Synthesis and biological evaluation of 3,3-difluoropyridine-2,4(1H,3H)-dione and 3-deaza-3-fluorouracil base and nucleoside derivatives.
New 3-deaza-3-halouracil nucleosides including 3-deaza-3-fluorouridine and its 2'-deoxy and arabino analogues have been prepared by fluorination of protected precursors. The resulting 3,3-difluoropyridine-2,4(1H,3H)-dione derivatives underwent palladium-catalyzed hydrogenolysis of one C-F bond at atmospheric pressure, and deprotection gave the 3-deaza-3-fluorouracil compounds. Selective reaction of a stabilized Wittig reagent at C4 of the 3,3-difluoro-2,4-dione intermediates gave exocyclic alkenes that underwent hydrogenation accompanied by spontaneous elimination of hydrogen fluoride. Ammonolysis of the exocyclic carbethoxymethyl substituent and ester protecting groups gave 4-(carboxamidomethyl)-3-deaza-3-fluorouridine and its analogues. Grignard additions at C4 of the ribo and 2'-deoxy 3,3-difluoro-2,4-dione intermediates followed by deprotection gave the 3-deaza-3,3-difluoro-4-hydroxy-4-(substituted)uracil nucleosides. The cytostatic activity of 3-fluoro-3-deazauridine (CC(50) = 4.4-9.6 microM) in three cancer cell lines paralleled that of 3-deazauridine, whereas no significant inhibitory activity was observed with a variety of virus-infected cell cultures.
Robins
Morris J
MJ
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA. morris_robins@byu.edu
Yang
Hong
H
Miranda
Karl
K
Peterson
Matt A
MA
De Clercq
Erik
E
Balzarini
Jan
J
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D054879:Halogenation; D006801:Humans; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry*; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D009705:Nucleosides; D011728:Pyridones