Synthesis, mode of action, and biological activities of rebeccamycin bromo derivatives.
Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.
Moreau
P
P
Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, Université Blaise Pascal, UMR 6504, 63177 Aubière, France.
Anizon
F
F
Sancelme
M
M
Prudhomme
M
M
Sevère
D
D
Riou
J F
JF
Goossens
J F
JF
Hénichart
J P
JP
Bailly
C
C
Labourier
E
E
Tazzi
J
J
Fabbro
D
D
Meyer
T
T
Aubertin
A M
AM
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001409:Bacillus cereus / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles; D020128:Inhibitory Concentration 50; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
C119214:3,9-dibromo-12-(4-O-methylglucopyranosyl)-6,7.12,13-tetrahydroindolo(2,3-a)pyrrolo(3,4-c)carbazole-5,7-dione; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D004247:DNA; C053339:rebeccamycin; D010770:Phosphotransferases; D011493:Protein Kinase C; D004264:DNA Topoisomerases, Type I; D005947:Glucose