Stereochemistry of internucleoside phosphorus atom affects sugar pucker and acid hydrolysis of N3′-P5′ thio-phosphoramidates

Abstract

Investigation of the sugar pucker of the two diastereomers of dinucleotide N3′-P5′-thio-phosphoramidates TNPSTNH2 and TNPSTOH shows that the Sp isomer adopts a more C3′-endo (North) sugar ring configuration than the Rp counterpart. In contrast, P-stereochemistry of oligonucleotide phosphorothioate (O3′-P5′) compounds has no effect on the nucleoside sugar puckering. This difference is also reflected in the different rate of acid hydrolysis for the two isomers. Thus, the Rp stereoisomer with less prevalent C3′-endo configuration has an acid hydrolysis rate constant ~50% higher than that of the Sp molecule. The TNPOTNH2 and TNPOTOH dinucleotides are hydrolyzed an order of magnitude faster than TNPSTNH2 and TNPSTOH, respectively. In addition, dinucleotides with the terminal 3′-OH group are hydrolyzed two times faster than their 3′-NH2 counterparts.