Syntheses and biological activities of rebeccamycin analogues. Introduction of a halogenoacetyl substituent.
In the course of structure-activity relationships on rebeccamycin analogues, a series of compounds bearing a halogenoacetyl substituent were synthesized with the expectation of increasing the interaction with DNA, possibly via covalent reaction with the double helix. Two rebeccamycin analogues bearing an acetyl instead of a bromoacetyl substituent were prepared to gain an insight into the role of the halogen atom. The new compounds show very little effect on protein kinase C and no covalent reaction with DNA was detected. However, the drugs behave as typical topoisomerase I poisons, and they are significantly more toxic toward P388 leukemia cells than to P388/CPT5 cells resistant to camptothecin. The introduction of a bromo- or chloro-acetyl substituent does not affect the capacity of the drug to interfere with topoisomerase I either in vitro or in cells. One of the bromoacetyl derivatives, compound 8, is the most cytotoxic rebeccamycin derivative among the hundred of derivatives we have synthesized to date. In addition, we determined the antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis, and against the Gram-negative bacterium Escherichia coli. The effect of the drugs on Candida albicans yeast growth and their anti-HIV-1 activities were also measured.
Moreau
P
P
Université Blaise Pascal, Synthèse Electrosynthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504 du CNRS, 63177 Aubière, France.
Anizon
F
F
Sancelme
M
M
Prudhomme
M
M
Bailly
C
C
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* / 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; D002176:Candida albicans / Q000187:drug effects; D002227:Carbazoles; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D007211:Indoles; D020128:Inhibitory Concentration 50; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013302:Streptomyces / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
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; D011493:Protein Kinase C