Rebeccamycin analogues from indolo[2,3-c]carbazole.
Glycosylated indolocarbazoles related to the antibiotic rebeccamycin represent an important series of antitumor drugs. In the course of structure-activity relationship studies, we report the synthesis of two new derivatives containing an indolo[2,3-c]carbazole chromophore instead of the conventional indolo[2,3-a]carbazole unit found in the natural metabolites. The N-methylated compound 8 containing one glucose residue behaves as a typical DNA intercalating agent, as judged from circular and electric linear dichroism measurements with purified DNA. In contrast, the bis-glycosylated derivative 7 containing a glucose residue on each indole nitrogen has lost its capacity to form stable complexes with DNA. DNA relaxation experiments reveal that the two drugs 7 and 8 have weak effects on human DNA topoisomerase I. The modified conformation of the indolocarbazole chromophore is detrimental to the stabilization of topoisomerase I-DNA complexes. The lack of potent topoisomerase I inhibition leads to decreased cytotoxicity but, however, we observed that the DNA-intercalating mono-glycosyl derivative 8 is about 5 times more cytoxic than the bis-glycosyl analogue 7. The study suggests that the naturally-occurring indolo[2,3-a]carbazole skeleton should be preserved to maintain the topoisomerase I inhibitory and cytotoxic activities.
Voldoire
A
A
Université Blaise Pascal, Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504, Aubière, France.
Sancelme
M
M
Prudhomme
M
M
Colson
P
P
Houssier
C
C
Bailly
C
C
Léonce
S
S
Lambel
S
S
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007211:Indoles; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology; D051379:Mice; D011089:Polydeoxyribonucleotides / Q000378:metabolism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D007364:Intercalating Agents; D011089:Polydeoxyribonucleotides; D059004:Topoisomerase I Inhibitors; C041514:carbazole; D004247:DNA; C427203:calf thymus DNA; C053339:rebeccamycin; D004264:DNA Topoisomerases, Type I