Asymmetrical bisintercalators as potential antitumor agents.
Ditercalinium and its analogues are dimeric molecules made up of two identical 7H-pyrido[4,3-c]carbazole rings linked by symmetrical linking chains. These dimers elicit antitumor properties through a new mechanism of action. Recently, a relationship was found between their antitumor properties and their cytotoxic effect on the polA Escherichia coli mutant strain, suggesting that 7H-pyrido[4,3-c]carbazole dimers might induce a DNA deformation that could be recognized by the E. coli SOS repair system. Thus, the role of symmetry in ditercalinium analogues for their DNA binding, antitumor properties, and bacterial toxicity is investigated in the present study, by introducing asymmetric parameters in their structures. Dimers were either synthesized with an asymmetrical rigid linking chain or made up of two chemically different chromophores, i.e., acridine and 7H-pyrido[4,3-c]carbazole. The asymmetrical dimers remain able to bisintercalate into DNA with high affinities, but a dramatic loss in their antitumor potency is observed. On the other hand, these asymmetrical dimers are cytotoxic for polA E. coli mutants, like their symmetrical analogues. These results show that the symmetry plays a crucial role for the antitumor potency in the 7H-pyrido[4,3-c]carbazole dimers series.
Léon
P
P
Département de Chimie Organique, U 266 INSERM, UA 498 CNRS, UER des Sciences Pharmaceutiques et Biologiques, Paris, France.
Garbay-Jaureguiberry
C
C
Lambert
B
B
Le Pecq
J B
JB
Roques
B P
BP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004269:DNA, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002227:Carbazoles; D004269:DNA, Bacterial; D007364:Intercalating Agents