Antitumor activity of bis-indole derivatives.
This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests including proteasome inhibition and inhibition of plasma membrane electron transport. The compound bearing the 5-methoxy-2-indolinone moiety was subjected to the first in vivo experiment (hollow fiber assay) and was active. It was therefore selected for the second in vivo experiment (human tumor xenograft in mice). In conclusion we demonstrated that this approach was successful, since some of the compounds described are much more active than the numerous, so far prepared and tested 3-indolylmethylene-2-indolinones.
Andreani
Aldo
A
Dipartimento di Scienze Farmaceutiche, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy. aldo.andreani@unibo.it
Burnelli
Silvia
S
Granaiola
Massimiliano
M
Leoni
Alberto
A
Locatelli
Alessandra
A
Morigi
Rita
R
Rambaldi
Mirella
M
Varoli
Lucilla
L
Landi
Laura
L
Prata
Cecilia
C
Berridge
Michael V
MV
Grasso
Carole
C
Fiebig
Heinz-Herbert
HH
Kelter
Gerhard
G
Burger
Angelika M
AM
Kunkel
Mark W
MW
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000970:Antineoplastic Agents; D007211:Indoles; C030374:indole; D044767:Ubiquitin-Protein Ligases