Heterocyclic mono-N-oxides with potential applications as bioreductive anti-tumour drugs: Part 1. 8-Alkylamino-substituted phenylimidazo [1,2-a] quinoxalines.
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Резюме
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.