Synthesis and antiproliferative activity of basic ethers of 1,2-dihydropyrrolo[1,2-a]indole, 6H-isoindolo[2,1-a]indole, and 6H-benz[5,6]isoindolo[2,1-a]indole.
Monobasic ethers of 1,2-dihydropyrrolo[1,2-a]indole, 6H-isoindolo[2,1-a]indole, and 6H-benz[5,6]isoindolo[2,1-a]indole and bis-basic ethers of 6H-isoindolo[2,1-a]indole were prepared using an intramolecular Wittig cyclization as a key step. All these compounds were firstly evaluated for their cytotoxicity effects against L1210 cell line. Only the tetracyclic bis-basic ether 14d displayed submicromolar cytotoxic effect. Moreover, despite the fact that the presence of these two amino side chains in 14c, 14d, and 14f led to strong DNA binding effect, they are not topoisomerase II inhibitors. Among the monobasic ethers 14a, 14b, 22, and 29, which do not bind to DNA, the pentacyclic analog 29 exhibited micromolar cytotoxic activity against L1210 and HT-29 cell lines and induced a weak topoisomerase II inhibition.
Guillaumel
Jean
J
Service de Chimie de l'Institut Curie, UMR 176 CNRS, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
Léonce
Stéphane
S
Pierré
Alain
A
Renard
Pierre
P
Pfeiffer
Bruno
B
Peruchon
Laure
L
Arimondo
Paola B
PB
Monneret
Claude
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004987:Ethers / Q000138:chemical synthesis* / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004987:Ethers; D007211:Indoles; D011758:Pyrroles; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II