Relationship between the size and position of substituents on 7H-pyrido[4,3-c]carbazole monomers and dimers and their DNA binding and anti-tumor properties.
Among the various DNA intercalating molecules prepared in our laboratory, ditercalinium, made up of two 7H-pyrido[4,3-c]carbazole rings linked by a rigid bis-ethylbipiperidine chain (NSC 366241) displays high anti-tumor properties. This dimeric molecule elicits its cytotoxicity through an original mechanism of action. At the molecular level, interaction of ditercalinium with the self-complementary d(CpGpCpG)2 nucleotide has been studied by 1H n.m.r. and the geometry of the bis-intercalating complex has been elucidated. Ditercalinium bis-intercalates through the major groove with the convex face of the 7H-pyrido[4,3-c]carbazole ring oriented toward the sugar moiety. Previous studies have shown the strong modulating effect brought about by substitution of the intercalating ring by methyl groups on both the DNA binding and anti-tumor potency of 7H-pyridocarbazole monomers and dimers. In order to further investigate structure activity relationships in the ditercalinium and related monomers series, a new family of monomeric and dimeric 7H-pyrido[4,3-c]carbazoles was prepared with ethyl, isopropyl or hydroxyethyl substitution on position 6 or 7 of the aromatic ring. DNA binding and anti-tumor potency of these compounds are reported. In contrast to their methylated analogs, none of the 6- or 7-substituted monomers studied here are active although most of them remain able to intercalate into DNA. Substitution of dimeric molecules by substituents of increasing size induces a progressive decrease in the anti-tumor potency, concomitantly with a disappearance of bis-intercalative properties. The modulating effect of the size of substituents on the DNA binding and anti-tumor properties of dimers is more pronounced in the 7-substituted series. These results are discussed in relation to the geometry of intercalation of ditercalinium and its related monomer into d(CpGpCpG)2.
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
Le Pecq
J B
JB
Roques
B P
BP
D000970:Antineoplastic Agents; D002227:Carbazoles; D004247:DNA; D007364:Intercalating Agents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002227:Carbazoles; D007364:Intercalating Agents; D004247:DNA; C042804:ditercalinium