Synthesis, spectroscopic structure identification, X-ray study and anticancer activities of new angularly fused quinobenzothiazines

Abstract

© 2016 Published by Elsevier B.V.Synthesis of 16 new tetracyclic angularly fused azaphenothiazines, 8-, 9- and 10-substituted quinobenzo-1,4-thiazines (benzo[a]-3-azaphenothiazines) was based on the reactions of dichlorodiquinolinyl disulfide and diquinodithiin with substituted anilines. Whereas the reactions with p-fluoroaniline and p-methylthioaniline led to only one product, the reaction with m-triflouromethylaniline led to isomeric compounds. The obtained 8-10-substituted 12H-quinobenzothiazines were further transformed into 12-substituted derivatives through alkylation of the thiazine nitrogen atom. The structure analysis was based on 1D and 2D NMR (NOESY, COSY, HSQC and HMBC) spectra which enabled to distinguish the isomers and to exclude retro-Smiles rearrangement and the azine nitrogen atom alkylation pathways. This supposition was fully confirmed by X-ray analysis showing the quinobenzothiazine system to be folded and the substituent at the thiazine nitrogen atom in an equatorial position. Some compounds exhibited anticancer activity against MCF-7, MDA-MB-231 and SNB-19 cell lines similar to a reference drug cisplatin. The structure-activity relationship of the compounds were discussed.