Synthesis and cytotoxic activity of carboxamide derivatives of benzimidazo[2,1-a]isoquinoline and pyrido[3',2':4,5]imidazo[2,1-a]isoquinoline.
A series of benzimidazo[2,1-a]isoquinolines with carboxamide side chains at the 1-, 6-, 9- and 11-positions were prepared, in order to study the biological effects of varying the position of the side chain in this tetracyclic series. The 6-, 9- and 11-analogues were obtained by modifications to published chemistry. The 1-carboxamide analogue was obtained via a one-pot isocoumarin/isoquinolone conversion of 3-methylisocoumarin-8-carboxylic acid with o-phenylenediamine in buffered aqueous acid, which gave the required 1-acid. The compounds were evaluated in a panel of cell lines in culture. The 6-carboxamides, where the side chain is attached to one of the central rings, were not active, but the 1- and 11-carboxamides, where the side chain is attached to one of the terminal rings off the chromophore short axis, were reasonably cytotoxic (IC50s < 1 microM). Overall, the structure-activity relationships are broadly in line with those seen with other tri- and tetracyclic carboxamides, and are consistent with recent crystal structure studies of acridine-4-carboxamides bound to DNA. The most potent 1-carboxamide was highly active in vivo against s.c. colon 38 tumours in mice, providing a growth delay of 12 days.
Deady
L W
LW
Chemistry Department, La Trobe University, Bundoora, Victoria, Australia. l.deady@latrobe.edu.au
Rodemann
T
T
Finlay
G J
GJ
Baguley
B C
BC
Denny
W A
WA
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007093:Imidazoles; D007202:Indicators and Reagents; D007546:Isoquinolines; C427107:benzimidazo(2,1-a)isoquinoline; C427123:pyrido(2,1-a)isoquinoline