Synthesis and in vitro antiproliferative activity of new 11-aminoalkylamino-substituted chromeno[2,3-b]indoles

To search for new biological activities of the chromeno[2,3-b]indoles, the 5-oxa analog of the indolo[2,3-b]quinolines that are known to have a potent antitumor activity, a series of 11-amino derivatives with various substituents at the C-2 position were prepared. The synthesis of the chromeno[2,3-b]indole structure involves the cyclization of 2-phenoxy-3-indolecarboxylates 3, accessible from the indole-3-carboxylate 1 and phenols 2, producing the chromeno[2,3-b]indol-11(6H)-ones 4, which is followed by dehydroxychlorination with phosphorus oxychloride to afford the 11-chlorochromeno[2,3-b]indoles 5. The treatment of 5 with various amines produced the corresponding 11-aminated chromeno[2,3-b]indoles 6, while some of the 11-ω-aminoalkylamino derivatives 6 were transformed into the 11-ω-sulfonylaminoalkylamino derivatives 8. The antiproliferative activity of these 11-aminochromeno[2,3-b]indoles 6 and 8in vitro were tested using MV4-11 (human leukemia), A549 (lung cancer), HCT116 (colon cancer), and the normal mice fibroblast (BALB/3T3) and their potencies were described.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► In vitro antiproliferative activity of thirty chromeno[2,3-b]indoles were tested. ► 11-(ω-Aminoalkylamino) substituents contributed highly to the activity. ► Most 11-aminoalkylamino derivatives were more active and less toxic than cisplatin. ► Alkylmonoamino substituents at the C-11 were less contributing to activity. ► The C-2 substituents brought synergy effect in combination with the C-11 groups.