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

评价了三类化合物的DNA裂解活性和对缺氧肿瘤细胞的放射治疗的适用性：（A）通过生物活化重排为不稳定的烯二炔结构的10元1，5-二炔化合物，（B）碱诱导异构化为活化的丙二烯形式的炔丙基砜，（C）具有亲电子硝基唑结构的炔丙基砜，其具有缺氧细胞敏化活性。得出以下结论。(1)10-元1，5-二炔化合物被证实是在缺氧细胞特有的酸性条件下显示DNA切割活性的前药。具有离去酯基的化合物比具有羟基或甲氧基的类似物的活性高10倍。(2)含苯基和2-萘基的10元1，5-二炔类化合物的DNA嵌入能力基本相当，而2-萘基的10元1，5-二炔类化合物的DNA切割活性较高。这表明DNA断裂可能是强的， ...更多信息 仅受嵌入DNA双链时的空间排列的影响。(3)具有2-硝基咪唑结构的炔丙基砜被证实是对EMT 6/KU细胞显示低氧选择性细胞毒性的前药。对这些新型炔丙基砜的DNA切割活性、谷胱甘肽捕获反应性、细胞渗透性和放射增敏活性进行了评价。(4)合成了具有不同取代基的炔丙基砜，以评价异构化为活化的丙二烯形式的速率、DNA切割活性和对小鼠肿瘤细胞的细胞毒性，从而阐明前药的活化机制。(5)引入吸电子硝基后，炔丙基砜类化合物具有更高的谷胱甘肽捕获活性，但亲水性较差。这通过引入额外的亲水基团得到改善，通过该亲水基团，炔丙基砜化合物恢复了在水中的溶解度，同时保持相对高的谷胱甘肽捕获反应性。少

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