Non-Nucleosidic Analogues of Polyaminonucleosides and Their Influence on Thermodynamic Properties of Derived Oligonucleotides

Abstract

The rationale for the synthesis of cationic modified nucleosides is higher expected nuclease resistance and potentially better cellular uptake due to an overall reduced negative charge based on internal charge compensation. Due to the ideal distance between cationic groups, polyamines are perfect counterions for oligodeoxyribonucleotides. We have synthesized non-nucleosidic analogues built from units that carry different diol structures instead of sugar residues and functionalized with polyamines. The non-nucleosidic analogues were attached as internal or 5'-terminal modifications in oligodeoxyribonucleotide strands. The thermodynamic studies of these polyaminooligonucleotide analogues revealed stabilizing or destabilizing effects that depend on the linker or polyamine used.

Keywords: duplex DNA; non-nucleosidic analogue; oligonucleotide; polyaminonucleoside analogue; putrescine; spermine; thermodynamic stability.

Figure 1

Substrates for the non-nucleosidic polyaminonucleoside analogues.

Scheme 1

Synthetic routes to non-nucleosidic polyaminonucleoside analogues: (i) benzaldehyde, p-TsOH, DMF; (ii) SOCl₂, putrescine, Et₃N, DCM; (iii) (F₃CCO)₂O, pyridine; (iv) (a) 6 M HCl, reflux, (b) DMTCl, pyridine; (v) (iPr₂N)₂POCH₂CH₂CN, 5-ethylthio-1H-tetrazole, DCM; (vi) spermine, MeOH; (vii) (a) p-TsOH, MeOH, (b) DMTCl, pyridine; (viii) TBDMSCl, DMAP, imidazole, CH₃CN; (ix) spermine, MW, 40 min; (x) (a) TEAHF, THF/dioxane, (b) DMTCl, pyridine.

Figure 2

Non-nucleosidic polyamino-nucleoside analogues units in oligodeoxyribonucleotide strands.

Figure 3

Changes in free energy (ΔG) of polyamine modified duplexes: RF-RF3- reference duplexes, dCSp—spermine modified (dC^Sp = 4-N-[4,9,13-triazatridecan-1-yl]-2′-deoxycytidine) duplex [34]; ON3, ON7—non-nucleosidic putrescine analogues (Table 2); ON4–ON6 and ON8–ON9—non-nucleosidic spermine analogues (Table 2).