1′, 5′ ‐Anhydrohexitol Oligonucleotides: Synthesis, Base Pairing and Recognition by Regular Oligodeoxyribonucleotides and Oligoribonucleotides

Abstract

Oligonucleotides constructed of 1',5'-anhydrohexitol nucleoside building blocks (hexitol nucleic acids, HNA) are completely stable towards 3'-exonuclease and form very stable self-complementary duplexes as well as sequence-selective stable duplexes with the natural DNA and RNA. Triple-helix formation has also been observed. These hybridisation characteristics are highly dependcnt on the base sequence and the experimental conKeywords antisense systems -DNA recognitionnucleic acids * oligonucleotides -RNA ditions. When using a phosphate buffer containing 0.1 M NaCI, a homopurine HNA dodecamer gives a ATm of + 1.3 ' C i base pair with DNA as complement and a ATm of +3.O0C/base pair with RNA as complement. These oligomers may therefore be of considerable interest as antisense constructs.

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

“…Synthesis of HNA and ANA monomers was outlined before [10,30]. Assembly of ANA and HNA constructs likewise has been described previously [11,12].…”

“…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].…”

The Eight Stereoisomers of LNA (Locked Nucleic Acid): A Remarkable Family of Strong RNA Binding Molecules

“…However, the fact that all sequences contain a 3'-end natural thymidine monomer could have a minor influence on the T m data, as this monomer interacts differently with the RNA and the ent-RNA targets. It is noteworthy that only a very few of the large number of oligonucleotide analogues so far synthesized, such as the phosphodiester analogues HNA (hexitol nucleic acid) [10] and tricyclo-DNA, [11] have displayed binding affinities towards complementary RNA comparable with those obtained with the six stereoisomeric LNAs.…”

Nonenzymatic Template-Directed Reactions on Altritol Oligomers, Preorganized Analogues of Oligonucleotides

“…There is independent evidence that HNAs and ANAs are extensively pre-organized into such a structure. [19,20,23] It is perhaps surprising that activated HNA and ANA monomers are not good substrates in template-directed reactions, given that HNA and ANA oligomers are excellent templates. This finding demonstrates that the stability of a double-helical structure based on nucleotide analogues provides no guarantee that template-directed synthesis from monomers will be favored.…”

“…[29] The altritol and hexitol nucleic acid templates and nucleosides were synthesized and purified as described. [20,22,23] The monophosphates of the altritol and hexitol nucleic acid nucleosides were synthesized according to the method of Yoshikawa et al [30] pAG: Reaction conditions for the oligomerization of 2-MeImpG (or its mixture with equal amount of 2-MeImpC, 2-MeImpA, 2-MeImpU) on HNA or ANA C 4 XC 4 templates were chosen to permit comparison with earlier published work. [28,29] One set of reactions was run for 14 days at 0 8C in 0.2 m 2,6-lutidine-HCl buffer (pH 7.9 at 25 8C) containing 1.2 m NaCl, 0.2 m MgCl 2 , 0.5 mm of a template and 0.1m 2-MeImpG.…”