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

评估了三类化合物的DNA裂解活性和对低氧肿瘤细胞放射治疗的适用性：(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异构化形式的炔丙基砜；(C)具有电子亲合硝唑结构的具有缺氧细胞敏化活性的炔丙基砜。得到以下结论：(1)证实了10元1，5-二炔类化合物是具有DNA裂解活性的前体药物，在酸性条件下具有DNA裂解活性，具有细胞缺氧的特点。含离酯基的化合物比含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1，5-二炔类化合物具有几乎相同的DNA嵌入能力，但后者具有更高的DNA切割活性。这表明dna的裂解可能是串…。(3)含2-硝基咪唑结构的炔丙基砜类化合物对EMT6/KU细胞表现出低氧选择性细胞毒作用。评价了这些新型丙叉砜的DNA裂解活性、谷胱甘肽捕获活性、细胞通透性和放射增敏活性。(4)合成了不同取代基的丙叉砜，考察了异构化率、DNA裂解活性和对小鼠肿瘤细胞的细胞毒作用，从而阐明了前药的激活机理。(5)引入吸电子硝基后，丙叉磺酸化合物具有较高的谷胱甘肽捕获活性，但亲水性较差。通过引入额外的亲水基团，在保持相对较高的谷胱甘肽捕获反应活性的情况下，炔丙基砜化合物恢复了在水中的溶解性，从而改善了这一点。较少

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