Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

Abstract

AbstractThe formation of cyclic duplexes (pairing) of known oxymethylene‐linked self‐complementary U*[o]A(*) dinucleosides contrasts with the absence of pairing of the ethylene‐linked U*[ca]A(*) analogues. The origin of this difference, and the expected association of U*[x]A(*) and A*[x]U(*) dinucleosides with x=CH2, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson–Crick, reverse Watson–Crick, Hoogsteen, or reverse Hoogsteen H‐bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH2, O, or S were analysed. U*[x]A(*) dinucleosides with x=CH2 do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg‐conformation about the C(4′)C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt‐conformation about this bond.The temperature dependence of the chemical shift of HN(3) of the self‐complementary, oxymethylene‐linked U*[o]A(*) dinucleosides 1–6 in CDCl3 in the concentration range of 0.4–50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3, between the monoplex and cyclic duplexes for 6, and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4, and 5.The self‐complementary, thiomethylene‐linked U*[s]A(*) dinucleosides 27–32 and the sequence isomeric A*[s]U(*) analogues 33–38 were prepared by S‐alkylation of the 6‐(mesyloxymethyl)uridine 12 and the 8‐(bromomethyl)adenosine 22. The required thiolates were prepared in situ from the C(5′)‐acetylthio derivatives 9, 15, 19, and 25. The association in CHCl3 of the thiomethylene‐linked dinucleoside analogues was studied by 1H‐NMR and CD spectroscopy, and by vapour‐pressure osmometric determination of the apparent molecular mass. The U*[s]A(*) alcohols 28, 30, and 31 form cyclic duplexes connected by Watson–Crick H‐bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H‐bonds, and the resulting ribbons are cross‐linked by H‐bonds between HOCH2C(8/I) and N(3/I). Among the A*[s]U(*) dimers, only the C(8/I)‐hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34–36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl3. Temperature‐dependent CD spectra of 28, 30, 31, and 37 evidence π‐stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl3 solution is evidenced by a melting temperature of ca. 2°.