title: Novel nitroimidazole alkylsulfonamides as hypoxic cell radiosensitisers.
abstract: A novel class of nitroimidazole alkylsulfonamides have been prepared and evaluated as hypoxia-selective cytotoxins and radiosensitisers. The sulfonamide side chain markedly influences the physicochemical properties of the analogues: lowering aqueous solubility and raising the electron affinity of the nitroimidazole group. The addition of hydroxyl or basic amine groups increased aqueous solubility, with charged amine groups contributing to increased electron affinity. The analogues covered the range of electron affinity for effective radiosensitisation with one-electron reduction potentials ranging from -503 to -342mV. Cytotoxicity under normoxia or anoxia against a panel of human tumour cell lines was determined using a proliferation assay. 2-Nitroimidazole sulfonamides displayed significant hypoxia-selective cytotoxicity (6 to 64-fold), while 4- and 5-nitroimidazole analogues did not display hypoxia-selective cytotoxicity. All analogues sensitised anoxic HCT-116 human colorectal cells to radiation at non-toxic concentrations. 2-Nitroimidazole analogues provided modest sensitisation due to the relatively low concentrations used while several 5-nitroimidazole analogues provided equivalent sensitisation to misonidazole and etanidazole at similar molar concentrations.
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Muriel
authors.initials: M
authors.lastname: Bonnet
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Cho Rong
authors.initials: CR
authors.lastname: Hong
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Yongchuan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Anderson
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Jingli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Hicks
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: m.hay@auckland.ac.nz.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides
keywords: Hypoxia; Nitroimidazole; Radiosensitiser; Sulfonamide