2. Academic Validation
  3. Influence of 4'-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2

Influence of 4'-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2

  • ACS Med Chem Lett. 2020 Dec 9;12(1):88-92. doi: 10.1021/acsmedchemlett.0c00485.
Zihua Zheng 1,  Elisabetta Groaz 2,  Robert Snoeck 1,  Steven De Jonghe 1,  Piet Herdewijn 2,  Graciela Andrei 1
Affiliations

Affiliations

  • 1 Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49 bus 1043, 3000 Leuven, Belgium.
  • 2 Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
PMID: 33479570 DOI: 10.1021/acsmedchemlett.0c00485
Abstract

In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum Antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4'-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC50 of 0.042 μM and produced significant cytotoxicity (CC50 = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its Antiviral activity (EC50 = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.

Figures