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Preparation of novel types of acyclic nucleoside phosphonates for study of their interaction with enzymes of metabolism of nucleic acids
Kaiser, Martin Maxmilian ; Janeba, Zlatko (advisor) ; Jindřich, Jindřich (referee) ; Parkan, Kamil (referee)
This Ph.D. thesis is a part of detailed SAR studies among acyclic nucleoside phosphonates carried out in the group of the Nucleic acid chemistry (Prof. A. Holý) and later in the group of the Targeted analogues of nucleic acid components (Dr. Z. Janeba) at the IOCB AS CR, v.v.i. Three novel series of acyclic nucleoside phosphonates, namely carboxyphosphonomethoxyethyl (CPME), carboxyphos- phonoethoxyethyl (CPEE) and hydroxyphosphonoethoxypropyl (HPEP) derivatives were prepared in order to reveal their biological properties. The CPME compounds were designed as structural analogues of PMEA (9-[2- (phosphonomethoxy)ethyl]adenine, Adefovir) and (S)-HPMPA [(S)-9-(3-hydroxy-2- (phosphonomethoxy)propyl)adenine], well-known compounds with prominent antiviral effects. The key step in their synthesis was oxidation of primary hydroxyl group in HPMP precursors using TEMPO/sodium chlorite/sodium hypochlorite system. The initial docking studies indicated that (S)-CPMEA [(S)-3-(adenin-9-yl)-2- (phosphonomethoxy)propanoic acid)], 2'-carboxy analogue of PMEA, could be a candidate with promising anti-HIV activity. Although this compound did not show desired biological activity, its two prodrugs exhibited submicromolar anti-HCV activity. Prepared prodrugs of (S)-CPMEA were also shown to be weak inhibitors of adenylate...
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