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

  

Authors:	Perlman, M. E.; Watanabe, K. A.; Schinazi, R. F.; Fox, J. J.
Article Title:	Nucleosides. 133. Synthesis of 5-alkenyl-1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)cytosines and related pyrimidine nucleosides as potential antiviral agents
Abstract:	The synthesis of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)cytosines with a halovinyl (8 and 9) or vinyl (10) substituent at C-5 was accomplished from the corresponding 5-iodo (FIAC, 1) and/or 5-chloromercuri (5) nucleoside analogues with use of Li2PdCl4-and Pd(OAc)2-mediated coupling reactions. Thiation of the benzoylated derivative of the 5-ethyluracil nucleoside 3 followed by S-methylation and then ammonolysis provided 5-ethyl-2'-fluoro-ara-C (11). 5-Ethynyl-2'-fluoro-ara-C (19a) and 5-ethynyl-2'-fluoro-ara-U (19b) were also obtained from the persilylated 5-iodo nucleosides 1 and 16, respectively, by PdII/CuIcatalyzed 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 18a and 18b could be isolated. Most of the new compounds showed activity in vitro against both HSV-1 and HSV-2, as did the known corresponding 5-alkenyluracil nucleosides synthesized earlier. The 5-vinylcytosine and-uracil nucleosides 10 and 24, respectively, were highly effective against HSV-1 (ED90= 0.40 and 0.043 μM respectively) and HSV-2 (ED90= 0.59 and 0.56 μM, 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 (FMAU, 2). 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. © 1985, American Chemical Society. All rights reserved.
Keywords:	cancer chemotherapy; drug efficacy; nonhuman; mass spectrometry; animal cell; animal; mice; cell line; in vitro study; drug screening; drug synthesis; structure-activity relationship; drug mechanism; thymidine kinase; antivirus agent; drug cytotoxicity; radioisotope; herpes simplex virus 1; herpes simplex virus; therapy; nuclear magnetic resonance; synthesis; vero cell; bromodeoxyuridine; antiviral agents; drug identification; intoxication; herpes simplex virus 2; drug comparison; 5 (2 bromovinyl) 2' deoxyuridine; leukemia l1210; new drug; pyrimidine nucleoside; pyrimidine nucleosides; priority journal; ultraviolet spectrophotometry; leukemia p 388; leukemia l 1210; 2' fluorothymine arabinoside; 2' deoxy 2' fluorocytarabine derivative; 2' fluoro 2' deoxyuracil arabinoside derivative; blood and hemopoietic system; drug analysis; thymidine c 14
Journal Title:	Journal of Medicinal Chemistry
Volume:	28
Issue:	6
ISSN:	0022-2623
Publisher:	American Chemical Society
Date Published:	1985-06-01
Start Page:	741
End Page:	748
Language:	English
DOI:	10.1021/jm00383a009
PROVIDER:	scopus
PUBMED:	4009596
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0021849106&doi=10.1021%2fjm00383a009&partnerID=40&md5=11aa0b1e207a1ccd5b1bec497d833b7b
Notes:	Article -- Export Date: 26 October 2021 -- Source: Scopus

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