Synthesis and Photocytotoxicity of S-Glucosylated 5,10,15,20-Tetrakis(tetrafluorophenyl)porphyrin Metal Complexes as Efficient 1O2-Generating Glycoconjugates
Synthesis and Photocytotoxicity of S-Glucosylated 5,10,15,20-Tetrakis(tetrafluorophenyl)porphyrin Metal Complexes as Efficient 1O2-Generating Glycoconjugates
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DOI：
10.1021/bc800522y
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发表时间：
2009-05-01
影响因子：
4.7
通讯作者：
Tanihara, Masao
中科院分区：
文献类型：
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作者：
Hirohara, Shiho;Obata, Makoto;Tanihara, Masao
通过亲核取代，以优异的产率制备了 5,10,15,20-四(4-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖硫基)-2,3,5,6-四氟苯基)卟啉 2a 及其 Zn(II)、Pd(II) 和 Pt(II) 配合物 2b、2c 和 2d。游离碱卟啉和金属卟啉与乙酰基 2,3,4,6-四-O-乙酰基-1-硫代-β-D-吡喃葡萄糖苷。通过碱性水解对2a、2b、2c和2d进行脱保护，得到相应的S-葡萄糖基化卟啉3a及其金属配合物3b、3c和3d。所有新型光敏剂的结构和纯度均通过元素分析以及 H-1、C-13 和 F-19 NMR、UV-vis 和稳态发光光谱进行了确认。单线态氧 (O-1(2)) 产生的相对效率按照游离碱氟卟啉 (2a 和 3a) < Zn(II) 配合物 (2b 和 3b) < Pd(II) 配合物 (2c 和 3c) 的顺序增加，这可以用重原子效应来解释，而 Pt(II) 配合物 (2d 和 3d) 的 O-1(2) 产生效率异常低。在 HeLa 细胞中检查了这八种 S-葡萄糖基化光敏剂的体外光细胞毒性。尽管所有受保护的光敏剂2a、2b、2c和2d均未表现出光细胞毒性，但光敏剂3a、3b和3c却表现出有效的光细胞毒性。这些结果清楚地表明，3a、3b 和 3c 的糖部分不仅充当水溶性增强功能，而且充当细胞摄取增强元件。在活性氧抑制剂存在下对 3a、3b 和 3c 进行的光细胞毒性测试表明，O-1(2) 是细胞死亡的主要介质。因此，Zn(II) 和 Pd(II) 配合物 3b 和 3c 是有前途的光敏剂，具有细胞摄取促进单元（糖部分）并由于重原子效应而增强了 O-1(2) 的生成。
5,10,15,20-Tetrakis(4-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosylthio)-2,3,5,6-tetrafluorophenyl)porphyrin 2a and its Zn(II), Pd(II), and Pt(II) complexes 2b, 2c, and 2d were prepared in excellent yields by nucleophilic substitution of the corresponding free-base porphyrin and metalloporphyrins with acetyl 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranoside. Deprotection of 2a, 2b, 2c, and 2d by alkaline hydrolysis afforded the corresponding S-glucosylated porphyrin 3a and its metal complexes 3b, 3c, and 3d. The structures and purity of all new photosensitizers were confirmed by elemental analysis and H-1, C-13, and F-19 NMR, UV-vis, and steady-state luminescence spectroscopy. The relative efficiency of singlet oxygen (O-1(2)) production increased in the order of free-base fluoroporphyrins (2a and 3a) < Zn(II) complexes (2b and 3b) < Pd(II) complexes (2c and 3c), which can be explained in terms of the heavy-atom effect, while the O-1(2)-producing efficiency of Pt(II) complexes (2d and 3d) were exceptionally low. In vitro photocytotoxicity of these eight S-glucosylated photosensitizers was examined in HeLa cells. Although all protected photosensitizers 2a, 2b, 2c, and 2d showed no photocytotoxicity, the photosensitizers 3a, 3b, and 3c exerted potent photocytotoxicity. These results clearly indicated that the sugar moieties of 3a, 3b, and 3c act as not only water-solubility-enhancing functionalities but also cellular-uptake-enhancing elements. Photocytotoxicity testing of 3a, 3b, and 3c in the presence of reactive oxygen species inhibitors suggested that O-1(2) is the major mediator of cell death. Hence, the Zn(II) and Pd(II) complexes 3b and 3c are promising photosensitizers having cellular uptake-facilitating units (sugar moieties) and enhanced O-1(2) generation due to the heavy-atom effect.