Early efforts by chemists to redesign the backbones of the natural nucleic acids composed of 2'-deoxyribose or ribose linked by phosphodiester moieties got underway in the 1960s. Among the modifications investigated then were 2'-<i>O</i>-methyl RNA, 2'-fluoro RNA and the phosphorothioates, all of which continue to play important roles in modern-day oligonucleotide therapeutics. Modification of the backbone affects pairing selectivity and affinity, structure, chemical stability, hydration, nuclease resistance and metabolic stability, protein interactions, cellular uptake and biodistribution. We have used X-ray crystallography to analyze the structures of nucleic acids with reengineered sugar-phosphate backbones for over 25 years. This symposium to celebrate the 2021 winner of the Wolfrom Award by the ACS Carbohydrate Division, Professor Eriks Rozners, offers an opportunity to look back at insights gained from such studies. In quite a few cases these demonstrate the ‘Rozners touch’, epitomized by new synthetic approaches and the use of assays such as osmotic stressing, to uncover the detailed causes of the altered structure and stability of a modification. Examples that will be discussed include 2'-fluoro RNA, formacetal-linked DNA and RNA, and amide RNA.

Chemical modification of the DNA/RNA sugar-phosphate backbone: a backward glance

ACS Fall 2021

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