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

Zihua Zheng; Elisabetta Groaz; Robert Snoeck; Steven De Jonghe; Piet Herdewijn; Graciela Andrei

doi:10.1021/acsmedchemlett.0c00485

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. eCollection 2021 Jan 14.

Authors

Zihua Zheng¹, Elisabetta Groaz², Robert Snoeck¹, Steven De Jonghe¹, Piet Herdewijn², Graciela Andrei¹

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.

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.