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

Abstract

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 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 (ER ⩽ 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 (log P 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.