Induction of Apoptosis and Necrosis by Resistance Benzazoles and Benzoxazines on Tumour Cell Line Mouse Lymphoma L5718 Mdr+cells (original) (raw)
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In vivo (Athens, Greece)
Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for induction and inhibition of apoptosis on tumor cells (L5718, mouse lymphoma cell line containing the human mdr-1 gene). For evaluation of apoptosis, the cells were stained with FITC-labelled Annexin-V and propidium iodide and the results were analysed by flow cytometry. Nine of these substances were also checked for reversal of multidrug resistance. The reversal of multidrug resistance was determined by measuring the rhodamine-123 accumulation in the cancer cells. Rhodamine-123 shows a green fluorescence and its intracellular concentration correlates well with the inhibition of efflux pump activity. Three of the tested compounds, 5-(p-nitrobenzamido)-2-benzylbenzoxazole (BD-3), 6-methyl-2-(o-chlorophenyl) benzoxazole (A-9) and 5-(p-nitrophenoxyacetamido)-2-phenylbenzoxazole (D-30), showed an increased apoptotic effect on mouse lymphoma cells. Moreover, compounds BD-3, A-9 and 5-(2-thienylc...
Identification of some benzoxazepines as anticancer agents inducing cancer cell apoptosis
Future Medicinal Chemistry, 2018
Aim: Using cytotoxic agents with apoptosis induction may represent one of new strategies for cancer treatment to overcome the increased resistance of the disease. Methodology: Two series of benzo[f][1,4]oxazepine-3,5(2H,4H)-diones (compounds 5, 6a–f) and 3-phenylbenzo[f][1,4]oxazepin-5(4H)-ones (compounds 10, 11a-f) were synthesized and screened for their cytotoxicity against leukemia K-562 and breast T-47D cancer cell lines as well as normal fibroblasts WI-38. Results: The tested compounds revealed good cytotoxicity and selectivity toward cancer cell lines relative to the normal cells, especially compounds 6f, 10 and 11e, f. These compounds were screened for cell cycle disturbance and apoptosis induction. They were found to cause PreG1 apoptosis and complete cell growth arrest at G2/M. They induce apoptosis via caspase-3 and Bax activation and downregulation of Bcl2. Conclusion: benzo[f][1,4]oxazepine represents a scaffold for further optimization to obtain promising anticancer age...
2011
A series of N-(2-anilino-pyridyl) linked 2-amino benzothiazoles (4a-n) and [1,2,4]triazolo [1,5-b]benzothiadiazine conjugates (5a-j) have been designed, synthesized and evaluated for their antiproliferative activity. Some of these compounds (4h-k, 4n, and 5e) have exhibited potent cytotoxicity specifically against human leukemia HL-60 cell lines with IC 50 values in the range of 0.08-0.70 lM. All these compounds were tested for their effects on the cell cycle perturbations and induction of apoptosis. Morphological evidences of apoptosis, including fragmentation of nuclei and inter nucleosomal DNA laddering formation were clearly observed after 24 h exposure to compound 4i. Flow cytometry analysis revealed that compound 4i showed drastic cell cycle perturbations due to concentration dependant increase in the sub-G0 region which comprises of both the apoptotic and debris fraction, thus implying the extent of cell death. These compounds trigger the mitochondrial apoptotic pathway that results in the loss of mitochondrial membrane potential through activation of multiple caspases followed by activation of caspase-3, and finally cleavage of PARP. Further the mechanism of cell death was analysed by fluorescent microscopic analysis and also by scanning electron microscopy. The cytotoxicity of 4i correlated with induction of apoptosis, caspases activation and DNA damage and thus indicating the apoptotic pathway of anticancer effect of these compounds.
Synthesis and the effect of a novel benzoxazole compound on breast cancer cell line
Medicine Science | International Medical Journal, 2019
Breast cancer today is the most frequent cancer among women, and the second most common cause of cancer deaths among women. The aim of this study was to synthesize a new benzoxazole derivative, scan it for anti-cancer potential by MTT test using different breast cancer cell lines, and examine its effects on NF-κB and apopitosis-related proteins (APAF-1, cytochrome C, caspase-3, bcl-2) by the western blot method. newly-synthesized benzoxazole compound was applied to breast cancer cell lines (MDA-MB, MCF-7) and its cytotoxicity was measured quantitatively by MTT test. Later, the level of its effects on NF-κB and apopitosis-related proteins (APAF-1, cytochrome C, caspase-3, bcl-2) were examined by the western blot method. In our study, the structure of the synthesized new 5-[4-chlorobutanamido]-2-(p-methylphenyl)benzoxazole was proved by elemental analysis, 1H NMR and mass spectroscopy analysis methods. When the toxic effects of the application of the compound on the cell lines was examined by MTT, it had a greater toxic effect on MCF-7 when compared with MDA-MB, and IC50 levels were lower. When the protein was examined in immunohistochemistry with regard to VEGF, eNOS and TUNEL, it was observed that it caused a reduction in VEGF and an increase in eNOS and TUNEL. In the assay of the proteins by western blot, when benzoxazole compound was added to the MDA and MCF-7 cell line, there was no difference from the control group in Apaf-1 and BCL-2 levels, but a reduction was observed in caspase and Nfkβ levels compared with the control group. When the compound was added to the MDA-MB cell line, an increase was shown in the Cytochrome C level compared to the control group, but no difference was seen in the MCF-7 cell line. It is felt that this synthesized new benzoxazole compound increases apopitosis by reducing the activation of Nfkβ, and in this way has shown an effect of inhibiting tumor growth in cancer treatment. In addition, it is felt that this can provide hope in cancer treatment by the improved phase studies.
