The bifunctional hypoxia-specific cytotoxin RB90745, has a nitroimidazole moiety attached to an imidazol[1,2-a]quinoxaline mono-N-oxide with a spacer/linking group. The reduction chemistry of the drug was studied by pulse radiolysis using the one electron reductant CO2.-. As N-oxides and nitro compounds react with CO2.- at diffusion controlled rates, initial reaction produced a mixture of the nitro radical (lambda max 410 nm) and the N-oxide radical (lambda max 550 nm) in a few microseconds. Subsequently an intramolecular electron transfer (IET) was observed (k = 1.0 +/- 0.25 x 10(3) s-1 at pH 5-9), from the N-oxide to the more electron-affinic nitro group. This was confirmed by the first order decay rate of the radical at 550 nm and formation at 410 nm, which was independent of both the concentration of the parent compound and the radicals. The rates of electron transfer and the decay kinetics of the nitro anion radicals were pH dependent and three different pKas could be estimated for the one electron reduced species: 5.6 (nitroimidazole group) and 4.3, and 7.6 (N-oxide function). The radicals react with oxygen with rate constants of 3.1 x 10(7) and 2.8 x 10(6) dm3 mol-1 s-1 observed at 575 nm and 410 nm respectively. Steady state radiolysis studies indicated four electron stoichiometry for the reduction of the compound.

Anti-Cancer Drug Design

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

作者: Adams, G. E. ; Sutton, B. ; Stephens, M. A. ; Tocher, J. H. ; Nolan, J. ; Stratford, I. J. ; Naylor, M. A. ; Fielden, E. M.

A series of imidazo[1,2-a]quinoxaline mono-N-oxides and their 6- and 9-aza analogs, e.g., I (R = R¹ = H, Y = N, Y¹ = CH; R = piperidino, R¹ = H, Y = N, CH, Y¹ = CH; R = 4-methylpiperazino, R¹ = H, Y = N, CH, Y¹ = CH, ; R = H, R¹ = 4-methylpiperazino, Y = Y¹ = N; etc.), 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 I (R = 4-methylpiperazino, R¹ = H, Y = N, Y¹ = CH) had differential hypoxic:oxic toxicity of 15.3 and some novel analogs 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 I (R = morpholino, R¹ = H, Y = N, CH, Y¹ = CH) had differential hypoxic:oxic toxicities of 3-4.Substitution of the 4-Ph 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 analog I (R = R¹ = H, Y = N, Y¹ = CH) was 6-fold less potent, but had comparable differential cytotoxicity in vitro.The most effective novel hypoxia-selective cytotoxins synthesized were the bifunctional 2-nitroimidazole derivative 1,2-dihydro-8-[(4-(3-(2-nitro-1-imidazolyl)-1-hydroxypropyl)piperazin-1-yl)]-4-phenylimidazo[1,2-a]quinoxaline 5-oxide bishydrochloride (II) and its 9-aza analog.These compounds also exhibited the lowest aerobic toxicities in vitro of the new compounds

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