Grant: Alliance Grants

As fundamental biomolecules, nucleosides play key roles in diverse cellular processes ranging from cell signalling to metabolism. Not surprisingly, synthetic nucleoside analogues (NAs), designed to mimic their natural counterparts, are widely exploited in medicinal chemistry and used as tool compounds in chemical biology. In fact, NAs have been in use for over half a century for the treatment of cancer and represent the largest class of small molecule antivirals. The Britton research group in collaboration with scientists in the Process Research Department at Merck have developed a straightforward synthesis of NA that involves inexpensive and scalable chemistry. Importantly, this rapid and flexible process addresses several major and longstanding challenges in NA synthesis by enabling direct access to modified NAs that are critical to support drug discovery and development efforts. In several instances this process was demonstrated on scales ranging up to ~1 kg, indicating that this technology can broadly support both medicinal chemistry and process research efforts. Our recent discoveries provide unique opportunities and here we will improve and adapt our NA syntheses and explore a process where we add the nucleobase at the last step. This is important for the rapid production of NAs for biological screening purposes. We will further develop a new class of NAs that we have termed aerial NAs that may have utility in oligonucleotide therapeutics or as a treatment for molybdenum cofactor deficiency. We will also extend our chemistry platform to make nucleosides with sulfur replacing the oxygen atom in the ribose ring (thionucleosides) and their derivatives. This research will be carried out with scientists in the Process Research and Development group at Merck with whom we have a strong relationship and have collaborated successfully in the past.