The synthesis of 5-(azidomethyl)-2'-deoxyuridine (10) has been accomplished by two independent methods. The first involved tosylation of 5-(hydroxymethyl)-2'-deoxyuridine (1) to furnish a mixture of two mono- and a ditosyl nucleosides which were converted into the corresponding 5-(azidomethyl) (10), 5-(azidomethyl)-5'-azido (14), and 5-(hydroxymethyl)-5'-azido (15) derivatives of 2'-deoxyuridine. The second method was more selective and required the formation of the intermediate 5-(bromomethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (8), followed by displacement of the bromo group by lithium azide and deacetylation. Catalytic hydrogenation of the azides 9, 10, 14, and 15 gave the corresponding amines 16, 2, 6, and 7, respectively. Compounds 1, 2, 10, and 16 inhibited the growth of murine Sarcoma 180 and L1210 in culture, and the activity of 2 was prevented by 2'-deoxypyrimidine nucleosides but not by purine nucleosides. The replication of herpes simplex virus type 1 (HSV-1) was strongly inhibited only by 1 and 10. Studies on the binding of the various thymidine analogues to HSV-1 encoded pyrimidine deoxyribonucleoside kinase indicate that 1 and 10 have good affinity for the enzyme.

The three-dimensional structure of 5-hydroxymethyl-2'-deoxyuridine, an inhibitor of herpes simplex and vaccinia viruses, was determined by X-ray crystallography. The crystals belong to the monoclinic space group P21, and the cell dimensions are u = 9.301 ( I ) , b = 12.302 ( I ) , c = 4.862 ( I ) A, 0 = 97.18 (I)'. Intensity data were measured with a diffractometer, and the structure was solved by direct methods; least-squares refinement converged at R = 0.050. In the -CH20H substituent at C(5), the hydroxy group occupies two different positions. The conformation about the glycosyl bond is anti (XCN = 56.4'), while the -CH20H side chain attached to the sugar ring adopts the gauche-gauche conformation. The deoxyribose ring has the relatively rare C( 1') exo pucker, possibly stabilized by a previously unobserved intramolecular hydrogen bond C(6)-H-O(4'). IH NMR spectroscopy was used to determine the conformation in solution. The spectra indicate an anti conformation about the glycosyl bond and a 43% contribution of the gauche-gauche conformation in the -CHzOH side chain. The sugar ring may exist in a 32:68 equilibrium of ' E and 2E conformers. However, the conventional interpretation may be inadequate since better agreement with observed coupling constants is obtained by assuming equal contributions of 3E, ! E , and 2E conformers.A survey of 5-substituted 2'-deoxyuridines reveals no correlation between the electronegativity of the substituents and either bond lengths or antiviral properties of these substances. (hmsdU)3 inhibits the replication of Escherichia coli 1 5T-,4 the reproduction of Ehrlich ascites carcinoma cellsS as well as a number of other mammalian cells,6 and the propagation of vaccinia and herpes simplex v i r~s e s .~ Early studies on the synthesis and metabolism of S h ydroxymethylpyrimidines and their derivatives have been reviewed by Ulbricht.8 Baker et aL9 prepared hmSdU by basecatalyzed hydroxymethylation of 2'-deoxyuridine, and, recently, hm5dU has been synthesized by Langen and Barwolff5 by selective monobromination of the 5-methyl carbon of thymidine under ultraviolet catalysis. 5-Hydroxymethylpyrimidine 2'-deoxyribonucleotides have also been prepared enzymically.I0 5-Hydroxymethyl-2'-deoxyuridylate competitively inhibits both prokaryotic and eukaryotic thymidylate synthetase' and has been found in the DNA of several Bacillus subtilis phages in place of thymidine.Is 5-Hydroxymethyl-2'-deoxyuridineSanti and SakaiI2 suggested that the inhibitory effect depends not only on the 5 substituent being of a size that avoids steric hindrance, but also on its electron-withdrawing property. More recently, Egert et a1.I6 attempted to demonstrate the influence of 5 substitution on the bond lengths in several uridine derivatives. An X-ray analysis of hmsdU, yielding both steric and electronic information about the -CH20H substituent at C(5), was expected to contribute to our understanding of the effects of such substituents. Furthermore, bearing in mind that its conformation must be related to its biologi...

A new class of chloroethyl- and methylnitrosourea analogues of thymidine, 5a,b, 6, 10, and 11, has been synthesized from the corresponding amino nucleosides, 2 and 7. The 3'-chloroethyl and 3'-methyl derivatives, 10 and 11, inhibited L1210 cell growth in culture (ED50 = 1.5 and 1.0 micrometer, respectively) more effectively than 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (ED50 = 4 micrometer) and the 5'-nitrosourea analogues. Neither the alkylating nor the carbamoylating activities of these compounds correlated with their biological activity.

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