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Synthesis and properties of aminopropyl nucleosides and nucleic acids
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Nucleoside analogs are known as antivirals already for a long time. Among them, the acyclic nucleoside phosphonates are a class of highly effective nucleotide analogs with broad spectrum antiviral activity. Prime examples are 9-(S)-[3-hydroxy-2-(phosphono-methoxy)propyl]cytosine [(S)-HPMPC; cidofovir, Vistide] and 9-[2-(phosphono-methoxy)ethyl]adenine [PMEA, adefovir, Viread]. These are used for the treatment of human cytomegalovirus retinitis in immunocompromised patients, and for the treatment of AIDS, respectively. In search for potent and selective antiviral nucleoside phosphonates, we decided to study the synthesis and properties of compounds bearing in the side-chain amino groups in addition to the hydroxyl functionalities with either purine or pyrimidine bases. Several compounds were evaluated but only a few displayed marginal activity against HSV and VZV. Replacement of the oxygen atom in the acyclic chain of HPMPC with a nitrogen functionality thus results in a large reduction in biological activity.
In a second part of our work, these same new nucleoside analogs were used in an effort to obtain the simplest nucleic acid alternative: aminopropyl nucleic acids (APNAs). Scientists have put forth the theory that RNA - ribonucleic acid - was the predecessor to DNA, which actually is the central information storage for life on earth. In this view, RNA therefore has evolved into DNA. But as RNA itself is very complex, what is the ancestor then of RNA?
One recent report suggests that it may have been another nucleic acid called (L)-a-threofuranosyl oligonucleotides, also known as TNA. They found that complementary TNA strands can form stable double helices and also pair up with complementary strands of both RNA and DNA. This ability is thought to be one of the requirements of any system that would be considered a possible ancestor of RNA. The current interest in potential antisense reagents (which is a strategy to block information transfer) prompted us to design some new members of aminopropyl nucleosides (R or S-3’-APNA and R or S-2’-APNA) by reducing the number of carbon atoms in a NH-TNA nucleotide structure with concomitant reduction of the number of chiral centers. Hereto, some new synthetic strategies were developed. However, the study of the effect of consecutive acyclic building blocks in homothymidine polymers showed that their incorporation decreased the stability of the duplex with complementary DNA. Unfortunately, no interactions (as measured by hypochromicity studies) could be detected by thermal denaturation experiments, neither for self-pairing, homochiral pairing nor cross-pairing with DNA or RNA, due to self-aggregation or rearrangement.
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Project number:
3M060396
Duration of the project:
01.10.2002 - 25.09.2006
Funded research
Nederlands
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