Abstract
We studied the duplex stability and the antimessenger activity of 9-aminoellipticine-5′-functionalized α- and β-anomeric DNA sequences complementary to the first 14 nucleotides of the rabbit β-globin mRNA. The duplex formed by the β-conjugate with the natural mRNA target possessed a marginally better stability to that of the duplex formed by the unfunctionalized compound, as measured by thermal elution. The α-conjugate did not anneal to native mRNA, possibly due to the interference of the 9-aminoellipticine with the cap structure and, unlike the β-adduct, was practically inactive as inhibitor of translation in a cell-free system. However, it did hybridize to an RNA construction containing the β-globin mRNA plus an additional 50 bases in 5′. Surprisingly, translation from this construction was inhibited by the α-species in spite of the nonvicinity of the target to the cap. Both α and β conjugates hybridized to a DNA 14-mer of the same sequence as that targeted onto the mRNA. Thermal denaturation and fluorescence spectroscopy showed that the drug brought no considerable stabilization to the duplex, the linker presumably being unfavorable to intercalation. An increased stability of the complex and a higher inhibitory effect on cell-free β-globin translation were obtained with two contiguous β-oligomers of which one was functionalized.
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