Dimeric analogues of non-cationic tricyclic aromatic carboxamides are a new class of cytotoxic agents

A series of tricyclic aromatic carboxamides, and their corresponding dimeri c analogues, were prepared and their growth-inhibitory properties were eval uated in a series of cell lines. The dimeric compounds were prepared by rea ction of the appropriate acids with carbonyl-1,1'-diimidazole, isolating th e resulting imidazolides, and reacting these with a stoichiometric amount o f the diamine. The monomeric carboxamides containing a (CH2)(2)NMe2 side ch ain had widely differing inhibitory potencies, with the known nitronaphthal imide (mitonafide) and acridine-4-carboxamide (DACA) being the most potent. The corresponding bis analogues, linked by a (CH2)(3)NMe(CH2)(3) chain, we re generally more potent, with the largest increases (dimer/monomer ratio 2 0- to 30-fold) seen for the nitronaphthalimides and the phenazines. Based o n the intrinsic cytotoxicity of the monomers and the highest degree of incr ease in cytotoxicity on dimerization, the most interesting chromophores app ear to be the acridine-4-carboxamide and phenazine-l-carboxamide. Both of t hese compounds showed significant growth delays (similar to 6 days) in an i n vivo colon 38 tumour model in mice.