120362-47-2Relevant academic research and scientific papers
Preparation, Properties, Reactions, and Adenosine Receptor Affinities of Sulfophenylxanthine Nitrophenyl Esters: Toward the Development of Sulfonic Acid Prodrugs with Peroral Bioavailability
Yan, Luo,Müller, Christa E.
, p. 1031 - 1043 (2007/10/03)
Many currently known antagonists for P2 purinergic receptors are anionic molecules bearing one or several phenylsulfonate groups. Among the P1 (adenosine) receptor antagonists, the xanthine phenylsulfonates are a potent class of compounds. Due to their high acidity, phenylsulfonates are negatively charged at physiologic pH values and do not easily penetrate cell membranes. The present study was aimed at developing lipophilic, perorally bioavailable prodrugs of sulfonates by converting them into chemically stable nitrophenyl esters. Initial stability tests at different pH values using nitrophenyl tosylates as model compounds showed that m-nitrophenyl esters were stable over a wide pH range, while the ortho and para isomers were less stable under strongly acidic or basic conditions. A series of m- and p-nitrophenyl esters of p-sulfophenylxanthine derivatives were synthesized as model compounds. The target xanthine derivatives were obtained in high yields by condensation of the appropriate 5,6-diaminouracils with 4-(nitrophenoxysulfonyl)benzoic acids in the presence of a carbodiimide, followed by ring closure with polyphosphoric acid trimethylsilyl ester. The chemical and enzymatic stability of the m-nitrophenyl esters was investigated in vitro by means of capillary electrophoresis. High stability in aqueous solution, in artificial gastric acid, and in serum was observed. However, compound 5d, used as a prototypic xanthine m-nitrophenylsulfonate, was hydrolyzed by rat liver homogenate indicating an enzymatic pathway of hydrolysis. Thus, nitrophenyl esters of sulfonic acids have a potential as peroral prodrugs of drugs bearing a sulfonate group. The nitrophenyl esters of sulfophenylxanthines were additionally investigated for their adenosine receptor affinities. They showed high affinity at A 2, A2A, and A2B, but not at A3 ARs. One of the most potent compounds was 1-propyl-8-[4-[[p-nitrophenoxy]sulfonyl]-phenyl]xanthine (9d), a mixed A 1/A2B antagonist (KiA1 3.6 nM, KiA2B 5.4 nM) selective versus the other subtypes. As a further result of this study, the m-nitrophenoxy group was found to be a suitable protecting group for sulfonates in organic synthesis due to its high lipophilicity and stability; it can be split off under strongly basic conditions. This new protection strategy allowed for the upscaling of the synthesis of 1-propyl-8-p-sulfophenylxanthine (PSB-1115), a selective A 2B antagonist.
Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions
Shamim,Ukena,Padgett,Daly
, p. 1231 - 1237 (2007/10/02)
The effects of 8-phenyl and 8-cycloalkyl substituents on the activity of theophylline, caffeine, 1,3-dipropylxanthine, 1,3-dipropyl-7-methylxanthine, 3-propylxanthine, and 1-propylxanthine at A1 adenosine receptors of rat brain and fat cels and at A2 adenosine receptors of rat pheochromocytoma PC12 cells and human platelets are compared. An 8-phenyl substituent has little effect on the activity of caffeine or 1,3-dipropyl-7-methylxanthine at adenosine receptors, while markedly increasing activity of theophylline, 1,3-dipropylxanthine, 1-isoamyl-3-isobutylxanthine, 1-methylxanthine, and 3-propylxanthine. 8-Phenyl-1-propylxanthine is potent (K(i) = 20-70 nM) at all receptors. A p-carboxy or p-sulfo substituent, which is introduced on the 8-phenyl ring to increase water solubility, in most cases decreases the activity and selectivity for the A1 receptor. Among the 8-p-sulfo analogues, only 8-(p-sulfophenyl)theophylline and 1,3-dipropyl-8-(p-sulfophenyl)xanthine are selective for the A1 receptors. 8-p-Sulfophenyl derivatives of caffeine, 1,3-dipropyl-7-methylxanthine, and 3-propylxanthine are somewhat selective for the A2 receptors. 8-Cycloalkyl substituents (cyclopentyl, cyclohexyl) markedly increase activity of caffeine and 1,3-dipropyl-7-methylxanthine at the A2 receptor. 8-Cyclohexylcaffeine is potent (K(i) = 190 nM) and very selective for the human platelet A2 receptors, but is not as selective for the rat PC12 cell A2 receptor. Such A2 selectivity is in contrast to the marked A1 selectivity of 8-cycloalkyltheophyllines and 8-cycloalkyl-1,3-dipropylxanthines. The apparent selectivity of certain xanthines is dependent on the assay systems that are compared.
