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

Investigation of the sugar pucker of the two diastereomers of dinucleotide N3'-P5'-thio-phosphoramidates TNPSTNH2 and TNPSTOH shows that the S-p isomer adopts a more C3'-endo (North) sugar ring configuration than the R-p 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 R-p stereoisomer with less prevalent C3'-endo configuration has an acid hydrolysis rate constant similar to 50% higher than that of the S-p 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. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

The study revealed distinct differences in sugar conformation and acid hydrolysis rate between the diastereomers of dinucleotide N3'-P5'-thio-phosphoramidates, while the P-stereochemistry of oligonucleotide phosphorothioate compounds showed no effect on nucleoside sugar puckering.