Synthesis, antitumour activity and structure-activity relationships of 5H-benzo[b]carbazoles.
A series of novel 5H-benzo[b]carbazoles related to the ellipticines was obtained from the reactions of p-benzoquinones with 2-aminomethylene-1-indanones. Most of the compounds were evaluated for their antitumour activity in the National Cancer Institute's in vitro human tumour cell line screening panel. Among them, particularly derivative 15c bearing a p-quinone methide moiety in ring C of the heterocycle was found to show in vitro activity comparable to clinically well established anticancer agents such as amsacrine or mitomycin C. Compounds 9d, 9e and 12k showed increased potency to distinct cell lines like the leukemia or melanoma subpanel of cell lines. Based on the test results, structure-activity relationships for this series of compounds were developed. For instance, it was found that a quinonoid substructure in ring C leads to a noticeable increase in activity. The same observation was made for a 2-hydroxyl substituent at the ring system. 2-Acetoxy and 2-methoxy derivatives as well as 2-unsubstituted 5H-benzo[b]carbazoles either had a decreased potency or were found to be inactive. A COMPARE analysis with some of these compounds showed poor or no correlation with anticancer drugs of the NCI's standard agents database indicating a novel mechanism of action. Additionally, UV-vis titrations in the series of 5H-benzo[b]carbazoles indicated interactions with calf thymus DNA only for the highly active quinone methide 15c.
Asche
Christian
C
LEDSS, UMR CNRS 5616, Université Joseph Fourier, BP 53, 38041 Grenoble Cédex 9, France. christian.asche@ujf-grenoble.fr
Frank
Walter
W
Albert
Antje
A
Kucklaender
Uwe
U
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002227:Carbazoles; D004247:DNA