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

Abstract

Enantiomerically pure, protected acyclic nucleosides of the GNA type (glycol nucleic acids) (GN′), 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-GN′) 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 GNPST (GN = GA, GC, GG, GT). The absolute configuration at the phosphorus atom for all eight GNPST was established enzymatically and verified chemically, and correlated with chromatographic mobility of the OTP-GN′ monomers on silica gel. The GNPS 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 GN units in the oligonucleotide strands. These results correlate with the changes of conformation assessed from circular dichroism spectra.