Identification of some benzoxazepines as anticancer agents inducing cancer cell apoptosis (original) (raw)
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Antitumor activity of a new series of benzoxazepine derivatives in breast cancer
Bioorganic & Medicinal Chemistry Letters, 2010
A series of new benzoxazepine derivatives substituted with different alkoxy and aryloxy group were synthesized comprising synthetic steps of Mitsunobu reaction, lithium aluminum hydride (LAH) reduction, followed by debenzylation and finally intramolecular Mitsunobu cyclization. The new benzoxazepines specifically inhibited growth of breast cancer cell lines, MCF-7 and MDA-MB-231, but lack cytotoxicity to normal HEK-293 cells. The cell growth inhibition induced by the active compounds was due to cell cycle arrest at G 0 /G 1 phase. The active compound could cause significant reduction in tumor volume of MCF-7 xenograft tumor in nude mice model and their activity was comparable to that of tamoxifen citrate at 16 mg kg À1 dose at 30 days of treatment. The identified most active compounds of the series have specific advantages as anti-cancer agent in breast cancer than tamoxifen.
Pyrrolo-1,5-benzoxazepines: a new class of apoptotic agents
Biochemical Society Transactions, 2001
Some members of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) potently induce apoptosis in a number of human cancerous cell lines including HL-60 cells and the drug-resistant chronic myelogenous leukaemia cell line, K562. The apoptotic induction seems to be independent of the mitochondrial peripheral-type benzodiazepine receptor (PBR), which binds these PBOXs with high affinity, due to a lack of correlation between their affinities for the receptor and their apoptotic potencies and their high apoptotic activity in PBR-deficient cells. PBOX-6, a potent member of the series, induces a transient activation of c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which correlates with induction of apoptosis. Expression of a cytoplasmic inhibitor of the JNK signal transduction pathway, Jip-1, prevents JNK activity and significantly reduces the extent of apoptosis induced by PBOX-6. This demonstrates the requirement for JNK in the cellular response to this apoptotic agent. In a...
2005
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 FITClabelled 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. ) showed an anti-apoptotic effect. No positive correlation was found between the increased drug accumulation effect and the programmed cell death induced by the compounds studied.
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...
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.
Proceedings of the National Academy of Sciences, 2000
Two distinct benzodiazepine binding sites have been identified, ( i ) a central site restricted to brain and ( ii ) a ubiquitously expressed mitochondrial binding site, the so-called peripheral-type benzodiazepine receptor (PBR). In this paper, we show that a benzazepine referred to as BBL22 (2-amino 9-chloro-7-(2-fluorophenyl)-5H-pyrimidol[5,4- d ][2]benzazepine), which is classified as a PBR ligand based on structure, induces arrest in G 2 /M phase of the cell cycle in human tumor cell lines of both epithelial and hematopoietic cellular origin. After G 2 /M arrest, several tumor types, notably prostate and certain breast cancer lines exhibited significant apoptosis. Ideally, cancer therapies should selectively target tumor cells while sparing normal cell counterparts. BBL22 exhibited such selectivity, as it did not affect the growth and survival of nonmalignant breast and prostate epithelial lines. Moreover, BBL22 demonstrated structural requirements for this selective antitumor a...
Synthesis and Cytotoxicity Studies of Novel Triazolo-Benzoxazepine as New Anticancer Agents
Chemical Biology & Drug Design, 2013
Cancer continues to be one of the biggest threats to the human civilization because there is no cure of it. Small heterocyclic molecule with low molecular weight and novel structural feature is therapeutically highly demanding. These molecules have the capability to disrupt signaling pathways leading to anticancer activities. Therefore, the search for new anticancer agents continues to draw attention to the research community. In this study, a small triazolo-benzoxazepine scaffolds was synthesized using a one-pot four-step synthetic methodology involving click reaction. Small libraries of 12 compounds were successfully synthesized and screened them against different cancer cell lines. Low micromolar anticancer activity was recorded using MTT assay, and further confirmation of cell death was obtained by phase contrast, fluorescent, and confocal images.
Journal of medicinal …, 2005
We have recently developed five novel pyrrolo-1,5-benzoxazepines as proapoptotic agents. Their JNK-dependent induction of apoptosis in tumor cells suggested their potential as novel anticancer agents. The core structure of the apoptotic agent 6 was investigated, and the SARs were expanded with the design and synthesis of several analogues. To define the apoptotic mechanism of the new compounds and the localization of their drug target, two analogues of 6 were designed and synthesized to delineate events leading to JNK activation. The cell-penetrating compound 16 induced apoptosis in tumor cells, while its nonpenetrating analogue, 17, was incapable of inducing apoptosis or activating JNK. Plasma membrane permeabilization of tumor cells resulted in 17-induced JNK activation, suggesting that the pyrrolo-1,5-benzoxazepine molecular target is intracellular. Interestingly, compound 6 displayed cytotoxic activity against a panel of human tumor cell lines but demonstrated negligible toxicity in vivo with no effect on the animals' hematology parameters.
