Aromatic Phosphorodichloridites and Phosphorodichloridothioates. III. Structure and Physical Properties

Tolkmith, Henry

doi:10.1021/jo01105a027

Cited by 4 publications

(3 citation statements)

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“…Synthesis. The reaction scheme for the synthesis of adenosine 3'.5'-cyclic phosphorothioate is shown in Scheme I. Bis(pnitrophenyl) phosphorochloridothioate was synthesized by adaption of a procedure given for the synthesis of p-nitrophenyl phosphorochloridothioate (Tolkmith, 1958). Both com-pounds are obtained by this method and can easily be separated.…”

Section: Resultsmentioning

confidence: 99%

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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%

“…Yield of the dichloride 15 g, mp 52°( lit. 53-54°;Tolkmith, 1958); yield of the monochloride 5.5 g, mp 82°. Anal.…”

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confidence: 99%

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

Eckstein¹,

Lp²,

Hp³

1974

Biochemistry

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“…Synthesis. Cyclohexylammonium salts of O-aryl phosphorothioates were prepared from thiophosphoryl chloride and the appropriate phenol via the O-aryl phosphorodichloridothioates (Tolkmith, 1958) with subsequent hydrolysis. A typical procedure, described for dicyclohexylammonium O-phenyl phosphothioate, was as follows.…”

Section: Methodsmentioning

confidence: 99%

The nature of the transition state for enzyme-catalyzed phosphoryl transfer. Hydrolysis of O-aryl phosphorothioates by alkaline phosphatase

Hollfelder¹,

Herschlag²

1995

Biochemistry

150

240

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There has been much speculation that enzymes change the nature of the transition state for phosphoryl transfer from the dissociative transition state observed in solution reactions to an associative transition state at the enzyme's active site. This proposal can be tested by comparing linear free energy relationships (LFERs) for nonenzymatic and enzymatic reactions, provided that the specificity of the enzyme's binding site does not perturb the dependence of rate on the intrinsic reactivity of a series of substrates. The shallow binding groove of Escherichia coli alkaline phosphatase (AP) and its wide specificity suggest that this enzyme may be suited for such an approach. A second requirement of this approach is that the actual chemical step is rate-limiting. Comparisons of the reactions of aryl phosphorothioates and aryl phosphates support the previous conclusion that a nonchemical step limits kcat/KM for reactions of aryl phosphates, but suggest that the chemical cleavage step is rate-limiting for the aryl phosphorothioates. We therefore determined the dependence of the rate of AP-catalyzed cleavage of a series of aryl phosphorothioates on the intrinsic reactivity of the substrates. The large negative values of beta leaving group = -0.8 for the enzymatic reaction (kcat/KM) and -1.1 for the nonenzymatic hydrolysis reaction suggest that there is considerable dissociative character in both the enzymatic and nonenzymatic transition states. Despite the wide specificity of AP, certain substrates deviate from the LFER, underscoring that extreme care is required in applying LFERs to enzymatic reactions. The large negative value of beta leaving group suggests that AP can achieve substantial catalysis via a transition state with dissociative character.

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Molecular Refractivity and Polarizability

Fèvre

1965

Advances in Physical Organic Chemistry

271

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Aromatic Phosphorodichloridites and Phosphorodichloridothioates. III. Structure and Physical Properties

Cited by 4 publications

References 0 publications

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

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

The nature of the transition state for enzyme-catalyzed phosphoryl transfer. Hydrolysis of O-aryl phosphorothioates by alkaline phosphatase

Molecular Refractivity and Polarizability

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