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

We have designed sugar-hybrid TX-1877 derivatives conjugated with sugar moieties including beta-glucose (beta-Glc), beta-galactose (beta-Gal), alpha-mannose (alpha-Man) and N-acetyl-beta-galactosamine (beta-GalNAc). Compound 1 (TX-1877) was glycosylated with appropriate peracetylated sugars using BF(3)-OEt(2) 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 (ER1.43) and lower n-octanol/water partition coefficient (P(oct)) values (P(oct)<1.00x10(-2)) than does 1 (TX-1877, ER=1.75, P(oct): 5.60x10(-2)). All acetylated hybrids have similar P(oct) values (3.55x10(-2)-1.05x10(-1)) to 1 (TX-1877) and have improved ER values (ER>or=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.