Synthesis, cytotoxicity, DNA interaction and topoisomerase II inhibition properties of tetrahydropyrrolo[3,4-a]carbazole-1,3-dione and tetrahydropyrido-[3,2-b]pyrrolo[3,4-g]indole derivatives

Three tetrahydropyrrolo[3,4-a]carbazole-1,3-diones (6-8) and two tetrahydro pyrido[3,2-b]pyrrolo[3,3,4-g]indole,1,3-diones (11-12) have been synthesize d. Their interaction with DNA was probed by absorption and thermal melting studies. Compounds 8 and 12 both equipped with a hydroxyethyl-aminoethyl si de-chain demonstrated higher affinities for poly(dA-dT)(2) than compounds 6 , 7 and 11 bearing a dimethylaminoethyl side-chain. Circular and electric l inear dichroism measurements showed that all five drugs behave as typical D NA intercalating agents. A. plasmid cleavage assay was used to evaluate the capacity of the drugs to inhibit human topoisomerase II. Compounds 8 and 1 2 which bind strongly to DNA were found to stabilize DNA-topoisomerase II c ovalent complexes but their topoisomerase II inhibitory properties do not c orrelate with their cytotoxic potential. Compounds 6 and 7 are essentially inactive whereas compounds 8, 11 and 12 exhibit a high toxicity to P388 mur ine leukemia cells and provoke a marked accumulation in the G2/M phase of t he cell cycle. These compounds form a new class of DNA-targeted antitumor a gents. (C) 2001 Elsevier Science Ltd. All rights reserved.