Molecular Construction of Sulfonamide Antisense Oligonucleotides

Abstract

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Synthesis, gene silencing activity, thermal stability, and serum stability of siRNA containing four (S)-5′-C-aminopropyl-2′-O-methylnucleosides (A, adenosine; U, uridine; G, guanosine; and C, cytidine)

“…( S )-5′- C -aminopropyl-2′- O -methyladenosine phosphoramidite 22 was synthesized from the common synthetic intermediate 12 (Scheme 2). The stereoselective glycosylation of the 5- C -substituted ribofuranoside derivative 12 with N 6 -benzoyl adenine using tin( iv ) chloride (SnCl 4 ), 28,29 followed by deacetylation using potassium carbonate (K 2 CO 3 ) in CH 3 OH afforded a 2′-OH derivative 14 . The methylation of the 2′-OH moiety of 14 using CH 3 I and NaH afforded the 2′- O -methyl derivative 15 in 72% yield.…”

“…The residue was puried by column chromatography (66% ethyl acetate in hexane) to afford desired product 28 as a white solid (0.77 g, 1.42 mmol, 83%). 1 (29). Under argon atmosphere, BCl 3 (8.30 mL of a 1 M solution in CH 2 Cl 2 ) was added to a solution of compound 28 (0.75 g, 1.38 mmol) in CH 2 Cl 2 (11 mL) at À78 C. Aer the mixture was stirred at À78 C for 4 h, the mixture was warmed to À50 C and stirred for 4 hours.…”

DNA with zwitterionic and negatively charged phosphate modifications: formation of DNA triplexes, duplexes and cell permeability studies

“…3) monomers to replace the phosphodiester backbone led to charge-neutral sulfonamide antisense oligonucleotides (SaASOs), which resulted in a slight destabilisation DNA-RNA duplex compared to a DNA-DNA duplex. 65 In contrast, incorporation of BCNS (Fig. 3) groups into the DNA backbone led to self-neutralising ONs that did not induce a change of T m when binding complementary DNA sequences, 66 85 The Ts-modification stabilised duplex formation with RNA at 100 mM salt, but destabilised the RNA duplex at a low salt concentration.…”

“…3) dimer into the DNA backbone led to decreased thermal stability of the duplex formed with either complementary DNA or RNA, with the ON-RNA duplex being less stable than the ON-DNA duplex. 65 Branched, chargeneutralising sleeves (BCNS, Fig. 3) incorporated on the ON backbone 66 formed selfneutralising ONs with good aqueous solubility, enhanced resistance to nucleases, low cytotoxicity and increased thermal stability in the context of 2ʼ-OMe-RNA duplexes.…”

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

“…Several studies have focused on the introduction of positively charged groups to a nucleobase [47,48], a sugar [49,50], or the DNA backbone [51][52][53] leading to the formation of more stable duplexes and triplexes [54]. The introduction of sulfonamide RNA (SaRNA monomers) to replace the phosphodiester backbone led to charge-neutral sulfonamide antisense oligonucleotides (SaASOs), which resulted in a lower destabilisation (a more stable) DNA-RNA duplex compared to a DNA-DNA duplex [55]. In contrast, the incorporation of branched, charge-neutralising sleeve (BCNS) groups onto the DNA backbone led to self-neutralising ONs that did not induce a change of T m when binding complementary DNA sequences [56], regardless of the number of BCNSs incorporated.…”