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Antiviral and Cytostatic Evaluation of 5‐(1‐Halo‐2‐sulfonylvinyl)‐ and 5‐(2‐Furyl)uracil Nucleosides

Transition metal‐catalyzed halosulfonylation of 5‐ethynyl uracil nucleosides provided (E)‐5‐(1‐chloro‐2‐tosylvinyl)uridines. Tetrabutylammonium fluoride‐mediated direct CH arylation of 5‐iodouracil nucleosides with furan or 2‐heptylfuran gave 5‐furyl‐substituted nucleosides without the necessity of using the organometallic substrates. These two classes of 5‐substituted uracil nucleosides as well their corresponding ester derivatives were tested against a broad range of DNA and RNA viruses and the human immunodeficiency virus (HIV). The 3′,5′‐di‐O‐acetyl‐5‐(E)‐(1‐chloro‐2‐tosylvinyl)‐2′‐deoxyuridine (24) inhibited the growth of L1210, CEM and HeLa cancer cells in the lower micromolar range. The (β‐chloro)vinyl sulfone 24 and 5‐(5‐heptylfur‐2‐yl)‐2′‐deoxyuridine (10) displayed micromolar activity against varicella zoster virus (VZV). The 5‐(5‐heptylfur‐2‐yl) analog 10 and its 3′,5′‐di‐O‐acetyl‐protected derivative showed similar activity against the cytomegalovirus (CMV). The 5‐(fur‐2‐yl) derivatives of 2′‐deoxyuridine and arabino‐uridine inhibited the replication of herpes simplex virus (HSV) TK+ strains while the 5‐(5‐heptylfur‐2‐yl) derivative 10 displayed antiviral activity against the parainfluenza virus.

Uracil nucleosides substituted at C5 with 2‐sulfonylvinyl or heteroaren‐2‐yl scaffolds were synthesized and evaluated for their antiviral and cytostatic activities. The 3′,5′‐di‐O‐acetyl‐5‐(E)‐(1‐chloro‐2‐tosylvinyl)‐2′‐deoxyuridine 24 inhibited the growth of L1210 cells in the lower micromolar range (IC50 = 5.6 ± 4.7  μM) and displayed micromolar activity against varicella zoster virus (EC50 = 4 µM).

Autoren:   Zhiwei Wen, Sazzad H. Suzol, Jufang Peng, Yong Liang, Robert Snoeck, Graciela Andrei, Sandra Liekens, Stanislaw F. Wnuk
Journal:   Archiv der Pharmazie
Jahrgang:   2017
Seiten:   n/a
DOI:   10.1002/ardp.201700023
Erscheinungsdatum:   17.03.2017
Fakten, Hintergründe, Dossiers
  • Herpes Simplex Virus
  • Ester
  • CEM
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