Utility of beta-2-microglobulin concentrations as a marker of infection with human immunodeficiency virus.
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Biomarkers↗
Biomedical subjects
P Léon
Publications and source records attributed to P Léon.
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.
Animals↗
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.
Antineoplastic Agents↗
Modulation of the antitumor activity by methyl substitutions in the series of 7H-pyridocarbazole monomers and dimers.
The structure of the dimeric antitumor drug ditercalinium (NSC 366241) [2,2'-([4,4'-bipiperidine]-1,1'-diyldi-2,1-ethanediyl)bis[10 -methoxy-7H-pyrido[4,3-c]carbazolium] tetramethanesulfonate] was modified by introduction of methyl groups in various positions of the aromatic ring. Monomeric analogues with the nitrogen atom of the pyridinic ring in different positions have also been synthesized. Pharmacological properties and DNA interactions of the new compounds are reported. In contrast with the monomeric analogue of ditercalinium, which was inactive, methyl substitutions on the 10-methoxy-7H-pyrido[4,3-c]carbazolium in positions 6 or 7 led to monomers endowed with small but significant activity. As expected, dimerization of the methyl-substituted pyridocarbazoles yielded DNA bisintercalators with affinity slightly higher than that of the unsubstituted parent compounds. These dimers, characterized by a relatively better therapeutic index, have the same mechanism of action as ditercalinium. Otherwise, in monomeric and dimeric series, methyl substitution in position 4 or 5 provided inactive compounds unable to intercalate into DNA. All these results are in agreement with the previously proposed geometry for the complex of ditercalinium with DNA.
Animals↗