degree of butyrylation and biological activity on thyroid function. Evidently other factors besides penetration, e.g., binding requirements of various enzyme systems involved in the mechanism of action of cAMP, will have to be considered to explain our results.Several groups26-27 have reported variations in the PDE isoenzyme composition of different tissues and we might speculate that there are also differences in the protein kinase system of various tissues.Comparing the effect of the various cyclic nucleotides on the thyroidal function with results previously obtained on the release of growth hormone28-29 or prolactin,30 we find some degree of tissue specificity. For example, Bt2-8HS-cAMP, which was one of the most active compounds on growth hormone release, shows only a marginal effect on thyroid function. On the other hand, 8H2N-cAMP, which is a very strong stimulator of the thyroid, is one of the least active cAMP analogues with respect to growth hormone release. This observation of relative specificity of certain cAMP derivatives could contribute to a better understanding of the mechanism of action of cAMP and lead to further study of possible therapeutic applications of cyclic nucleotides.Acknowledgment. The authors wish to thank Professor T. Postemak for stimulating discussions and helping us with his expertise in the field. They are very grateful to Nuclear Medical Systems, Inc., Newport Beach, Calif., for performing the radioimmunoassays of T4. We also wish to express our appreciation to Mrs. Helia Gergely and Mr. Robert W. Mancuso for their excellent technical assistance.
Die Inhibierung von aus Kalbsthymus und von aus Tumorzellen (Ehrlich‐Ascitestumor) gewonnener Thymidylat‐synthetase durch die Titelverbindung (I) (erhältlich durch Phosphorylierung des entsprechenden Nucleosids mit POCl3) wird untersucht.
A series of substituted 5-aminomethyl-2'-deoxyuridines was synthesized as analogues of 5-thymidylyltetrahydrofolic acid, a proposed intermediate in the thymidylate synthetase catalyzed reaction. 1-(3,5-Di-O-p-toluoyl-2-deoxy-beta-D-ribofuranosyl)-5-chloromethyluracil (3) was treated with the appropriate amine to give the ester protected 5-aminomethyl nucleoside. Removal of the ester groups was accomplished with anhydrous potassium carbonate in methanol to afford the free beta-nucleoside. In this way 5-(2-dimethylaminoethylaminomethyl)-2'-deoxyuridine (5a), 5-dimethylaminomethyl-2'-deoxyuridine (5b), 5-N-mehtylpiperazinylmethyl-2'-deoxyuridine (5c), and 5-pyrrolidinylmethyl-2'-deoxyuridine (5d) were prepared. Compounds 5a,b,d were converted to the respective 5'-phosphates 6a,b,d. All three compounds were subtrate competitive inhibitors of thymidylate synthetase purified from Escherichia coli, calf thymus, and Ehrlich ascites tumor cells. The most active compound was 6a with KI's of 6,3.1, and 14 micronM observed for the respective enzymes.
Aus dem geschützten Chlormethyl‐uracil (I) werden die Substitutionsprodukte (IIa)‐(IId) hergestellt und nach Abspaltung der Toluoyl‐Schutzgruppen über (III) zu (IV) phosphoryliert.
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