Synthesis and cytotoxicity of bis(benzo[g]indole-3-carboxamides) and related compounds

A series of bis(benzo[ g ]indoles) bridged by CX-(CH 2 ) n N(Me)(CH 2 ) n -CX (X = O, S, H 2 ; n = 2,3) was synthesized as bifunctional antitumor agents and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. The parent compounds 2a,b exhibited a good level of activity and derivates 2c - g,i,k demonstrated significant inhibitory effects, all with IC 50 values in the low micromolar range. The thioamide analogue 2j showed less potency. It is interesting to note that introduction of substituents on the benzene ring of the benzo[ g ]indole portion of 2a,b did not affect activity, with the only exception of the 7,8-dichloro derivative 2h which became less potent. One member of this series, 2i, was then tested in the hollow fiber cell assay to evaluate, in a preliminary fashion, its in vivo antineoplastic activity. Molecular modelling studies were performed on amide 2a and thioamide 2j to explain the loss of activity of 2j as to 2a. Finally, compound 2a behaved as a typical DNAintercalating agent, as judged from viscosity measurements with Poly(dA-dT) .. poly(dA-dT).