TheScientificWorldJOURNAL, 2001
INTRODUCTION. Chronic myeloid leukemia (CML), which accounts for 20% of all leukemias, expresses the transforming oncogene, bcr-abl. Expression of bcr-abl results in the production of an abnormal tyrosine kinase and is reported to confer resistance against apoptosis induced by many chemotherapeutic agents. Recently a novel series of pyrrolo-1,5benzoxazepines (PBOXs) were synthesised (Campiani et al., 1996) and some of these compounds induce apoptosis in a number of cancerous cells (Zisterer et al., 2000). In this study, a number of these novel pyrrolo-1, 5-benzoxazepines were found to induce apoptosis in CML cells. We examined whether Bcr-Abl becomes downregulated and whether its protein tyrosine kinase activity is altered during apoptosis (Mc Gee et al., in press). METHOD. Cells were cytocentrifuged onto slides and stained with eosin Y and methyl blue. Apoptotic cells were characterised by cell shrinkage, membrane blebbing, nuclear condensation and DNA fragmentation (Fig. 1). Levels of Bcr-Abl expression, protein tyrosine phosphorylation and PARP cleavage were measured by Western blot. Caspase 3-like protease activity was measured using a substrate, Ac-DEVD-AMC, which is cleaved and fluorogenic AMC released. RESULTS. A representative pyrrolo benxozaxepine, PBOX-6, was found to induce 40-50% apoptosis in CML cells in a time and dose dependent manner (Fig. 2). Downregulation of Bcrabl was not detected and the tyrosine phosphorylation status of proteins was unchanged up to 24 hours following treatment with PBOX-6. Caspase 3-like proteases were activated in K562 and LAMA 84 cells, but not in KYO.1 cells although apoptosis was induced to the same extent. Pretreatment of cells with a caspase 3-like inhibitor, Z-DEVD-fmk, prior to PBOX-6 inhibited caspase 3-like protease activity, but failed to prevent against apoptosis. DISCUSSION. We have shown that PBOX-6 is a potent inducer of apoptosis in CML cells and is able to bypass Bcr-Abl mediated resistance. Downregulation of Bcr-Abl did not accompany but rather followed the induction of apoptosis. The tyrosine phosphorylation status of proteins remained unchanged up to 24 hours following treatment with PBOX-6. These results suggest that a reduction in Bcr-Abl expression, or inhibition of tyrosine kinase activity is not the only mechanism by which cells can escape the anti-apoptotic effect of the bcr-abl gene. Activation of caspase 3-like proteases is not required for the induction of apoptosis by PBOX-6 in the CML cells examined. Results from this study suggest the potential of this compound as a novel anti-cancer agent for the treatment of CML.
Journal of the Brazilian Chemical Society, 2023
Synthesized benzoxazepine derivatives have been characterized and evaluated using 1 H, 13 C nuclear magnetic resonance (NMR), DEPT 135 (distortionless enhancement by polarization transfer), and high resolution mass spectrometry (HRMS) to confirm the leading benzoxazepine chemical structures. X-ray crystal structure of compounds 10 and 13 (10,11-dimethyl-6,7-dihydrobenzo[f] benzo[4,5]imidazo[1,2-d][1,4]oxazepine and 8,9-dihydrobenzo[4,5]imidazo[1,2-d]naphtho[1,2-f] [1,4]oxazepine) were obtained after successful diffraction of the compound crystals. The anti-microbial, anti-cancer and anti-inflammatory activities of the synthesized benzoxazepine derivatives were evaluated. The effect of benzoxazepine derivatives on cancer cell proliferation and microbial growth was studied. Our results revealed limited antimicrobial activity to the synthesized benzoxazepine derivatives with significant activities against certain bacterial pathogens for two compounds. The synthesized benzoxazepine derivatives displayed cytotoxicity against selected solid tumor cell lines with varying effects on the release of human interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines depending on the cancer cell type used. The results of the study suggest that the synthesized benzoxazepine derivatives show anti-cancer and anti-inflammatory agents, though with dependence on the type of cancer cell line.