P -Stereodefined phosphorothioate analogs of glycol nucleic acids-synthesis and structural properties.

Enantiomerically pure, protected acyclic nucleosides of the GNA type (glycol nucleic acids) ( G N'), obtained from ( R )-(+)- and ( S )-(-)-glycidols and the four canonical DNA nucleobases (Ade, Cyt, Gua and Thy), were transformed into 3'- O -DMT-protected 2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane derivatives (OTP- G N') containing a second stereogenic center at the phosphorus atom. These monomers were chromatographically separated into P -diastereoisomers, which were further used for the synthesis of P -stereodefined "dinucleoside" phosphorothioates G N PS T ( G N = G A, G C, G G, G T). The absolute configuration at the phosphorus atom for all eight G N PS T was established enzymatically and verified chemically, and correlated with chromatographic mobility of the OTP- G N' monomers on silica gel. The G N PS units (derived from ( R )-(+)-glycidol) were introduced into self-complementary PS-(DNA/GNA) octamers of preselected, uniform absolute configuration at P-atoms. Thermal dissociation experiments showed that the thermodynamic stability of the duplexes depends on the stereochemistry of the phosphorus centers and relative arrangement of the G N units in the oligonucleotide strands. These results correlate with the changes of conformation assessed from circular dichroism spectra.