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 ^GN_PST (^GN = ^GA, ^GC, ^GG, ^GT). The absolute configuration at the phosphorus atom for all eight ^GN_PST was established enzymatically and verified chemically, and correlated with chromatographic mobility of the OTP-^GN′ monomers on silica gel. The ^GN_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 ^GN units in the oligonucleotide strands. These results correlate with the changes of conformation assessed from circular dichroism spectra.