Structure-Editing of Nucleic Acids for Selective Targeting of RNA

Abstract

The synthesis of backbone-modified nucleic acids has been an area of very intense research over the last two decades. The main reason for this research activity is the instability of nucleic acid based drugs in the intracellular conditions. Changes in the sugar-phosphate backbone invariably bring about the changes in the complementation properties of the nucleic acids. The naturally occurring deoxyribose- (DNA) and ribose (RNA) sugar-phosphate backbones are endowed with considerable differences in their binding affinities towards themselves. This occurs because of the different sugar conformations prevalent in DNA and RNA and the subtle structural changes accruing from these in hydrogen bonding, base-stacking interactions and hydration of major/minor grooves. The six-atom phosphodiester linkages and pentose-sugars give immense opportunities for chemical modifications that lead to several backbone-modified nucleic acid structures. This article is focused on such modifications that impart RNA-selective binding properties to the modified nucleic acid mimics and the rationale behind the said selectivity. It is found that the six-atom sugar-phosphate backbone could be replaced by either one-atom extended or one-atom edited repeating units, leading to the folded or extended geometries to maintain the internucleoside distance-complementarity. Other important contributions come from electronegativity of the substituent groups, hydration in the major/minor groove, base stacking etc.

Influence of Pendant Chiral Cγ-(Alkylideneamino/Guanidino) Cationic Side-chains of PNA Backbone on Hybridization with Complementary DNA/RNA and Cell Permeability

“…mp = 92−94°C; R f = 0.47 EtOAc; [α] 25 D − 8.1 (c 1, methanol); IR (neat) 3332, 2978, 1671, 1519, 1464, 1369 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.86 (maj) 9.56 (min) (br, 1H), 7.37−7.27 (m, 5H), 7.05 (min) 6.98 (maj) (s, 1H), 5.67−5.63 (maj) 5.58−5.56 (min) (comp, 1H), 5.11−5.04 (m, 2H), 4.82 (min) 4.78 (maj) (br, 1H), 4.47−4.37 (m, 1H), 4.28−4.13 (m, 3H), 3.94− 3.51 (m, 3H), 3.43−3.02 (m, 3H), 2.17 (br, 1H), 1.89 (min) 1.87 (maj) (s, 3H), 1.69−1.67 (comp, 1H), 1.41 (maj) 1.39 (min) (s, 9H), 1.31−1.23 (m, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.1, 167.5, 164.4, 156.7, 151.5, 140.9, 136.5, 128.4, 128.0, 110.8, 79.6, 66.6, 62.3, 52.1, 51.5, 49.8, 48.6, 47.8, 47.2, 37.6, 32.9, 28.3, 14.0, 12.3; HRMS (ESI-TOF) m/z calcd for C 28 H 39 N 5 O 9 [M + Na] + 612.2645, found 612.2646. (S )-2-(N-(4-(((Benzyloxy)carbonyl)amino)-2-((tertbutoxycarbonyl)amino)butyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)acetic Acid(11). To a stirred solution of compound 10 (500 mg, 0.8 mmol) in MeOH was added aq LiOH (10%), and the reaction mixture was stirred for 3 h at room temperature.…”

Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides

“…Additionally, PNAs exhibit numerous disadvantages, including low solubility in an aqueous medium, ambiguous directional selectivity of DNA/RNA binding, and low cell permeability. To address some of the above-mentioned issues, several modifications have been performed on the original PNA structure [22][23][24]. For instance, the incorporation of N-(2-aminoethyl)-D-Lysine residues led to the synthesis of cationic PNAs, which combined the nucleic acid recognition ability of PNA with the cell permeability of cationic cell penetrating peptides (CPP).…”

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

“…Some conformationally restricted protonated PNA or pyrrolidine oligonucleotide mimics exhibit selective binding with RNA but not with DNA [16–17]. It has been shown that conjugation of PMO with cationic peptides or other cationic residues facilitates penetration of PMO into cells and efficiently prevents the growth of E. coli in vitro and in vivo [18].…”