Evaluation of angularly condensed diquinothiazines as potential anticancer agents

Abstract

© 2019 We present efficient synthesis of isomeric types of angularly fused diquinothiazines in the reactions of 2,2′-dichloro-3,3′-diquinolinyl disulfide and diquinodithiin with 3-, 5-, 6- and 8-aminoquinolines. The pentacyclic diquinothiazine ring systems were identified as diquino[3,2-b;3′,4′-e][1,4]thiazine, diquino[3,2-b;5′,6′-e][1,4]thiazine, diquino[3,2-b;6′,5′-e][1,4]thiazine and diquino[3,2-b;8′,7′-e][1,4]thiazine with advanced two-dimensional 1 H and 13 C NMR techniques (COSY, ROESY, HSQC and HMBC) of N-methyl derivatives. The identification of pentacyclic ring system was confirmed by X-ray diffraction analysis of selected N-alkyl derivatives. The X-ray analysis revealed different spatial structures of the ring system (planar and folded). NH-diquinothiazines were further transformed into N-alkyl and N-dialkylaminoalkyl derivatives. Most of diquinothiazines exhibited significant cancer cell growth inhibition against the human glioblastoma SNB-19, colorectal carcinoma Caco-2, breast cancer MDA-MB-231 and lung cancer A549 cell lines with the IC 50 values < 3 µM. This anti-proliferative activity was found to be more than for cisplatin. The most promising compound, 7-dimethylaminopropyldiquino[3,2-b;6′,5′-e]thiazine, was used for gene expression analysis by reverse transcription–quantitative real-time PCR (RT–QPCR) method. The expression of H3, TP53, CDKN1A, BCL-2 and BAX genes revealed that this compound inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2) in two cancer cell lines (SNB-19 and Caco-2).