Bioorganic & Medicinal Chemistry, 2011
A series of N-(2-anilino-pyridyl) linked 2-amino benzothiazoles (4a-n) and [1,2,4]triazolo [1,5-b]benzothiadiazine conjugates (5a-j) have been designed, synthesized and evaluated for their antiproliferative activity. Some of these compounds (4h-k, 4n, and 5e) have exhibited potent cytotoxicity specifically against human leukemia HL-60 cell lines with IC 50 values in the range of 0.08-0.70 lM. All these compounds were tested for their effects on the cell cycle perturbations and induction of apoptosis. Morphological evidences of apoptosis, including fragmentation of nuclei and inter nucleosomal DNA laddering formation were clearly observed after 24 h exposure to compound 4i. Flow cytometry analysis revealed that compound 4i showed drastic cell cycle perturbations due to concentration dependant increase in the sub-G0 region which comprises of both the apoptotic and debris fraction, thus implying the extent of cell death. These compounds trigger the mitochondrial apoptotic pathway that results in the loss of mitochondrial membrane potential through activation of multiple caspases followed by activation of caspase-3, and finally cleavage of PARP. Further the mechanism of cell death was analysed by fluorescent microscopic analysis and also by scanning electron microscopy. The cytotoxicity of 4i correlated with induction of apoptosis, caspases activation and DNA damage and thus indicating the apoptotic pathway of anticancer effect of these compounds.
Acta Pharmaceutica, 2000
2 The present work deals with the synthesis of some novel heterocyclic compounds such as benzoxazoles , 7, 13 and 19, imidazoles 3, 8, 14 and 20, benzimidazoles 4, 9, 15 and 21, and tetrazoles 10, 16, and 22. The synthesized compounds were characterized by IR, 1H NMR, mass spectrometry and elemental analysis. The compounds were evaluated for cytotoxicity against human cancer cell lines such as MCF-7 (breast cancer) and HT-29 (colon cancer) by the MTT assay method. Among the tested compounds, 4,4’-sulfonylbis(N-(2-(1H-benzo[d]imidazol- -2-yl)ethyl)aniline (9), N-bis(2-(benzo[d]oxazol-2-yl)-ethyl)- 6-phenyl-1,3,5-triazine-2,4-diamine (13), N-bis(2-(1H-benzo[ d]imidazol-2-yl)ethyl)-6-phenyl-1,3,5-triazine-2,4-diamine (15) and N-tris(2-1H-benzo[d]imidazol-2-yl)ethyl)- 1,3,5-triazine-2,4,6-triamine (21) showed potent cytotoxicity.
In vitro apoptotic activity of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones in L5178Y cells
Life Sciences, 2007
Compounds containing B-N bonds have shown interesting biological activity. One class of such molecules is the 2,2-diphenyl-1,3,2oxazaborolidin-5-ones (3a-j), which contain a B-N bond, have an α-amino acid moiety in the heterocycle, and have an exocyclic moiety related to an amino acid. The purpose of this work was to determine the inhibitory effects of 3a-j on the proliferation of murine L5178Y lymphoma cells. A new five-membered heterocyclic nucleus with apoptotic activity was found. The target products showed potent cytotoxicity in the L5178Y cell line. Among them, 3a exhibited the highest antineoplastic activity in L5178Y cells with an IC 50 value of 22.5 ± 0.2 μM.
Cytotoxic activities of some benzothiazole-piperazine derivatives
Journal of Enzyme Inhibition and Medicinal Chemistry, 2014
Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Based on the GI 50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Compound 1d is highly cytotoxic against all tested cancer cell lines. Further investigation of compound 1d by Hoechst Staining and Fluorescence-Activated Cell Sorting Analysis (FACS) revealed that this compound causes apoptosis by cell cycle arrest at subG 1 phase.
In vivo (Athens, Greece)
Tumor-specificity (TS) and anti-inflammatory activity of benzo[b]cyclohept[e][1,4]oxazin-6(11H)-one, generally known as benzoxazinotropone (BOT), have been reported. In order to find a new biological activity, the combination effect of BOT and three apoptosis-inducing agents was investigated. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and five human oral normal cells (gingival fibroblasts, periodontal ligament fibroblasts, pulp cells, oral keratinocytes and primary gingival epithelial cells) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. TS was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal oral cells to the one against OSCC cell lines. Synergy was evaluated by CompuSyn software program. Expression of cleaved forms of poly ADP-ribose polymerase and caspsase-3 was evaluated by western blot analysis. BOT induced activation of caspase 3, suggesting the apoptosis induc...
RSC Advances, 2017
Colorectal cancer is the third most common form of cancer affecting both men and women around the world. The chemical and biological studies of heterocyclic compounds have been an interesting area in pharmaceutical and medicinal chemistry. A new synthetic compound namely 2-(1,1-dimethyl-1H-benzo [e]indol-2-yl)-3-((2-hydroxyphenyl)amino)acrylaldehyde, abbreviated as DBID was screened for the antiproliferation effects against the colorectal cancer cell line, HT-29 and its possible mechanism of action was elucidated. To determine the IC 50 value, MTT assay was employed and further verified by the LDH release assay and apoptosis-inducing effect. DBID inhibited the proliferation of HT-29 cells and significantly increased the levels of caspase-8,-9 and-3/7 in the treated cells compared to untreated cells. Apoptosis features in HT-29 cells were detected in treated cells by using the AO/PI staining and flow cytometric analysis of Annexin V. The changes in expression of some apoptotic genes were confirmed by gene quantification using RT-PCR. The current study showed that the DBID compound exhibited chemotherapeutic activity, which was evident by significant increases in the expression and activation of caspase, up-regulation of the expression of specific apoptotic genes and exploitation of the apoptotic signaling pathways to trigger cancer cell death.