Synthesis and Molecular Modelling of Double‐Functionalised Nucleosides with Aromatic Moieties in the 5′‐(S)‐Position and Minor Groove Interactions in DNA Zipper Structures

Abstract

A series of six double-functionalised nucleosides, in which aromatic moieties were inserted into the 5'-(S)-C-position, were synthesised and incorporated into DNA duplexes. The aromatic moieties were thymine-1-yl, phenyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 4-(uracil-5-yl)-1,2,3-triazol-1-yl and 4-phenyl-1,2,3-triazol-1-yl. The DNA duplexes were studied with UV melting curves, CD spectroscopy and molecular modelling. The results showed that the aromatic moieties in some cases interact in the minor groove forming DNA zipper structures. The strongest specific interaction was found between two thymines or between a thymine and a phenyl group in a crossed (-3)-zipper motif (i.e., with two base pairs interspacing the modifications). Modelling revealed that the interaction is aromatic stacking across the minor groove. Also, the extended uracil-triazole moiety demonstrated zipper contacts in the minor groove as well as binding to the floor of the groove.

Double-headed nucleotides introducing thymine nucleobases in the major groove of nucleic acid duplexes

“…Preparation of 3-benzoyl-1-(3-iodophenyl)-5-methylpyrimidine-2,4(1H,3H)-dione (6) To a stirred suspension of dry Cu(OAc) 2 (1.099 g, 6.052 mmol), 13 Preparation of 3-benzoyl-5-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (7) To a stirred solution of compound 6 (1.0 g, 2.315 mmol), Pd(OAc) 2 (15.6 mg, 69 μmol) and KOAc (682 mg, 6.944 mmol) in DMF (20.0 mL) was added bis( pinacolato)diboron (882 mg, 3.472 mmol) and the mixture was stirred at 60°C for 3 h. The mixture was added Et 2 O (50 mL) and washed with water (3 × 25 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by flash chromatography (0-30% EtOAc in DCM) to give the product 7 (480 mg, 48%) as a white solid.…”

Double-headed nucleotides in DNA-zipper structures; base–base interactions and UV-induced cross-coupling in the minor groove

“…The pixyl group has been preferred over the more standard DMT-group for 59-OHprotection of all our 59-modified nucleoside analogues ( Fig. 1), 5,6,8 as it is more conveniently attached to sterically hindered secondary alcohols and works with similar efficiency in the automated solid phase DNA-synthesis. 18 However, pixylation of the 59-hydroxy group of 3 proved very problematic and several conditions were tested.…”

“…[1][2][3] Recently, we and others have focused on interactions either at the duplex surface or in the duplex core by the introduction of double-headed or double-functionalized nucleotides into the duplex. [4][5][6][7][8][9][10][11][12][13] As an example, a doubleheaded nucleotide with an additional thymine nucleobase positioned in the 59(S)-position trough a methylene linker has been investigated. 5 Each incorporation of this modification (termed T T in Fig.…”

“…1). 8 A range of double-functionalized nucleotides where the additional thymine of T T has been replaced by substituted or unsubstituted triazoles have also been investigated ( Fig. 1, T tPh /T tU /T tT and T 4t /T 1t , respectively).…”

Synthesis of 5-hetaryluracil derivatives via 1,3-dipolar cycloaddition reaction

“…[46][47][48][49][50][51][52][53][54] Several papers have described the formation of 5-(1,2,3-triazol-4-yl)uracil derivatives from 5-ethynyluracil and organic azides in the presence of CuI-sodium ascorbate catalytic system. [46][47][48][49][50][51] The formation of both possible regioisomers 1,4-and 1,5-disubstituted triazoles, depending on the applied catalyst, has been found. Thus, the use of the copper salt-sodium ascorbate system as a catalyst has led to the formation of 1,4-regioisomers, whereas 1,5-regioisomers were obtained with Cp*RuCl(PPh 3 ) 2 employed instead of the standard Cu catalyst.…”