Synthesis and biological activity of some purine 5'-thio-5'-deoxynucleoside 3',5'-cyclic phosphorothioates

Shuman, Dennis A.; Miller, Jon P.; Scholten, Mieka B.; Simon, Lionel N.; Robins, Roland K.

doi:10.1021/bi00739a001

Cited by 23 publications

(14 citation statements)

References 26 publications

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“…For the diastereomers of 5'-deoxy-5'-aminoadenosine 3',5'-cyclic phosphorothioate it has been reported that one is hydrolyzed by cyclic nucleotide phosphodiesterase whereas the other is not (Jastorff and Bar, 1973). It is interesting to compare cAMPS with the recently synthesized isomeric S'-thio-S'-deoxyadenosine 3',5'cyclic phosphorothioate where a sulfur atom replaces the 5'oxygen (Shuman et al, 1973). A comparison of the data indicates that both compounds have very similar K\ values when tested with the phosphodiesterase from beef heart.…”

Section: Resultsmentioning

confidence: 99%

Adenosine 3',5'-cyclic phosphorothioate. Synthesis and biological properties

Eckstein¹,

Lp²,

Hp³

1974

Biochemistry

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Adenosine 3/,5'-cyclic phosphorothioate (cAMPS) was synthesized. Its interaction with cyclic nucleotide phosphodiesterase from beef heart and rabbit brain as well as with cAMP-dependent protein kinase from beef heart was studied and compared with that of cAMP. Both diastereomers of cAMPS are slowly hydrolyzed by the diesterases w'ith rates about '/so to Vi 50 that of cAMP. The hydrolysis of cAMP (ATm In an effort to modify the biological properties of adenosine 3/,5/-cyclic phosphate, a large number of analogs has been synthesized with alterations in the base, the sugar, and the phosphate part of the molecule (Simon et al.. 1973). In an attempt to synthesize cAMPS, one of us has reacted adenosine 5'-phosphorothioate with ', '-dimethylformamide dimethyl acetal and triisopropylbenzenesulfonyl chloride (Eckstein, 1970). Although certain aspects of the reaction could not be explained, such as the absence of any cAMP formation as well as the inability to detect the two expected diastereomers. the product was assumed to be cAMPS based on its electrophoretic mobility, its elementary analysis, and its chemical shift in the P nmr.This compound was, unexpectedly, neither substrate nor inhibitor for 3',5/-cyclic nucleotide phosphodiesterases from various sources (Eckstein and Bar, 1969). Because of these discrepancies it was desirable to develop an independent synthesis for cAMPS.In this publication evidence is presented that the compound synthesized previously (Eckstein, 1970) was adenosine 5'-.Smethylphosphorothioate and that cAMPS can be obtained by reacting adenosine S'-O.O-bisf/z-nitrophenyOphosphorothioate with potassium zerz-butoxide. The interactions of cAMPS with 3',5'-cyclic nucleotide phosphodiesterases as well as with cAMP-dependent protein kinase from beef heart are described. Experimental SectionGeneral Procedures and MaterialsElectrophoresis was performed using Schleicher and Schiitl 2043 b (washed) paper in 0.1 M triethylammonium bicarbonate (pH 7.5) or borate buffer (pH 10) at 2000 V. The same paper was used for paper chromatography. Ultraviolet absorption measurements were carried out using a Zeiss PMQ II which was equipped with a Servogor recorder for kinetic stud-3From the Max-Planck-Instituí für experimentelle Medizin, Abteilung Chemie. Gottingen, Germany (F. F..

