Preparation, properties, reactions, and adenosine receptor affinities of sulfophenylxanthine nitrophenyl esters: toward the development of sulfonic acid prodrugs with peroral bioavailability.
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(1), A(2A), and A(2B), but not at A(3) ARs. One of the most potent compounds was 1-propyl-8-[4-[[p-nitrophenoxy]sulfonyl]phenyl]xanthine (9d), a mixed A(1)/A(2B) antagonist (K(i)A(1) 3.6 nM, K(i)A(2B) 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.
Yan
Luo
L
University of Bonn, Pharmaceutical Chemistry Poppelsdorf, Pharmaceutical Sciences, Bonn, Germany.
Müller
Christa E
CE
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D004355:Drug Stability; D004952:Esters; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C483206:1-butyl-8-(4-((4-nitrophenoxy)sulfonyl)phenyl)xanthine; C483205:1-propyl-8-(4-((4-nitrophenoxy)sulfonyl)phenyl)xanthine; C518874:1-propyl-8-(4-sulfophenyl)xanthine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D004952:Esters; D009578:Nitrobenzenes; D011355:Prodrugs; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D013451:Sulfonic Acids; D014970:Xanthines