Methods for the chemical synthesis of RNA have been available for almost half century, and presently, RNA
could be chemically synthesized by automated synthesizers, using protected ribonucleosides preactivated as phosphoramidites,
which has already been covered by many reviews. In addition to advancement on synthetic methods, a variety of
modifications have also been made on the synthesized oligonucleotides, and previous reviews on the general synthesis of
RNAs have not covered this area. In this tutorial review, three types of modifications have been summarized standing at
the viewpoint of medicinal chemistry: (1) modifications on nucleobase, comprising substituent introduction and replacement
with pseudobase; (2) modifications on ribose, consisting of modifications on the 2’, 3’ or 5’-position, alternation of
configuration, and conformational restriction on ribose; (3) modifications on internucleoside linkages, including amide,
formacetal, sulfide, sulfone, ether, phosphorothiolate and phosphorothioate linkages. Synthetic methods achieving these
modifications along with the functions or values of these modifications have also been discussed and commented on.
Keywords: Bioactive RNAs, small non-coding RNA, oligoribonucleotide, structural modification, chemical synthesis, nucleobase,
pseudobase, ribose, conformational restriction, internucleoside linkage.
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