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Section: Resultsmentioning

confidence: 99%

Adenosine 3',5'-cyclic phosphorothioate. Synthesis and biological properties

Eckstein¹,

Lp²,

Hp³

1974

Biochemistry

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“…A number of excellent reports dealing with sugar phosphate variations in cyclic nucleotides are not discussed here (10,183,185,311).…”

Section: Rabbit Lungmentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterases: Properties, Activators, Inhibitors, Structure–Activity Relationships, and Possible Role in Drug Development

Amer

Kreighbaum

1975

Journal of Pharmaceutical Sciences

205

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“…The substantial activity in this assay of many of the heterocycles structurally related to cytokinins is consistent with their behavior in phytohemagglutinin-transformed human lymphocytes and mouse fibroblasts (S. M. Hecht and R. B. Frye, in preparation), in which they promote the same effects as the cytokinins. t It is important to note that the cytokinins and related heterocycles differ from many other reported inhibitors of this high Km phosphodiesterase activity (35)(36)(37) in that they are neither very potent inhibitors of the low Km phosphodiesterase activity nor cyclic nucleotide derivatives themselves.…”

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confidence: 95%

Competitive Inhibition of Beef Heart Cyclic AMP Phosphodiesterase by Cytokinins and Related Compounds

Hecht¹,

Faulkner²,

Hawrelak³

1974

Proc. Natl. Acad. Sci. U.S.A.

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Two cytokinins and four related analogs, none of which is a cyclic ribonucleotide, have been shown to act as competitive inhibitors of the high Km cyclic-AMP phosphodiesterase (3': 5'-cyclic-AMP 5'-nucleotidohydrolase, EC 3.1.4.1-7) activity from beef heart. Weak inhibition of the low Km cyclic AMP phosphodiesterase activity was also observed, suggesting a possible mechanism for regulation of intracellular cyclic AMP levels by the exogenously added compounds. In addition to the kinetic data, obtained on the six inhibitors in four different heterocyclic series, 15 other cytokinins and related compounds have been shown to inhibit the high Km cyclic AMP phosphodiesterase activity at single concentrations of substrate and inhibitor. Heterocycles such as adenosine and 7-amino-3-methiylpyrazolo [4,3-d]pyrimidine, which lack the N-substituent, were inactive as cyclic AMP phosphodiesterase inhibitors. The observed inhibition of cyclic AMP phoplhodiesterase supports prior observations which implicate exogenously added cytokinins in cyclic AMP metabolism.Cytokinins were first isolated as plant factors responsible for the promotion of cell division and growth (1, 2). The compounds, which are typically N6-substituted adenine and adenosine derivatives, occur at the purine, ribonucleoside, and ribonucleotide levels in plants, as well as in the transfer RNAs of most forms of life (2-5). In spite of the widespread natural occurrence of cytokinins and the diverse metabolic effects which they are now known to promote in both plants and animals (1-13), relatively little has been learned about their mechanism of action at the molecular level. This prompted the design and synthesis of a class of potent anticytokinins, structurally related to the cytokinins, in the hope that the antimetabolites might extend the study of cytokinins to new biological systems and provide useful information pertinent to the mechanism of cytokinin action (14)(15)(16)(17).On the basis of the similar effects obtained with N6-(A2-isopentenyl)adenosine and dibutyryl cyclic AMP, the cytokinins have been postulated to mediate their effects in phytohemagglutinin-treated human lymphocytes by involvement in cyclic AMP metabolism (13). This postulate was consistent with the finding that the cytokinin trans-zeatin ribonucleoside was inhibitory to the cyclic AMP phosphodiesterases from beef brain and crown-gall tumor cells, the latter of which was Abbreviations: Dibutyryl cyclic AM1P, N6,02'-(dibutyryl)adenosine cyclic 3': 5'-monophosphate; cyclic AMP, adenosine cyclic 3': 5'-monophosphate; trans-zeatin ribonucleoside, N6-(4-hydroxy-3-methyl-trans-2-butenyl)adenosine; 8-bromo

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Synthesis and biological activity of some purine 5'-thio-5'-deoxynucleoside 3',5'-cyclic phosphorothioates

Cited by 23 publications

References 26 publications

Adenosine 3',5'-cyclic phosphorothioate. Synthesis and biological properties

Adenosine 3',5'-cyclic phosphorothioate. Synthesis and biological properties

Cyclic Nucleotide Phosphodiesterases: Properties, Activators, Inhibitors, Structure–Activity Relationships, and Possible Role in Drug Development

Competitive Inhibition of Beef Heart Cyclic AMP Phosphodiesterase by Cytokinins and Related Compounds

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