The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium-catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide in N,N-dimethylformamide containing triethylamine gives 2-alkynyladenosines (5a-r). An economical synthetic method for the preparation of 9-(2,3,5-tri-O-acetyl-1-beta-D-ribofuranosyl)-6-chloro-2-iodopurine++ + (2), which is a precursor of 4a, is also included. Several transformation reactions of 2-(1-octyn-1-yl)adenosine (5e) and 2-(1-ethyn-1-yl)adenosine (9) and a similar cross-coupling reaction of 6-chloropurine derivative 11 and 8-bromoadenosine (13) with 1-octyne are also reported. Many of these 2-alkynyladenosines tested for A1 and A2 adenosine receptor binding activities in rat brain are selective for the A2 adenosine receptor. Among them, 2-(1-hexyn-1-yl)adenosine (5c) has the highest affinity for both A1 and A2 receptors with Ki values of 126.5 and 2.8 nM, respectively. The structure-activity relationship of this series of compounds including 6- or 8-alkynylpurine nucleosides and 2-alkyl- and 2-alkenyladenosines is discussed in terms of potency at both receptor subtypes. Additionally, we describe how hypotensive activity and heart rate decrease brought on by 5 and some other compounds with spontaneously hypertensive rats are proportional to the order of the potency to both A1 and A2 binding affinities. Thus, 2-alkynyladenosines are interesting and promising as antihypertensive agents that should be considered for further detailed preclinical evaluation.

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A phase Ia study of a 2-nitroimidazole nucleoside analog radiosensitizer doranidazole was conducted to evaluate its toxicity and pharmacokinetics in patients undergoing conventional external beam radiotherapy. Twenty-nine patients, aged 40-74 years, with a WHO performance status of 0-2 and with adequate organ functions, were entered in the study. Single administration of doranidazole was investigated first with 13 patients and then a course of five consecutive daily administrations was tested in 16 patients. Doranidazole was given i.v. 25 min before irradiation. Doranidazole doses of 400, 800, 1300 and 2000 mg/m2 were evaluated in the former study, and daily doses of 800, 1300 and 2000 mg/m2 were investigated in the latter study. All patients tolerated doranidazole administration. Although a transient decrease in the 24-h creatinine clearance rate was observed in five patients (one in the single administration study and four in the repeat administration study), this was not considered to be the dose-limiting toxicity. Other toxicities (hematological and gastrointestinal), which may not be related to doranidazole administration, were also mild and were not dose limiting. No neurotoxicity was observed. The average maximum concentration, area under the time-concentration curve and half-life of doranidazole in serum were 172-194 microg/ml, 502-582 microg x h/l and 4.2-4.6 h, respectively, at 2000 mg/m2. At the tested doses, administration of doranidazole was tolerable and achieved serum concentrations at which reasonable radiosensitization could be expected. A phase Ib/II study to evaluate the feasibility and efficacy of up to 30 repeat administrations seems to be warranted.