Chemistry and Pharmacology of Apiose
Journal of Medicinal Chemistry, 1974, Vol. 17, No. 10 1055
Chemistry and Pharmacology of Apiose. 7.t Susceptibility of Some Branched-Chain Sugar Nucleosides to Enzymatic Deamination Jean M. J . Tronchet,* Jeannine Tronchet, and Rent! Graf Znstitute of Pharmaceutical Chemistry, 30 quai Ernest Ansermet, 1211 Geneve 4, Switzerland. Received March 11, 1974 The synthesis of a new branched-chain sugar nucleoside 9-(5-deoxy-3-C-hydroxymethyl-P-D-xylofuranosy1)adenine (1) is described. This compound and 9-(3-C-hydroxymethyl-a-~-threofuranosyl)adenine (2) are substrates of calf adenosine deaminase whereas the 3’ epimer of 2 (3) is not deaminated. This shows that a C-3’ carbon ramification on a nucleoside does not always abolish susceptibility to enzymatic deamination and that the configuration at the branching point plays an important role in substrate specificity.
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The therapeutic value of numerous adenosine analogs is limited by their facile degradation into inosine derivatives 0 %C oN;Q-oAc * by adenosine deaminase. Hence, it is of interest to study the effect of the chemical manipulation of nucleosides on I 0-CH, OAc 0-CH, their susceptibility to deamination by this enzyme. A num5 4 ber of structural analogs of adenosine modified in the base p i 2 or in the sugar have been studied as substrates of adenosine deaminase. In 1966, Walton, et U L . , ~ reported that a biologically active nucleoside of a new type, containing a branched-chain sugar, 3’-C-methyladenosine, was not deaminated by the enzyme. This paper describes the synthesis of a new branchedchain sugar nucleoside, the 5’-deoxy-3’-C-hydroxymethyl6-D-xylofuranosyladenine ( I ) , and the susceptibility to enzymatic deamination of this compound along with that of O-tH, OAc 0-CH? OAC two other adenosine analogs we have previously de6 ~ c r i b e d , ~namely, . ~ . ~ 9-(3-C-hydroxymethyl-a-~-threofuranosy1)adenine (2) and 9-(3-C-hydroxymethyl-@-~-erythrothy.9 With 0.06 unit of enzyme per milliliter of assay mixfuranosy1)adenine (3). ture (1 unit being definedlO as that amount of enzyme which causes the deamination of 1 kmol of adenosine to inosine per minute at pH 7.5 and 25”), it was found that only 1 and 2 were subject to deamination with an initial velocity relative to adenosine of 0.003 for 1 and 0.012 for 2. Nucleoside 3 was not deaminated even in the presence of 30 times this amount of enzyme. These results indicate that a carbon ramification a t C-3’ of an adenosine analog does not always abolish its susceptibility to deamination and that the stereochemisI I try a t that position plays a very important role in estabHOH,C OH OH OH lishing substrate activity. Thus, the only C-3’ branched1 2 3 chain sugar nucleosides susceptible to deamination so far described (1 and 2) bear their ramification in a position Chemistry. Treatment with phosgene of 5-deoxy-3-Ctrans to the base. We have sh0wnl9~3~ that the configurahydroxymethyl- 1,2- 0 -isopropylidene-a-D-xylofuranose5 tion a t (2-3‘ controls the conformation of the furanose ring gave 4 whose acetolysis in the usual manner6 afforded a of these molecules, the carbon ramification adopting an mixture of the a and P anomers of 5. Assignment of the equatorial position. However, it does not seem that the anomeric configuration was made by nmr, mainly on the conformation of the furanose ring as such is an important basis of the J1.2 coupling constant (a 4.5 Hz and P
