Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro.
Several N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) (HPMP) and N-(2-phosphonylmethoxyethyl) (PME) derivatives of purine bases (adenine, guanine, 2-aminoadenine, 3-deazaadenine) and cytosine inhibit the growth of various DNA viruses. PME-derivatives (PMEA, PMEG and PMEDAP) are also active against retroviruses. Both types of nucleotide analogues undergo phosphorylation by cellular nucleotide kinases to their mono- and diphosphates. The phosphorylation with crude extracts of L-1210 cells is potentiated by an ATP-regenerating system. HPMPA is phosphorylated faster than PMEA with or without the ATP-regenerating system. The HPMP and PME analogues inhibit several virus-encoded target enzymes and their cellular counterparts: (1) HSV-1 DNA polymerase is inhibited by the diphosphates of the PME series; the virus-encoded enzyme is more sensitive than HeLa DNA pol alpha and beta. PMEApp terminates the growing DNA chain; it specifically replaces dATP. HPMPApp also acts as an alternative substrate of dATP, but, in contrast with PMEApp, it permits limited chain growth. (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp. The enzyme isolated from a PMEA-resistant HSV-1 mutant proved less sensitive to PMEApp, hydroxyurea and HPMPApp. (3) Diphosphates of PME derivatives efficiently inhibit AMV(MAV) reverse transcriptase. (4) The purine HPMP and PME analogues and, even more so, their monophosphate derivatives inhibit purine nucleoside phosphorylase from L-1210 cells.
Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Prague.
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A
Holý
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I
Votruba
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A
Merta
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Cerný
J
J
Veselý
J
J
Vlach
K
K
Sedivá
I
I
Rosenberg
M
M
Otmar
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H
Hrebabecký
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004267:DNA Viruses / Q000187:drug effects* / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D012264:Ribonucleotide Reductases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000494:pharmacology
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; C018258:3-deazaadenosine; C058654:9-(3-hydroxy-2-phosphonomethoxypropyl)guanine; C033854:2-aminoadenosine; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D006147:Guanine; C053001:adefovir; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D012264:Ribonucleotide Reductases; D011683:Purine-Nucleoside Phosphorylase; D000225:Adenine; D000077404:Cidofovir; D000241:Adenosine; D014372:Tubercidin