Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus

0500199 - ÚOCHB 2019 RIV GB eng J - Článek v odborném periodiku
Baszczyňski, Ondřej - Kaiser, Martin Maxmilian - Česnek, Michal - Břehová, Petra - Jansa, Petr - Procházková, Eliška - Dračínský, Martin - Snoeck, R. - Andrei, G. - Janeba, Zlatko
Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus.
Antiviral Chemistry and Chemotherapy. Roč. 26, Nov 29 (2018), s. 1-13. ISSN 0956-3202
Institucionální podpora: RVO:61388963
Klíčová slova: acyclic nucleoside phosphonates * xanthine * PMEX * antiviral * HCMV * VZV
Obor OECD: Organic chemistry
https://journals.sagepub.com/doi/10.1177/2040206618813050

While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy) ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit mM activity against VZV (EC50=2.6 µM, TK+ Oka strain) and HCMV (EC50=8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK- VZV 07-1 strain with EC50=4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.
Trvalý link: http://hdl.handle.net/11104/0292843