SYNTHESIS AND BIOLOGICAL PROPERTIES OF A NEW SERIES OF N-PYRIDO SUBSTITUTED TETRAHYDROCARBAZOLES

A series of methyl and ethyl quaternary pyridiniumtetrahydrocarbazoles was synthesized and studied in comparison with ellipticine, chosen as a reference. In general, their antiproliferative activity, tested in different biological substrates, appeared to be higher than that of th e corresponding non-quaternarized compounds. This fact could be attrib uted to the introduction of a positive charge in the molecule, which c an stabilize the molecular complex they form with DNA. In a prokaryoti c system, the T2 bacteriophage, both quaternarized and non-quaternariz ed compounds inhibited its infectivity moderately, in a similar way to ellipticine. This effect seemed to be connected to a direct activity on the virions rather than on the indicator bacteria. In mammalian cel ls, the pyridiniumtetrahydrocarbazoles were more effective. In particu lar, they appeared to be very active in inhibiting DNA synthesis in Eh rlich ascites cells; some of them were as effective as ellipticine. Ho wever, pyridiniumtetrahydrocarbazoles were less active in comparison w ith ellipticine when their capacity for inhibiting the clonal growth i n Chinese hamster ovary (CHO) cells was tested. A similar picture was obtained studying the formation of chromosome aberrations and of siste r chromatid exchanges in the same cells. These different responses can be explained considering that the data on DNA synthesis reflect effec ts only on DNA replication within a short time, without considering an y later consequences; on the contrary, in the long-term tests, other e vents, which lead to cell killing or genotoxicity, can take place. Pyr idiniumtetrahydrocarbazoles damage DNA, inducing double-strand breaks efficiently. These observations, together with the data already obtain ed on unsubstituted derivatives, suggest the pyridiniumtetrahydrocarba zoles induce antiproliferative and genotoxic effects, very probably by inhibiting topoisomerase II. (C) 1998 Elsevier Science S.A. All right s reserved.