Synthesis and Base Pairing Properties of 1′,5′‐Anhydro‐L‐Hexitol Nucleic Acids (L‐HNA)

Abstract

Oligonucleotides composed of 1',5'-anhydro-arabino-hexitol nucleosides belonging to the L series (L-HNA) were prepared and preliminarily studied as a novel potential base-pairing system. Synthesis of enantiopure L-hexitol nucleotide monomers equipped with a 2'-(N(6)-benzoyladenin-9-yl) or a 2'-(thymin-1-yl) moiety was carried out by a de novo approach based on a domino reaction as key step. The L oligonucleotide analogues were evaluated in duplex formation with natural complements as well as with unnatural sugar-modified oligonucleotides. In many cases stable homo- and heterochiral associations were found. Besides T(m) measurements, detection of heterochiral complexes was unambiguously confirmed by LC-MS studies. Interestingly, circular dichroism measurements of the most stable duplexes suggested that L-HNA form left-handed helices with both D and L oligonucleotides.

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

“…Cleavage from the support and deprotection were performed in one step with AMA at 35°C for 2h. With RNA oligomers, the additional deprotection step was carried out with triethylamine trihydrofluoride as described before [14]. The crude ON solution was desalted on a NAP-25 column and purified by anion-exchange HPLC.…”

“…Another way to address this problem is to assemble carbohydrate-modified ONs, exemplified by hexitol nucleic acids [10][11][12][13][14], 2'-O-(2-methoxy)ethyl ONs [15,16] and bicyclic ONs [17], with the LNA monomers of the Wengel group [18] showing the strongest affinity for RNA, and having many alternative structures [19]. 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].…”

Enantiomeric Selection Properties of β‐homoDNA: Enhanced Pairing for Heterochiral Complexes

“…From a synthetic standpoint, while access to D ‐hexopyranosyl nucleosides was easily obtained by a carbohydrate‐based route,13 the synthesis of the corresponding L ‐enantiomers under the same reaction conditions was hampered by the limited commercial availability of almost all L ‐hexoses. In an alternative path, our long studied de novo approach to L ‐monosaccharides14 and other structurally‐related compounds9 was recently exploited15 for the preparation of the L ‐nucleosides 2 a , b (T and A Bz acting as model nucleobases) from the homologating agent 1 (Scheme ). Synthesis was based on a key stereoselective N ‐glycosidation involving in situ anomerization of α/β nucleosides (β/α up to 20:1).…”

The impact of an extended nucleobase-2′-deoxyribose linker in the biophysical and biological properties of oligonucleotides

“…5 The ability to restrict the conformation of some of these analogues was the key for the improvement of the hybridization properties. 5 Additionally, interesting results were obtained with other nucleoside analogues such as hexitol (HNA), 6 bicyclo, 7 arabino (ANA), 8,9 and uoroarabino (FANA) 8,9 nucleic acids. The discovery of RNA interference mechanism provide also an opportunity to the design of novel nucleic acid derivatives with more structural exibility such as unlocked (UNA), 10 acyclic threoninol (aTNA), 11 and serinol (SNA) 12 nucleic acid derivatives.…”