Radiosensitizing Effect of Antitumor Enediyne Prodrugs Possessing DNA-Cleaving Activity under Hypoxic Conditions

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DNA-Cleaving activity and applicability to radiation therapy of hypoxic-tumor cells are evaluated for three classes of compounds: (A) 10-membered 1,5-diyne compounds that are rearranged to unstable enediyne structures by bioactivation, (B) propargylic sulfones that are base-induced isomerized to activated allenic forms, (C) propargylic sulfones with electron-affinic nitroazole structures possessing hypoxic-cell sensitizing activity. The following conclusions were obtained.(1) 10-Membered 1,5-diyne compounds are confirmed to be prodrugs showing DNA-cleaving activity under acidic conditions that are characteristic of hypoxic cells. The compounds with leaving ester groups were 10 times more active than the analogues with hydroxyl group or methoxy group.(2) While 10-membered 1,5-diyne compounds with phenyl group and 2-naphtyl group, respectively, have almost equivalent DNA-intercalating ability, the latter showed higher DNA-cleaving activity. This indicates that the DNA cleavage may be str … More ongly influenced by the spatial arrangement upon intercalation into DNA double strand.(3) Propargylic sulfones bearing 2-nitroimidazole structures were confirmed to be prodrugs that showed hypoxic selective cytotoxicity towards EMT6/KU cells. The DNA-cleaving activity, glutathione-capturing reactivity, cell permeability, and radiosensitizing activity of these novel propargylic sulfones were evaluated.(4) Propargylic sulfones bearing various substituents were synthesized to evaluate rate of the isomerization to activated allenic forms, DNA-cleaving activity, and cytotoxicity towards mouse tumor cells, thus elucidating activation mechanism of the prodrugs.(5) Upon introduction of electron withdrawing nitro group the propargylic sulfone compounds have higher glutathione capturing reactivity but less hydrophilic property. This was improved by introduction of additional hydrophilic groups, by which the propargylic sulfone compounds recovered solubility in water with maintaining relatively high glutathione-capturing reactivity. Less