Chromophore-modified bis-benzo[ g ]indole carboxamides: synthesis and antiproliferative activity of bis-benzo[ g ]indazole-3-carboxamides and related dimers

Abstract Tricyclic pyrazole dimers that comprise two kinds of CONH(CH 2 ) n N(CH 3 )(CH 2 ) n NHCO bridges to which are linked potential DNA-intercalating groups such as 1 H -benzo[ g ]indazole, 2 H -benzo[ g ]indazole and 1,4-dihydroindeno[1,2- c ]pyrazole were designed, synthesized and some of them evaluated in vitro by NCI (Bethesda, USA) against nine types of cancer cells. Compounds 2a , 2f – i and 2o – r demonstrated significant antiproliferative activity, all with GI 50 values in the low micromolar range. Preliminary analysis of the structure–activity relationship for dimers 2 indicated that: (i) in the ground terms ( 2a and 2k ) antitumor activities were strongly related to the type of chromophore, (ii) in contrast, either 1 H -benzo[ g ]indazole- or 1,4-dihydroindeno[1,2- c ]pyrazole-dimers when bore a N 1 -aryl group ( 2g , 2h , 2i , 2o , 2p , 2q and 2r ) generally showed a good level of antitumor potency and (iii) for the most representative compounds (pairs of compounds: 2g , 2h ; 2o , 2p and 2q , 2r ) the length of the bridges did not significantly contribute to the variations in cytotoxicity. Two members of this series, 2f and 2q , were selected and tested in the hollow fiber cell assay to evaluate in a preliminary fashion their in vivo antitumor activity. Finally, viscosity measurement of 2f with poly(dA-dT) 2 , confirmed that these promising compounds behaved as typical DNA-intercalating agents.