Electron-affinic radiosensitizers possessing NPSH-reactive side chains: cytotoxicity and radiosensitizing activity towards hypoxic EMT6 cells in vitro.
Electron-affinic radiosensitizers possessing NPSH-reactive side chains: cytotoxicity and radiosensitizing activity towards hypoxic EMT6 cells in vitro.
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具有 NPSH 反应性侧链的亲电子放射增敏剂：体外对缺氧 EMT6 细胞的细胞毒性和放射增敏活性。
DOI：
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发表时间：
1995
影响因子：
2.6
通讯作者：
S. Nishimoto
中科院分区：
文献类型：
--
作者：
L. Zhou;S. Nishimoto
合成了一类由亲电子硝唑环和硫醇反应性 α、β-不饱和羰基侧链组成的新型双功能硝唑衍生物，以评估其理化性质、与谷胱甘肽 (GSH) 的反应性以及对 EMT6/KU 细胞的体外细胞毒性和放射增敏活性。在这类硝基唑化合物中，具有反式CH2CH=CHCO2CH3共同侧链结构的2-硝基咪唑衍生物(1)、3-硝基-1,2,4-三唑衍生物(2)和2-甲基-4-硝基咪唑衍生物(3)很容易在磷酸盐缓冲溶液(pH 7.2，310 K)中与GSH反应。这些化合物对需氧和缺氧 EMT6/KU 细胞均表现出比相应的具有 CH2CH2CH2CO2CH2CH3 侧链结构的 α、β 饱和对应物 (6-8) 更高的细胞毒性。 1 和 2 的缺氧细胞毒性与米索硝唑 (9) 具有相似的电子亲和力，其缺氧细胞毒性是通过 α、β-不饱和羰基侧链消耗非蛋白硫醇 (NPSH) 和硝唑环生物还原的综合作用而增强的。 1.0 mmol dm-3 剂量下的体外增敏剂增强比 (SERvitro) 为 1 (2.80 +/- 0.20) 和 2 (2.63 +/- 0.27) 与氧增强比 (OER = 2.90 +/- 0.10) 相当，并且显着大于其各自对应物 6 (1.28 +/- 0.06) 和 7 （1.22+/-0.09）。亲电子性较低的化合物 3 也产生较大的 SERvitro = 1.80 +/- 0.18，而对应的 8 在放射增敏缺氧细胞中无效 (1.10)。化合物1-3不仅改变了斜率，而且还减小了剂量-存活曲线的肩部。通过 C1-6 测量，这些“双功能”硝唑放射增敏剂显示出比先前报道的“异常”放射增敏剂（例如 5-取代 4-硝基咪唑放射增敏剂）低得多的体外放射增敏水平。
A new class of dual-function nitroazole derivatives that are composed of electron-affinic nitroazole rings and a thiol-reactive alpha, beta-unsaturated carbonyl side chain were synthesized to evaluate their physico-chemical properties, reactivity with glutathione (GSH), and cytotoxicity and radiosensitizing activity towards EMT6/KU cells in vitro. Among this class of nitroazole compounds, 2-nitroimidazole-derivative (1), 3-nitro-1,2,4-triazole derivative (2), and 2-methyl-4-nitroimidazole derivative (3) with a common side-chain structure of trans CH2CH = CHCO2CH3 readily reacted with GSH in phosphate-buffer solution (pH 7.2, 310 K). These compounds showed higher cytotoxicities to both aerobic and hypoxic EMT6/KU cells than the corresponding alpha, beta-saturated counterparts (6-8) with a side-chain structure of CH2CH2CH2CO2CH2CH3. The hypoxic cytotoxicity of 1 and 2 with similar electron affinities to that of misonidazole (9) was potentiated by the combined effects of depletion of non-protein thiols (NPSH) by the alpha, beta-unsaturated carbonyl side chains and bioreduction of the nitroazole rings. The sensitizer enhancement ratios in vitro (SERvitro) of 1 (2.80 +/- 0.20) and 2 (2.63 +/- 0.27) at a dose of 1.0 mmol dm-3 are comparable with the oxygen enhancement ratio (OER = 2.90 +/- 0.10) and are significantly larger than those of their respective counterparts 6 (1.28 +/- 0.06) and 7 (1.22 +/- 0.09). A less electron-affinic compound, 3, also gave a large SERvitro = 1.80 +/- 0.18, whereas the counterpart 8 was not effective (1.10) in radiosensitizing hypoxic cells. Compounds 1-3 not only altered the slope, but also reduced the shoulder of the dose-survival curve. These 'dual-function' nitroazole radiosensitizers show much lower levels of in vitro radiosensitization, as measured by the C1-6, than the previously reported 'anomalous' radiosensitizers such as 5-substituted 4-nitroimidazole radiosensitizers.
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DOI：
10.1016/0360-3016(82)90388-1
发表时间：
1982
期刊：
International journal of radiation oncology, biology, physics
影响因子：
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作者：
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DOI：
10.1016/0360-3016(86)90244-0
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期刊：
International journal of radiation oncology, biology, physics
影响因子：
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作者：
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DOI：
10.1016/0360-3016(82)90649-6
发表时间：
1982
期刊：
International journal of radiation oncology, biology, physics
影响因子：
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作者：
Astor,M;Hall,EJ;Martin,J;Flynn,M;Biaglow,J;Parham,JC
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Parham,JC
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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