Syntheses and biological evaluation of indolocarbazoles, analogues of rebeccamycin, modified at the imide heterocycle.
A series of 10 indolocarbazole derivatives, analogues to the antitumor antibiotic rebeccamycin, bearing modifications at the imide heterocycle were synthesized. They bear an N-methyl imide, N-methyl amide, or anhydride function instead of the original imide. Their inhibitory potencies toward topoisomerase I were examined using a DNA relaxation assay and by analyzing the drug-induced cleavage of 32P-labeled DNA. Protein kinase C (PKC) inhibition and interaction with DNA were also studied together with the in vitro antiproliferative activities against B16 melanoma and P388 leukemia cells. The antimicrobial activities against two Gram-positive bacteria (Bacillus cereus and Streptomyces chartreusis), a Gram-negative bacterium (Escherichia coli), and a yeast (Candida albicans) were tested as well as their antiviral activities toward HIV-1. The efficiency of the anhydride compounds was compared to that of the parent compound rebeccamycin and its dechlorinated analogue. All the compounds studied were inactive against PKC. The structural requirements for PKC and topoisomerase I inhibition are markedly different. In sharp contrast with the structure-PKC inhibition relationships, we found that an anhydride function does not affect topoisomerase I inhibition, whereas a methyl group on the indole nitrogen prevents the poisoning of topoisomerase I. The compounds exhibiting a marked toxicity to P388 leukemia cells had little or no effect on the growth of P388CPT5 cells which are resistant to the topoisomerase I inhibitor camptothecin. This study reinforces the conclusion that the DNA-topoisomerase I cleavable complex is the primary cellular target of the indolocarbazoles and significantly contributes to their cytotoxicity and possibly to their weak but noticeable anti-HIV-1 activities. The structure-activity relationships are also discussed.
Moreau
P
P
Synthèse et Etude de Systèmes à Intérêt Biologique, Université Blaise Pascal, UMR 6504 du CNRS, 63177 Aubière, France.
Anizon
F
F
Sancelme
M
M
Prudhomme
M
M
Bailly
C
C
Carrasco
C
C
Ollier
M
M
Sevère
D
D
Riou
J F
JF
Fabbro
D
D
Meyer
T
T
Aubertin
A M
AM
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001409:Bacillus cereus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002227:Carbazoles; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013302:Streptomyces / Q000187:drug effects; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D004247:DNA; C053339:rebeccamycin; D011493:Protein Kinase C; D004264:DNA Topoisomerases, Type I