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N-4-Acyl derivatives as lipophilic prodrugs of cidofovir and its 5-azacytosine analogue, (S)-HPMP-5-azaC: Chemistry and antiviral activity
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SYSNO ASEP 0428744 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title N-4-Acyl derivatives as lipophilic prodrugs of cidofovir and its 5-azacytosine analogue, (S)-HPMP-5-azaC: Chemistry and antiviral activity Author(s) Krečmerová, Marcela (UOCHB-X) RID, ORCID
Pohl, Radek (UOCHB-X) RID, ORCID
Masojídková, Milena (UOCHB-X)
Balzarini, J. (BE)
Snoeck, R. (BE)
Andrei, G. (BE)Number of authors 6 Source Title Bioorganic & Medicinal Chemistry. - : Elsevier - ISSN 0968-0896
Roč. 22, č. 10 (2014), s. 2896-2906Number of pages 11 s. Language eng - English Country GB - United Kingdom Keywords acyclic nucleoside phosphonate ; antivirals ; 5-azacytosine ; prodrug Subject RIV CC - Organic Chemistry R&D Projects FR-TI4/625 GA MPO - Ministry of Industry and Trade (MPO) Institutional support UOCHB-X - RVO:61388963 UT WOS 000334744500007 EID SCOPUS 84899536125 DOI 10.1016/j.bmc.2014.03.031 Annotation Even number fatty acid residues-docosanoyl (behenoyl) and stearoyl were selected for introduction to the N-4-position of (S)-1-[3-hydroxy-2-(phosphonomethoxy) propyl] cytosine) (HPMPC, cidofovir), and its 5-azacytosine counterpart, (S)-1-[3-hydroxy-2-(phosphonomethoxy) propyl] cytosine) (HPMP-5-azaC) with the aim to prepare a new type of lipophilic prodrugs. The study on the influence of these modifications to the stability and biological activity of both antivirals was performed. Different reactivity of both systems towards acylation reactions was also found: the 4-NH2 group of cidofovir was more reactive compared to that of HPMP-5-azaC. In 5-azacytosine derivatives, we found mostly a destabilizing effect of the N-4-acylation but this could be compensated by a positive influence of the esterification of the phosphonate group. Chemical stability of the 5-azacytosine moiety in the HPMP series is increasing in the following order: HPMP-5-azaC < cyclic HPMP-5-azaC < HPMP-5-azaC esters. From the view of prodrug development, the best chemical stability was observed in case of the double prodrug 7: the N-4-behenoyl derivative of the hexadecyloxyethyl ester of cyclic HPMP-5-azaC. The free phosphonic acid (N-4-behenoyl-HPMPC) appeared to be a more potent and selective inhibitor of herpesvirus replication than the parent HPMPC derivative. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2015
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