Heterocyclic mono-N-oxides with potential applications as bioreductive anti-tumour drugs: Part 1. 8-Alkylamino-substituted phenylimidazo [1,2-a] quinoxalines.
A series of imidazo [1,2-a] quinoxaline mono-N-oxides and their 6- and 9-aza analogues have been substituted in the 8-position with a variety of secondary and tertiary amines, and the compounds evaluated as bioreductively activated cytotoxins. Cytotoxic action against hypoxic cells in vitro was critically dependent upon the structural nature of the 8-substituent and its basicity, with little dependence upon reduction potential. 1,2-Dihydro-8-(4-methylpiperazin-1-yl)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide (11) had differential hypoxic:oxic toxicity of 15.3 and some novel analogues had differential hypoxic:oxic toxicities of 7.5-17. Other related compounds with either substituted or unsubstituted 8-piperazinyl substituents, or certain straight-chain aminoalkyl substituents, show comparable activity in vitro. Less basic 8-substituents abolished activity, although the 8-morpholinyl derivatives (7 and 8) had differential hypoxic:oxic toxicities of 3-4. Substitution of the 4-phenyl ring with an electron-withdrawing group (F) improved hypoxic potency, but only with a small effect on hypoxic:oxic toxicity, whereas an electron-donating substituent (MeO) reduced hypoxic potency. Perhaps significantly, the 8-unsubstituted analogue 3 was 6-fold less potent, but had comparable differential cytotoxicity in vitro. The most effective novel hypoxia-selective cytotoxins synthesized were the bifunctional 2-nitro-imidazole derivative 1,2-dihydro-8-((4-(3-(2-nitro-1-imidazoyl)-1-hydroxypropyl)- piperazin-1-yl))-4-phenylimidazo [1,2-a] quinoxaline 5-oxide bishydrochloride (37) and its 9-aza analogue 38. These compounds also exhibited the lowest aerobic toxicities in vitro of the new compounds.
Naylor
M A
MA
Department of Medicinal Chemistry, MRC Radiobiology Unit, Didcot, Oxon, UK.
Stephens
M A
MA
Nolan
J
J
Sutton
B
B
Tocher
J H
JH
Fielden
E M
EM
Adams
G E
GE
Stratford
I J
IJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007093:Imidazoles; D011719:Pyrazines; D011810:Quinoxalines