2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives.
A series of 2-nitroimidazoles bearing side chains terminating in or containing aziridinyl and oxiranyl groups has been prepared, and the compounds were evaluated in vitro as hypoxia-selective bioreductively-activated cytotoxins and selected compounds tested for their radiosensitizing properties toward hypoxic mammalian cells. Compounds were either the regioisomers of analogues of the potent dual-functional 2-nitroimidiazole alpha-[(1-aziridinyl)-methyl]-2-nitro-1H-imidazole-1- ethanol (RSU-1069, 1) with additional methyl groups or related oxiranes of varying side-chain length and type. Oxiranyl derivatives showed little differential toxicity, and those tested were less effective as radiosensitizers, and although these properties were influenced by side-chain length, differences were not great. Aziridinyl compounds related to 1 but with increased side-chain lengths were unstable. Methylation of 1 in various regions had little effect on radiosensitization and no clear advantages over 1 as differential cytotoxic drugs. Progressive methylation at C-3 was found to increase toxicity but decrease hypoxia selectivity. Incorporation of a cyclohexane side chain in 1,2-cis-2,3-trans-3-aziridin-1-yl-2-hydroxy-1-(2-nitroimidazol+ ++-1- yl)cyclohexane (26) abolished hypoxia-selective toxicity and unexpectedly reduced radiosensitizing efficiency. Of the aziridines, 1-(2-nitro-1-imidazolyl)-2-methyl-3-(1-aziridinyl)-2-propanol (20) was comparable in efficacy to 1 as a bioreductively-activated cytotoxin with slightly lower aerobic toxicity; however, the prodrugs of 1 remain as preferred candidates for clinical evaluation.
Naylor
M A
MA
MRC Radiobiology Unit, Chilton, Didcot, Oxon, United Kingdom.
Threadgill
M D
MD
Webb
P
P
Stratford
I J
IJ
Stephens
M A
MA
Fielden
E M
EM
Adams
G E
GE
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001388:Aziridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007536:Isomerism; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D001388:Aziridines; D009593:Nitroimidazoles