A novel chlorinated tetracyclic compound 13 of the class ethanoanthracene, as analogue of maprotiline, was prepared via multistep syntheses. The tetracyclic key intermediates 4 and 5 with its [2.2.2] system were built via a Diels-Alder reaction between acrolein and 1,8-dichloroanthracene.The synthesized chlorinated maprotiline analogues 6 , 7 and 13 as well intermediates 4 and 5 exerted antiproliferative activity against cancer cell lines A549 and HepG2 at low micromolar concentrations. In addition, the intermediates 4 and 5 exerted high antiproliferative activity against HCT cell line. Interestingly, the intermediate 4 was the most active against all treated cell lines.
To clarify the molecular basis of the chlorinated tetracyclic as antidepressant agents, computational studies were carried out. Molecular docking was carried out using Molegro Virtual Docker program; the 3D crystal structure of the recruited models were downloaded from PDB database (PDB ID: 2A65; l 2QJU). The optimized compounds and protein models were loaded to Molegro Virtual Docker program and the binding affinity as MolDock score function was calculated. The MolDock scores are in consistency with the theoretically calculated lipophilicity Clog P, The docking results of the all compounds 1-10 and reference drug maprotiline 11 showed significant interactions with binding site of the recruited models. Lipophilicity appears to play crucial role in these interactions.
The chlorinated tetracyclic 1,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-12-yl)-N-methylmethanamine 1, a maprotiline analogue, has been synthesized via reduction and Diels–Alder reaction followed by reductive amination of Aldehyde 2. Density Functional Theory calculations were performed to identify the possible isomers of the intermediate compound aldehyde 2, these calculations were in a good agreement with experimental result where aldehyde 2 could exist in three isomers with comparable energies. In addition, the side chain of this aldehyde 2 was extended via Wittig reaction to obtain the unsaturated ester 5 that subjected to selective olefinic catalytic hydrogenation to obtain the corresponding saturated ester 6. 1D-NMR (DEPT) and 2D-NMR (HSQC, DQF-COSY) techniques were recruited for structural elucidation in addition to HRMS.
A novel chlorinated tetracyclic compound 13 of the class ethanoanthracene, as analogue of maprotiline, was prepared via multistep syntheses. The tetracyclic key intermediates 4 and 5 with its [2.2.2] system were built via a Diels-Alder reaction between acrolein and 1,8-dichloroanthracene.The synthesized chlorinated maprotiline analogues 6, 7 and 13 as well intermediates 4 and 5 exerted antiproliferative activity against cancer cell lines A549 and HepG2 at low micromolar concentrations. In addition, the intermediates 4 and 5 were also exerted high antiproliferative activity against HCT cell line. Interestingly, the intermediate 4 was the most active against all treated cell lines.
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