Design, synthesis, and radiosensitizing activities of sugar-hybrid hypoxic cell radiosensitizers

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• 作者：Takashi Nakae ; Yoshihiro Uto ; Motoko Tanaka ; Haruna Shibata ; Eiji Nakata ; Masahide Tominaga ; Hiroshi Maezawa ; Toshihiro Hashimoto ; Kenneth L. Kirk ; Hideko Nagasawa ; Hitoshi Hori
• 关键词：Hypoxic cell radiosensitizers ; Sugar-hybrids ; Electronic states ; Hydrophobicity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 January 2008
• 年：2008
• 卷：16
• 期：2
• 页码：675-682
• 全文大小：597 K

文摘

We have designed sugar-hybrid TX-1877 derivatives conjugated with sugar moieties including β-glucose (β-Glc), β-galactose (β-Gal), α-mannose (α-Man) and N-acetyl-β-galactosamine (β-GalNAc). Compound 1 (TX-1877) was glycosylated with appropriate peracetylated sugars using BF₃-OEt₂ to give acetylated sugar-hybrids, 5 (TX-2244), 6 (TX-2245), 7 (TX-2246), and 10 (TX-2243). Removal of the acetyl groups afforded the sugar-hybrids having free hydroxyl groups, 11 (TX-2141), 12 (TX-2218), 13 (TX-2217) and 14 (TX-2068). We evaluated their radiosensitizing activities by an in vitro radiosensitization assay. All free hydroxyl hybrids have lower enhancement ratio (ER) values (ER less-than-or-equals, slant"" border=0> 1.43) and lower n-octanol/water partition coefficient (P_oct) values (P_oct < 1.00 × 10⁻²) than does 1 (TX-1877, ER = 1.75, P_oct: 5.60 × 10⁻²). All acetylated hybrids have similar P_oct values (3.55 × 10⁻²–1.05 × 10⁻¹) to 1 (TX-1877) and have improved ER values (ER 1.47) compared to the hybrids having free hydroxyl groups. Among these, 5 (TX-2244) is the most active radiosensitizer (ER = 2.30). We found a good correlation (r = 0.866) between the magnitude of P_oct (logP_oct) and the ER value of 5 (TX-2244), 6 (TX-2245), 7 (TX-2246), 10 (TX-2243) and 1 (TX-1877), suggesting that increasing the hydrophobicity is reflected in increased in vitro radiosensitizing activity. In the present study, we have succeeded in producing sugar-hybrid hypoxic cell radiosensitizers that have an increased radiosensitizing activity that does not depend on increased hydrophobicity.