Synthesis and cytotoxic activity of carboxamide derivatives of benzimidazo[2,1-a]isoquinoline and pyrido[3',2':4,5]imidazo[2,1-a]isoquinoline

A series of benzimidazo[2,1-a]isoquinolines with carboxamide side chains at the 1-, 6-, 9- and 11-positions were prepd., to study the biol. effects of varying the position of the side chain in this tetracyclic series. The 6-, 9- and 11-analogs were obtained by modifications to published chem. The 1-carboxamide analog was obtained via a one-pot isocoumarin/isoquinolone conversion of 3-methylisocoumarin-8-carboxylic acid with o-phenylenediamine in buffered aq. acid, which gave the required 1-acid. The compds. were evaluated in a panel of cell lines in culture. The 6-carboxamides, where the side chain is attached to one of the central rings, were not active, but the 1- and 11-carboxamides, where the side chain is attached to one of the terminal rings off the chromophore short axis, were reasonably cytotoxic (IC50s < 1 μM). Overall, the structure-activity relationships are broadly in line with those seen with other tri- and tetracyclic carboxamides, and are consistent with recent crystal structure studies of acridine-4-carboxamides bound to DNA. The most potent 1-carboxamide was highly active in vivo against s.c. colon 38 tumors in mice, providing a growth delay of 12 days.