Construction of quaternary stereocenters at carbon 2' of nucleosides.

The non-natural nucleosides with a quaternary stereogenic center at C2' are crucial to drug discovery. They have become a cornerstone for the treatment of cancer and various viral infections as exemplified by gemcitabine and sofosbuvir. Major research effort has been expended to gain synthetic access to these nucleoside analogues with a significant steric bulk at C2' in the furanoside ring. The 2'-ketonucleosides and 2'-deoxy-2'-methylenenucleosides emerged as key intermediates in these synthetic strategies. For example, α-face addition of methyl lithium to the 2'-ketonucleosides followed by fluorination of resulting tertiary arabino alcohol with DAST provided 2'-fluoro-2'-C-methyluridine - a core nucleoside component of sofosbuvir. The α-face addition of HCN or HN3 to the 2'-deoxy-2'-methylene nucleosides gave access to the synthetically versatile 2'-cyano-2'-C-methyl and 2'-azido-2'-C-methyl nucleosides. Likewise, the addition of diazomethane to the 2'-exomethylene group gave access to the 2'-spirocyclopropyl analogue. This review primarily discusses synthetic strategies which employs natural nucleosides as substrates but selected approaches involving coupling of the preelaborated sugar precursors with nucleobases are also examined.

Not Every Hit-Identification Technique Works on 1-Deoxy-d-Xylulose 5-Phosphate Synthase (DXPS): Making the Most of a Virtual Screening Campaign.

In this work, we demonstrate how important it is to investigate not only on-target activity but to keep antibiotic activity against critical pathogens in mind. Since antimicrobial resistance is spreading in bacteria such as Mycobacterium tuberculosis, investigations into new targets are urgently needed. One promising new target is 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) of the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. We have recently solved the crystal structure of truncated M. tuberculosis DXPS and used it to perform a virtual screening in collaboration with Atomwise Inc. using their deep convolutional neural network-based AtomNet® platform. Of 94 virtual hit compounds only one showed interesting results in binding and activity studies. We synthesized 30 close derivatives using a straightforward synthetic route that allowed for easy derivatization. However, no improvement in activity was observed for any of the derivatives. Therefore, we tested them against a variety of pathogens and found them to be good inhibitors against Escherichia coli.