Nucleosides. 133. Synthesis of 5-alkenyl-1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)cytosines and related pyrimidine nucleosides as potential antiviral agents

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Abstract
The synthesis of 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)cytosines with a halovinyl [5(E)-(2-bromovinyl)-1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)cytosine and 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5(E)-(2-iodovinyl)cytosine] or vinyl [1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-vinylcytosine] substituent at C-5 was accomplished from the corresponding 5-iodo and/or 5-chloromercuri nucleoside analogs with use of Li2PdCl4- and Pd(OAc)2-mediated coupling reactions. Thiation of the benzoylated derivative of the 5-ethyluracil nucleoside followed by S-methylation and then ammonolysis provided 5-ethyl-2''-fluoro-ara-C. 5-Ethynyl-2''-fluoro-ara-C and 5-ethynyl-2''-fluoro-ara-U were also obtained from the persilylated 5-iodo nucleosides by PdII/CuI catalyzed coupling with (trimethylsilyl)acetylene. With use of selective sugar deprotection of the initial coupling products with H2O/Me2SO, the corresponding 5-[2-(trimethylsilyl)ethynyl] derivatives [1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-[2-(trimethylsilyl)ethynyl]cytosine and 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-[2-(trimethylsilyl)ethynyl]uracil] could be isolated. Most of the new compounds showed activity in vitro against both HSV-1 [herpes simplex virus type 1] and HSV-2, as did the known corresponding 5-alkenyluracil nucleosides synthesized earlier. The 5-vinylcytosine and -uracil nucleosides were highly effective against HSV-1 (ED90 [90% effective dose] = 0.40 and 0.043 .mu.M, respectively), and HSV-2 (ED90 = 0.59 and 0.56 .mu.M, respectively). Unlike BVDU, the 2''-fluoroarabinosyl derivatives of 5-(halovinyl)cytosine and -uracil showed activity against both types of herpes simplex virus. The therapeutic indices of these compounds are in some cases superior to those of 2''-fluoro-5-methyl-ara-U. Moderate antileukemic activity was observed in vitro for the 5-alkynyl and 5-vinyl compounds. The competition of these compounds with thymidine for viral-induced thymidine kinases was also studied.