Dataset Information

Synthesis and biological evaluation of oxazinonaphthalene-3-one derivatives as potential anticancer agents and tubulin inhibitors.

ABSTRACT:

Objectives

In the present study, a new series of oxazinonaphthalene-3-one analogs was designed and synthesized as novel tubulin inhibitors.

Materials and methods

The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including A2780 (human ovarian carcinoma), A2780/RCIS (cisplatin resistant human ovarian carcinoma), MCF-7 (human breast cancer cells), and MCF-7/MX (mitoxantrone resistant human breast cancer cells), those compounds which demonstrated the most antiproliferative activity in the MTT test were selected to investigate their tubulin inhibition activity and their effects on cell cycle arrest (at the G2/M phase). Moreover, molecular docking studies of the selected compounds in the catalytic site of tubulin (PDB ID: 4O2B) were carried out to describe the results of biological experiments.

Results

Most of our compounds exhibited signi?cant to moderate cytotoxic activity against four human cancer cell lines. Among them, Compounds 4d, 5c, and 5g, possessing trimethoxy phenyl, showed the most antiproliferative activity with IC50 values ranging from 4.47 to 52.8 ?M.

Conclusion

The flow cytometric analysis of A2780 cancer cell line treated with compounds 4d, 5c, and 5g showed that these compounds induced cell cycle arrest at the G2/M phase. Compound 5g, the most antiproliferative compound, inhibited tubulin polymerization in a dose-dependent manner. Molecular docking studies of 5g into the colchicine-binding site of tubulin displayed a possible mode of interaction between this compound and tubulin.

SUBMITTER: Mirzaei S

PROVIDER: S-EPMC7671423 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

Synthesis and biological evaluation of oxazinonaphthalene-3-one derivatives as potential anticancer agents and tubulin inhibitors.

Mirzaei Salimeh S Qayumov Maqsudjon M Gangi Fahimeh F Behravan Javad J Ghodsi Razieh R

Iranian journal of basic medical sciences 20201101 11

<h4>Objectives</h4>In the present study, a new series of oxazinonaphthalene-3-one analogs was designed and synthesized as novel tubulin inhibitors.<h4>Materials and methods</h4>The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including A2780 (human ovarian carcinoma), A2780/RCIS (cisplatin resistant human ovarian carcinoma), MCF-7 (human breast cancer cells), and MCF-7/MX (mitoxantrone resistant human breast cancer cells), those compounds whi ...[more]

PMID: 33235695

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Project description:Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 μM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

Dataset Information

Synthesis and biological evaluation of oxazinonaphthalene-3-one derivatives as potential anticancer agents and tubulin inhibitors.

Objectives

Materials and methods

Results

Conclusion

Publications

Synthesis and biological evaluation of oxazinonaphthalene-3-one derivatives as potential anticancer agents and tubulin inhibitors.

Similar Datasets

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