Nucleic Acids with a Six‐Membered ‘Carbohydrate’ Mimic in the Backbone

Abstract

Starting from pyranose nucleic acids, several series of modified nucleic acids with a six-membered carbohydrate moiety (mimic) have been synthesized and analyzed over a period of 20 years, and this work is summarized here. The process starts with structural and conformational considerations, followed by synthetic efforts and a structural analysis, and ends up with a biological confirmation of the concept, demonstrating that these modified nucleic acids represent very valuable tools in chemistry and biology.

Ätiologie potentiell primordialer Biomolekül‐Strukturen: Vom Vitamin B12zu den Nukleinsäuren und der Frage nach der Chemie der Entstehung des Lebens – ein Rückblick

“…[94] Piet Herdewijn, der unabhängig von der ETHGruppe ursprünglich mit medizinalchemischer Zielsetzung ebenfalls homo-DNA-Oligomere synthetisiert hatte, [88,106] gelang die wichtige Entdeckung der zu homo-DNA konstitutionsisomeren HNA ("hexitolnucleic acid"; Abbildung 24), [95] deren Eigenschaft, mit RNA und DNA im Watson-Crick-Modus Kreuzpaarungen mit antiparalleler Stranganordnung einzugehen, den wichtigen Nachweis erbrachte, dass eine sechsgliedrige Ringstruktur einer Zuckereinheit in Oligonukleotiden nicht an sich die Bildung helikaler Duplextrukturen des natürlichen Typs ausschließt. Im Rahmen von umfassenden Untersuchungen zur Chemie von Pyranoseoligonukleotiden hat dies Herdewijn [107,108] zudem durch die Synthese der zur ursprünglichen homo-DNA anomeren a-homo-DNA gezeigt; [109][110][111][112] diese paart im Unterschied zur ersteren mit RNA, wenn auch schwach, und in paralleler Stranganordnung.…”

Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

“…The strong hybridization characteristics between these structures and complementary RNA are generally attributed to the formation of a preorganized conformation, fitting the A-form of dsRNA, with strong stacking interactions between the bases, adequate interaction of the latter in a Watson-Crick type geometry with their complement, and efficient hydration of the double-stranded helix [20]. More recently, the structural analysis and biological effects of nucleic acids with in particular a six-membered carbohydrate mimic in the backbone, have been discussed [21]. Likewise, the advantages of these hexitol containing constructs were illustrated.…”

Insights from Crystal Structures into the Opposite Effects on RNA Affinity Caused by the S- and R-6′-Methyl Backbone Modifications of 3′-Fluoro Hexitol Nucleic Acid

“…However, in both 6′-Me-FHNA structures, the sugar-phosphate backbone geometries of modified residues conform to the standard sc − , ap , sc + , sc + (60° in HNAs 15,17 ), ap , sc − (α to ζ) genus of A-form duplexes. In both the S - and R -6′-Me decamers, residue A5 exhibits an extended backbone variant with α, β and γ in the ap conformations.…”