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 the corresponding non-quaternarized compounds. This fact could be attributed to the introduction of a positive charge in the molecule, which can stabilize the molecular complex they form with DNA. In a prokaryotic system, the T2 bacteriophage, both quaternarized and non-quaternarized 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 cells, the pyridiniumtetrahydrocarbazoles were more effective. In particular, they appeared to be very active in inhibiting DNA synthesis in Ehrlich ascites cells; some of them were as effective as ellipticine. However, pyridiniumtetrahydrocarbazoles were less active in comparison with ellipticine when their capacity for inhibiting the clonal growth in Chinese hamster ovary (CHO) cells was tested. A similar picture was obtained studying the formation of chromosome aberrations and of sister chromatid exchanges in the same cells. These different responses can be explained considering that the data on DNA synthesis reflect effects only on DNA replication within a short time, without considering any later consequences; on the contrary, in the long-term tests, other events, which lead to cell killing or genotoxicity, can take place. Pyridiniumtetrahydrocarbazoles damage DNA, inducing double-strand breaks efficiently. These observations, together with the data already obtained on unsubstituted derivatives, suggest the pyridiniumtetrahydrocarbazoles induce antiproliferative and genotoxic effects, very probably by inhibiting topoisomerase II.
Department of Pharmaceutical Chemistry and Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR (associated with the National Institute for the Chemistry of Biological Systems), Padua University, Italy.
M G
MG
Ferlin
G
G
Chiarelotto
C
C
Marzano
E
E
Severin
F
F
Baccichetti
F
F
Carlassare
M
M
Simonato
F
F
Bordin
D000818:Animals; D001435:Bacteriophages / Q000187:drug effects; D016466:CHO Cells; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival; D002869:Chromosome Aberrations; D006224:Cricetinae; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D012854:Sister Chromatid Exchange; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured
D002227:Carbazoles