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