Syntheses and antiproliferative activities of new rebeccamycin derivatives with the sugar unit linked to both indole nitrogens.
The synthesis of new rebeccamycin derivatives, in which the carbohydrate moiety is attached to both indole nitrogens, is described. The newly synthesized compounds were tested for their abilities to block the cell cycle of murine leukemia L1210 cells and their in vitro antiproliferative activities against four tumor cell lines (murine L1210 leukemia and human HT29 colon carcinoma, A549 non-small-cell lung carcinoma, K-562 leukemia). Their biological activities are compared with those of the parent compound rebeccamycin. Some of the new compounds exhibit potent antiproliferative activities, either against the four cell lines or mostly the two leukemias (L1210 and K-562 cell lines). The 3,9-diformyl analogue 9 was selective toward L1210 cells, whereas the 3,9-dibromo 16 was strongly cytotoxic toward the four cell lines tested. Nonselective compound 16 and 3,9-dinitro 13, which exhibited selectivity toward leukemia tumor cell lines, were selected for in-depth evaluation, including in vivo experiments.
Marminon
Christelle
C
Synthèse et Etude de Systèmes à Intérêt Biologique, Université Blaise Pascal, UMR 6504, 63177 Aubière, France.
Anizon
Fabrice
F
Moreau
Pascale
P
Léonce
Stéphane
S
Pierré
Alain
A
Pfeiffer
Bruno
B
Renard
Pierre
P
Prudhomme
Michelle
M
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D020014:K562 Cells / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D011720:Pyrazoles; C053339:rebeccamycin