Many recent scientific inquiries involve attempts to better understand and control the behavior, structure, and function of RNA. Due to its significant role in many cellular processes, methodologies to functionalize strands of RNA at one or various positions have a shown potential uses in medical therapies and in such as antisense applications. Our goal is to functionalize oligonucleotides of RNA at the C2’-O- position using photoactive groups (λmax &gt; 290 nm) and utilize this reactivity to alter their structure reversibly. To this end, we are using 2-methyl-benzothiophenyl-e based functional groups that have a response to light and undergo a 2+2 photocycloaddition reaction from irradiation at 300 nm. It is expected that the reactivity between the proposed modifications will allow us to control RNA structure and thus its function. We decided to functionalize Adenosine and Uridine with 2-methyl-benzothiophenyline units as models for our initial studies. The first step in the synthesis of the probe was to produce 2-hydroxymethyl benzothiophene, obtained from the reaction of benzothiophene in the presence of n-butyl lithium and paraformaldehyde (60-70%). Bromination of this alcohol was carried out in the presence of was achieved by reacting with carbon tetrabromide in the presence of tri-phenyl phosphineand triphenylphosphine to yield the corresponding 2-bromomethylbenzothiophene group (70%). Functionalization at the C2’-O- position of adenosine as a free nucleoside in the presence of sodium hydride resulted in low yields due to the presence of various alkylated by-products. This result. This was circumvented via selective protection of the C3’- and C5’- position using di-t-butylsilylbis(trifluoromethanesulfonate) and allowing its exclusive functionalization at the C2’-O- position (75%). Desilylation in the formation of hydrogen fluoride resulted in the C2’-O- functionalized nucleoside in quantitative yields. Current focus is being placed on the synthesis of the corresponding phosphoramidites for their incorporation into oligonucleotides of RNA. We will use dodecamers that form duplex structures and their characterization will be achieved via circular dichroism and UV-Vis spectroscopy. The modified oligomers and synthetic intermediates will be characterized via mass spectrometry (MAACDTMALDI-TOF and ESI respectively), 1HNMR, and IR. All structural and biophysical parameters will be described in detail hereinwill be reported.

Synthesis of functionalized oligonucleotides of RNA using 2-methylbenzothiophenyl groups at the C2’-O- position of uridine and adenosine

253rd National Meeting (2017)

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