We have previously reported that the 2-amino-6-vinylpurine (AVP) nucleoside exhibits a highly efficient and selective crosslinking reaction toward cytosine and displayed an improved antisense inhibition in cultured cells. In this study, we further investigated the alkyl-connected AVP nucleoside analogs for more efficient crosslinking to the cytosine base (rC) of the target RNA. We synthesized three AVP analogs which connect the 2-amino-6-vinylpurine unit to the 2'-deoxyribose through a methylene, an ethylene, or a butylene linker. The ODN incorporating the AVP analog with the methylene or the butylene linker showed a slightly higher crosslinking to the target rC of RNA than the original AVP with no linker. In contrast, the AVP with the ethylene linker formed a selective and efficient crosslink to the rC of the target RNA.
We have previously reported that the 2-amino-6-vinylpurine (AVP) in oligonucleotide (ODN) showed the highly selective and effective cross-linking reaction toward cytosine within target complementary sequences. Recently, we revealed that the PEGylated ODN containing AVP analogues exhibited the effective antisense effect in the cultured cell. However, subsequent studies showed that the cross-linking ability of AVP for cytosine was affected by the target RNA sequences. We therefore developed new intelligent nucleoside analogues connected AVP to sugar through the ethylene linker (et-AVP), that exhibited highly effective cross-linking ability to rC in the target RNA. In this paper, we described the synthesis of the PEGylated ODN containing cross-linking nucleoside analogues and properties of it about RNase H activity and antisense effect in cell lysate. As a result, the PEGylated ODN containing et-AVP showed the effective antisense effect in the non-cell system for targeting the luciferase mRNA by non-RNase-H mechanism.
We have previously reported that the 2-amino-6-vinylpurine nucleoside exhibits the highly efficient and selective cross-linking reaction toward the cytosine base at the target site in the duplex DNA. The nucleoside analogues that connect the 2-amino-6-vinylpurine to the 2'-deoxyribose skeleton through the ethylene or the butylene linker formed the cross-link selectively to the adenine base of the TA pair or the cytosine base of the GC pair in the triplex DNA, respectively. They did not form cross-link in the duplex DNA. These results lead us to study in detail the relationship between the linker length and the cross-linking ability. In this study, we describe the synthesis of the new nucleoside analogue that connects 2-amino-6-vinylpurine to the 2'-deoxyribose unit via the methylene linker.
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