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

Synthesis, Antitumor Activity, and Mechanism of Action of Benzo[<i>b</i>]chromeno[6,5‑<i>g</i>][1,8]naphthyridin-7-one Analogs of Acronycine

A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-<i>7H</i>-benzo­[<i>b</i>]­chromeno­[6,5<i>-g</i>]­[1,8]­naphthyridin-7-one (<b>4</b>), 13-aza derivatives of benzo­[<i>b</i>]­acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-<i>6H-</i>benzo­[<i>b</i>]­chromeno­[7,6<i>-g</i>]­[1,8]­naphthyridin-6-one (<b>5</b>), and related <i>cis</i>-diols mono- and diesters were designed and synthesized. Their <i>in vitro</i> and <i>in vivo</i> biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate <b>21</b> showed a strong activity against KB-3-1 cell lines and was selected for <i>in vivo</i> evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds <b>21a</b> and <b>21b</b> were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different