Biomaterial Database

Synthesis of ester prodrugs of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as anti-poxvirus agents. 2010

Marcela Krecmerová, and Antoín Holý, and Graciela Andrei, and Karel Pomeisl, and Tomás Tichý, and Petra Brehová, and Milena Masojídková, and Martin Dracínský, and Radek Pohl, and Genevieve Laflamme, and Lieve Naesens, and Hon Hui, and Tomas Cihlar, and Johan Neyts, and Erik De Clercq, and Jan Balzarini, and Robert Snoeck

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. marcela@uochb.cas.cz

9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ∼10-fold lower than those observed for the parent compounds.

UI	MeSH Term	Description	Entries
D009943	Organophosphorus Compounds	Organic compounds that contain phosphorus as an integral part of the molecule. Included under this heading is broad array of synthetic compounds that are used as PESTICIDES and DRUGS.	Organophosphorus Compound,Organopyrophosphorus Compound,Organopyrophosphorus Compounds,Compound, Organophosphorus,Compound, Organopyrophosphorus,Compounds, Organophosphorus,Compounds, Organopyrophosphorus
D011212	Poxviridae	A family of double-stranded DNA viruses infecting mammals (including humans), birds and insects. There are two subfamilies: CHORDOPOXVIRINAE, poxviruses of vertebrates, and ENTOMOPOXVIRINAE, poxviruses of insects.	Poxviruses
D011355	Prodrugs	A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug.	Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D004952	Esters	Compounds derived from organic or inorganic acids in which at least one hydroxyl group is replaced by an –O-alkyl or another organic group. They can be represented by the structure formula RCOOR’ and are usually formed by the reaction between an acid and an alcohol with elimination of water.	Ester
D006564	Herpesviridae	A family of enveloped, linear, double-stranded DNA viruses infecting a wide variety of animals. Subfamilies, based on biological characteristics, include: ALPHAHERPESVIRINAE; BETAHERPESVIRINAE; and GAMMAHERPESVIRINAE.	Mouse Thymic Virus,Murid herpesvirus 3,Thymic Group Viruses,Herpesviruses,Mouse Thymic Viruses,Thymic Virus, Mouse,Thymic Viruses, Mouse
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000225	Adenine	A purine base and a fundamental unit of ADENINE NUCLEOTIDES.	Vitamin B 4,4, Vitamin B,B 4, Vitamin
D000998	Antiviral Agents	Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.	Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D012328	RNA Viruses	Viruses whose genetic material is RNA.	RNA Rodent Viruses,RNA Rodent Virus,RNA Virus,Rodent Virus, RNA,Rodent Viruses, RNA,Virus, RNA,Virus, RNA Rodent,Viruses, RNA,Viruses, RNA Rodent