be extracted from a variety of plants and show various activities. 17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eu...

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“…In combination with fluorescence microscopy, selective uptake of the two dyes allows on to distinguish the apoptosis from non-apoptotic cell death (necrosis). In our system, the PI uptake without chromatin condensation or nuclear fragmentation was considered as necrosis [13, 14]. The pictures in Fig.…”

Section: Resultsmentioning

confidence: 99%

In Vitro and In Vivo Activity of Fomitopsis Pinicola (Sw. Ex Fr.) Karst Chloroform (Fpkc) Extract Against S180 Tumor Cells

Gao¹,

Wang²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Non-toxic fomitopsis is has been traditionally used in folk medicine in many countries for its anti-inflammatory and anti-vascular disease activities. The present study investigates the antitumor effect of Fomitopsis pinicola (Sw. Ex Fr.) Karst chloroform extract (FPKc) on S180 tumor cells in vitro and in vivo and we determined the underlying mechanisms. Methods: HPLC was employed to analyze the constituents of FPKc. In-vitro 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to quantify the growth inhibition of FPKc; Propidium iodide (PI) exclusion assay and scanning electron microscopy (SEM) were used to observe the damage on the cell membrane and the changes of the cell morphology; Staining with Hoechst 33342/propidium iodide (HO/PI) and the application of the Annexin V-FITC/PI analysis permitted to observe the cell death triggered by FPKc; DNA damage and cell cycle arrest were detected by flow cytometry; Rhodamine 123 (RH123) and Cytochrome C were used as dyes to investigate the alterations of the mitochondria. In-vivo tumor inhibition and mice survival time were determined. Results: The results of the HPLC assay indicated that FPKc might contain DA (dehydroeburiconic acid), PA (pachymic acid), and ES (ergosterol), at percentages of 0.25%, 17.8%, and 10.5%, respectively. Concerning the study of the biological function, the results showed that FPKc exhibited preferential and significant suppression of proliferation on specific cell lines including S180, HL-60, U937, K562, SMMC-7721, and Eca-109 cells, which induced plasma membrane and cell morphology damages, triggering S180 tumor-cells late apoptosis and leading to DNA damage and S phase arrest. Mitochondria were suspected to play a vital role in these changes. In vivo data indicated that FPKc inhibited the solid tumor growth and prolonged the survival time of tumor-bearing mice. Moreover, FPKc provoked only little damage on normal cells in vitro and also on normal tissues in vivo. Conclusion: FPKc inhibited S180 tumor cells growth and prolonged the lifespan of mice. In vitro, we found that FPKc induced S180 tumor cells apoptosis and cell cycle arrest, possibly via the mitochondrial pathway.

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Synthesis, characterization and in vitro anti-neoplastic activity of gypsogenin derivatives

Cited by 17 publications

References 31 publications

A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF₂⁺ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF₂⁺ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

In Vitro and In Vivo Activity of Fomitopsis Pinicola (Sw. Ex Fr.) Karst Chloroform (Fpkc) Extract Against S180 Tumor Cells

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Synthesis, characterization and in vitro anti-neoplastic activity of gypsogenin derivatives

Cited by 17 publications

References 31 publications

A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF2+ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF2+ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

In Vitro and In Vivo Activity of Fomitopsis Pinicola (Sw. Ex Fr.) Karst Chloroform (Fpkc) Extract Against S180 Tumor Cells

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A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF₂⁺ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

A novel bidentate ligand containing oxime, hydrazone and indole moieties and its BF₂⁺ bridged transition metal complexes and their efficiency against prostate and breast cancer cells