title: 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 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.
authors.affiliation: Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Minamijosanjimacho-2, Tokushima 770-8506, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakae
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Motoko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Haruna
authors.initials: H
authors.lastname: Shibata
authors.forename: Eiji
authors.initials: E
authors.lastname: Nakata
authors.forename: Masahide
authors.initials: M
authors.lastname: Tominaga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maezawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Kirk
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D000465:Algorithms; D002241:Carbohydrates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C115855:2-nitroimidazole acetamide; D002241:Carbohydrates; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents