Novel Substituted Benzothiophene and Thienothiophene Carboxanilides and Quinolones: Synthesis, Photochemical Synthesis, DNA-Binding Properties, Antitumor Evaluation and 3D-Derived QSAR Analysis

A series of new <i>N</i>,<i>N</i>-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo­[<i>b</i>]­thienyl- and thieno­[2,3-<i>b</i>]­thienylcarboxanilides and benzo­[<i>b</i>]­thieno­[2,3-<i>c</i>]- and thieno­[3′,2′:4,5]­thieno­[2,3-<i>c</i>]­quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity. 2-Imidazolinyl-substituted derivatives showed very prominent activity. By use of the experimentally obtained antitumor measurements, 3D-derived QSAR analysis was performed for the set of compounds. Higly predicitive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides <b>6a</b>–<b>c</b> and quinolones <b>9a</b>–<b>c</b> and <b>11a</b> were evaluated for DNA binding propensities and topoisomerases I and II inhibition as part of their mechanism of action assessment. The evaluated differences in the mode of action nicely correlate with the results of the 3D-QSAR analysis. Taken together, the results indicate which modifications of the compounds from the series should further improve their anticancer properties

Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer Cells

Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly observed in cancer, and its inhibition by small molecules is promising for their reactivation. Here we designed bisubstrate analogues-based inhibitors, by mimicking each substrate, the <i>S</i>-adenosyl-l-methionine and the deoxycytidine, and linking them together. This approach resulted in quinazoline–quinoline derivatives as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. We highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group, and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of <i>CDKN2A</i> promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cell model system, we found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter, and the reactivation of a reporter gene