A double-headed nucleotide with two cytosines: DNA with condensed information and improved duplex stability

Base‐Pairing Properties of Double‐Headed Nucleotides

“…In this regard, we have recently shown that two or three doubleheaded nucleotides can be incorporated in the same DNA strand without compromising target binding. 29 With its favorable DNA binding properties, double-headed nucleotides represent an interesting candidate worthy of further exploration. The molecular modeling offers insight into underlying driving forces of base pairing in atomic detail, and into how double-headed nucleotides are housed in DNA duplexes.…”

“…The C2′-exo position of β-nucleosides emerges as the most reasonable site for introducing an additional base and enable dual Watson-Crick contacts. 18 In our preceding studies, we have gauged the potential of three designs (double-headed β-ᴅ-ribosides, 25 β-ᴅ-deoxyribosides 26,27 and β-ᴅarabinosides; 24,28,29 see Figure 1) in terms of their synthetic feasibility and dinucleotide potential. For convenience, uracil has invariably been used as the C1′-linked base.…”

Double‐Headed Nucleotides with Non‐Native Nucleobases: Synthesis and Duplex Studies

“…Currently, the full set of uridine-based analogues (U C , U G , U T , U A ) have been presented and evaluated together with selected cytosine-and adenosine-based analogues in the form of C C and A T . [23][24][25][26][27] These double-headed nucleotides are wellaccommodated in DNA duplexes when incorporated in exchange for the corresponding dinucleotide ( Figure 1). For instance, when central 5'-UC or 5'-UG dinucleotides are replaced with the U C or U G double-headed nucleotide monomers, respectively, the thermal duplex stability remains intact ( Figure 1, green bars).…”

“…In the latter case, given that the additional nucleobase is linked through a methylene to the 2′‐position of 2′‐deoxyuridine or arabinouridine (Figure 1, U X ), the double‐headed nucleotide has been shown to behave as a condensed dinucleotide. In practice, it can form two sets of Watson‐Crick base pairs with two individual nucleotides of the opposite strand: one through its 1′‐base to give a 1′⋅1′ base pair, and another through its 2′‐base to give a 2′⋅1′ base pair [24–26] . This feature allows for the condensation of genetic information to smaller entities with fewer phosphates, which might be an effective approach for e. g. enhancing cellular uptake or target recognition in future nucleic acid‐based therapeutics.…”

“…Currently, the full set of uridine‐based analogues ( U C , U G , U T , U A ) have been presented and evaluated together with selected cytosine‐ and adenosine‐based analogues in the form of C C and A T [23–27] . These double‐headed nucleotides are well‐accommodated in DNA duplexes when incorporated in exchange for the corresponding dinucleotide (Figure 1).…”