A1 Refereed original research article in a scientific journal
Bisphosphonate derivatives of nucleoside antimetabolites: Hydrolytic stability and hydroxyapatite adsorption of 5 '-beta,gamma-methylene and 5 '-beta,gamma-(1-hydroxyethylidene) triphosphates of 5-fluorouridine and ara-cytidine
Authors: Ora M, Lonnberg T, Florea-Wang D, Zinnen S, Karpeisky A, Lonnberg H
Publisher: AMER CHEMICAL SOC
Publication year: 2008
Journal:: Journal of Organic Chemistry
Journal name in source: JOURNAL OF ORGANIC CHEMISTRY
Journal acronym: J ORG CHEM
Volume: 73
Issue: 11
First page : 4123
Last page: 4130
Number of pages: 8
ISSN: 0022-3263
DOI: https://doi.org/10.1021/jo800317e
Abstract
Kinetics of the hydrolytic reactions of four bisphosphonate derivatives of nucleoside anti metabolites, viz., 5-fluorouridine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate (4), 5-fluorouridine 5'-beta,gamma-methylene triphosphate (5), ara-cytidine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate (6), and ara-cytidine 5'-beta,gamma-methylene triphosphate (7), have been studied over a wide pH range (pH 1.0-8.5) at 90 degrees C. With each compound, the disappearance of the starting material was accompanied by formation of the corresponding nucleoside 5'-monophosphate, the reaction being up to 2 orders of magnitude faster with the beta,gamma-(1-hydroxyethylidene) derivatives (4, 6) than with their beta,gamma-methylene counterparts (5, 7). With compound 7, deamination of the cytosine base competed with the phosphate hydrolysis at pH 3-6. The measurements at 37 degrees C (pH 7.4) in the absence and presence of divalent alkaline earth metal ions (Mg(2+) and Ca(2+)) showed no sign of metal ion catalysis. Under these conditions, the initial product, nucleoside 5'-monophosphate, underwent rapid dephosphorylation to the corresponding nucleoside. Hydrolysis of the beta,gamma-methylene derivatives (5, 7) to the corresponding nucleoside 5'-monophosphates was markedly faster in mouse serum than in aqueous buffer (pH 7.4), the rate-acceleration being 5600- and 3150-fold with 5 and 7, respectively. In human serum, the accelerations were 800- and 450-fold compared to buffer. In striking contrast, the beta,gamma-(1-hydroxyethylidene) derivatives did not experience a similar decrease in hydrolytic stability. The stability in human serum was comparable to that in aqueous buffer (tau(1/2) = 17 and 33 h with 4 and 6, respectively), and oil going to mouse serum, a 2- to 4-fold acceleration was observed. To elucidate the mineral-binding properties of 4-7, their retention on a hydroxyapatite column was studied and compared to that of zoledronate (1a) and nucleoside mono-, di-, and triphosphates.
Kinetics of the hydrolytic reactions of four bisphosphonate derivatives of nucleoside anti metabolites, viz., 5-fluorouridine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate (4), 5-fluorouridine 5'-beta,gamma-methylene triphosphate (5), ara-cytidine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate (6), and ara-cytidine 5'-beta,gamma-methylene triphosphate (7), have been studied over a wide pH range (pH 1.0-8.5) at 90 degrees C. With each compound, the disappearance of the starting material was accompanied by formation of the corresponding nucleoside 5'-monophosphate, the reaction being up to 2 orders of magnitude faster with the beta,gamma-(1-hydroxyethylidene) derivatives (4, 6) than with their beta,gamma-methylene counterparts (5, 7). With compound 7, deamination of the cytosine base competed with the phosphate hydrolysis at pH 3-6. The measurements at 37 degrees C (pH 7.4) in the absence and presence of divalent alkaline earth metal ions (Mg(2+) and Ca(2+)) showed no sign of metal ion catalysis. Under these conditions, the initial product, nucleoside 5'-monophosphate, underwent rapid dephosphorylation to the corresponding nucleoside. Hydrolysis of the beta,gamma-methylene derivatives (5, 7) to the corresponding nucleoside 5'-monophosphates was markedly faster in mouse serum than in aqueous buffer (pH 7.4), the rate-acceleration being 5600- and 3150-fold with 5 and 7, respectively. In human serum, the accelerations were 800- and 450-fold compared to buffer. In striking contrast, the beta,gamma-(1-hydroxyethylidene) derivatives did not experience a similar decrease in hydrolytic stability. The stability in human serum was comparable to that in aqueous buffer (tau(1/2) = 17 and 33 h with 4 and 6, respectively), and oil going to mouse serum, a 2- to 4-fold acceleration was observed. To elucidate the mineral-binding properties of 4-7, their retention on a hydroxyapatite column was studied and compared to that of zoledronate (1a) and nucleoside mono-, di-, and triphosphates.
UTU Research Portal