Title | ||
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Design, synthesis, evaluation of new 3-acetylisoxazolines and their hybrid analogous as anticancer agents: In vitro and in silico analysis |
Abstract | ||
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3-Acetylisoxazolines were synthesized by the reaction of natural (R)-limonene and (R)-carvone with acetone in the presence of iron (III) nitrate. The reaction showed to be highly peri- and regioselective. Next, using a 1,3-dipolar cycloaddition reaction, the mono-3-acylisoxazolines derived from these monoterpenes were evaluated for their reactivity with nitrilimines. Only the enone of carvone-isoxazoline was regioselectively reactive, providing a new fused isoxazoline-carvone-pyrazolines. The structure of all the newly synthesized mono-cycloadducts (3 & 5) and bis-cycloadducts (4 & 7a–c) were fully identified based on their HRMS and NMR spectral data. They have also been screened for their cytotoxic activity against four human cancer cell lines: fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast (MCF-7 and MDA-MB-231) cell lines. The obtained results showed that compound 4 was a potent cytotoxic agent against all selected cells. The possible mechanism of apoptosis induction by compound 4 was investigated using Annexin-V binding assay, caspase-3/7 activity and analysis cell cycle progression. The compound 4 induced the early apoptosis of both MCF-7 and MDA-MB-231 through caspase-3/7 activation, and the compound 4 have elicited S and G2/M phase arrest in MCF-7and MDA-MB-231 cancer cells, respectively. For further target investigations, a molecular docking study was employed and it showed that compound 4 has an inhibitory activity against Pim-1 protein kinase. Molecular dynamics study showed that compound 4/Pim-1 complex was stable during the simulation run at different time intervals. In-Silico ADMET predicted that compound 4 has good pharmacokinetic properties with high estimated oral bioavailability. |
Year | DOI | Venue |
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2022 | 10.1016/j.compbiolchem.2022.107666 | Computational Biology and Chemistry |
Keywords | DocType | Volume |
Monoterpenes,Isoxazoline,Cytotoxicity,Apoptosis,Cell cycle,Docking study | Journal | 98 |
ISSN | Citations | PageRank |
1476-9271 | 0 | 0.34 |
References | Authors | |
0 | 10 |
Name | Order | Citations | PageRank |
---|---|---|---|
Mourad Fawzi | 1 | 0 | 0.34 |
Ali Oubella | 2 | 0 | 0.34 |
Abdoullah Bimoussa | 3 | 0 | 0.34 |
Fatima Zahra Bamou | 4 | 0 | 0.34 |
Zein Alabdeen Khdar | 5 | 0 | 0.34 |
Aziz Auhmani | 6 | 0 | 0.34 |
Abdelkhalek Riahi | 7 | 0 | 0.34 |
Anthony Robert | 8 | 0 | 0.34 |
Hamid Morjani | 9 | 0 | 0.34 |
My Youssef Ait Itto | 10 | 0 | 0.34 |