Chemical properties which control selectivity and efficacy of aromatic N-oxide bioreductive drugs.
Pulse radiolysis was used to generate radicals from one electron reduction of 1,2,4-benzotriazine-1,4-dioxides (derivatives of tirapazamine), and of imidazo [1,2-a]quinoxaline-4-oxides (analogues of RB90740), which have selective toxicity towards hypoxic cells. Radicals from the mono N-oxides (from the latter compounds) react with oxygen approximately 10-40 times faster than does the tirapazamine radical. Radicals from the tirapazamine analogues studied react with oxygen up to approximately 10 times slower than tirapazamine radicals. The quinoxaline N-oxide radicals are involved in prototropic equilibria with pK(a) values (5.5 to 7.4) spanning that reported for tirapazamine (6.0). Generation of radicals radiolytically in the presence of H donors (formate, 2-propanol, deoxyribose) indicate a chain reaction ascribed to H abstraction by the drug radical. The protonated drug radical is much more reactive than the radical anion (H abstraction rate constant approximately equal to 10(2) - 10(3) dm3 mol-1 s-1). Chain termination is ascribed to drug radical-radical reactions, i.e. radical stability in anoxia, with rate constants 2k approximately equal to 1 x 10(7) to 2 x 10(8) dm3 mol-1 s-1 at pH approximately 7.4. Estimates of the reduction potentials of the drug-radical couples in water at pH 7 for two of the mono-N-oxides were in the range-0.7 to 0.8 V vs NHE at pH 7.
Wardman
P
P
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Priyadarsini
K I
KI
Dennis
M F
MF
Everett
S A
SA
Naylor
M A
MA
Patel
K B
KB
Stratford
I J
IJ
Stratford
M R
MR
Tracy
M
M
D000970:Antineoplastic Agents / Q000737:chemistry*; D005609:Free Radicals; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D010087:Oxides / Q000737:chemistry; D011675:Pulse Radiolysis; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D005609:Free Radicals; D010087:Oxides; D011719:Pyrazines; C087409:RB 90740; D014227:Triazines; D000077704:Tirapazamine