Further SAR in the new antitumor 1-amino-substituted gamma-carbolines and 5H-benzo[e]pyrido[4,3-b]indoles series.
Using previously described techniques, various new 1-amino-substituted 5H-pyrido[4,3-b]indoles (gamma-carbolines, gamma-C) and 5H-benzo[e]pyrido[4,3-b]indoles (BPI) have been synthesized and evaluated. For known compounds containing a 1-[(dimethylamino)propyl] group, 1a and 1b in the gamma-C series and 2 in the BPI series are the most active. Studies with newly synthesized derivatives show that: (i) in the gamma-C series, the 4-unsubstituted-8-hydroxy-compound was inactive, whereas the 4-unsubstituted-9-hydroxy-5H-benzo[e]pyrido[4,3-b]indole is active; (ii) the 4-ethyl-8-hydroxy-5H-pyrido[4,3-b]indole derivative retains antitumor properties, but the 1-amino-substituted 4-ethyl-9-hydroxy-5H-benzo[e]pyrido[4,3-b]indole analog is devoid of biological activity; (iii) in the 5H-benzo[e]pyrido[4,3-b]indole series, the displacement of a hydroxyl group from the 9- to 10-position leads to inactive compounds. Based on the structural analogies, these results were unexpected because the same substituents on the 4-position lead to different biological properties in the two series.
Nguyen
C H
CH
URA 1387 CNRS, Synthèse Organique, Institut Curie, Orsay, France.
Lavelle
F
F
Riou
J F
JF
Bissery
M C
MC
Huel
C
C
Bisagni
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002243:Carbolines / Q000138:chemical synthesis / Q000494:pharmacology*; D007191:Indazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D002243:Carbolines; D007191:Indazoles; D059004:Topoisomerase I Inhibitors