Efficient Synthesis of Halogenated Nucleosides & Novel NAD+ Modulating Compounds
- Others
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- (2009) Cen, Y and Sauve AA. Diastereocontrolled Electrophilic Fluorinations of 2-Deoxyribonolactone: Syntheses of All Corresponding 2-Deoxy-2-fluoro-lactones and 2'-Deoxy-2'-fluoro-NAD+s. J Org Chem. 74(16):5779-89.
- (2010) Cen Y, Sauve AA. Efficient syntheses of clofarabine and gemcitabine from 2-deoxyribonolactone. Nucleosides Nucleotides Nucleic Acids. Feb;29(2):113-22.
- *Abstract
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Inventions
- More efficient, safer, and diastereoselective synthesis of halogenated (and other substituted) lactones and nucleosides
- Novel halogenated (and other substituted) lactones and nucleosides and their polymers
Gemcitabine is a blockbuster cancer drug for Eli Lilly, with over $1.6B in sales per year. Genzyme's cancer drug, clofarabine, has sales of over $100M per year in an orphan indication. What do these drugs have in common? They are both fluorinated nucleosides.
This family of compounds - and the broader class of halogenated sugars - has attracted considerable attention from industry in recent years owing to the unique properties of the halogens. The replacement of hydrogen or oxygen with a halogen can dramatically change a small molecule's biological activity and pharmaceutical properties with modest change in size. They are also being explored as the basis for more stable aptamers and RNAi / antisense drugs.
The Cornell lab run by Anthony Sauve is in the vanguard of the revitalized field of B vitamin chemistry, which is at the heart of NAD+ catabolism, metabolism, and co-enzyme activity, which in turn drives hot topics in biology and medicine, like the role of PARPs and sirtuins in DNA repair, gene silencing and longevity.
His lab recently achieved the most efficient synthesis of nicotinamide riboside ever published, making it possible to study this novel B vitamin and to bring it to market.
The lab has now turned its attention to the broad class of substituted lactones. The lab's synthesis of gemcitabine, for instance, doubles the yield of other published and patented methods, and uses no dangerous intermediates (such as DAST). Likewise, their synthesis of clofarabine is twice as efficient as the best published methods.
The general pathway the lab established is to install a bulky protecting group at C3 and C5, protecting unstable enolate intermediates from undesirable reactions and directing diastereoselective installation of substituents at C2.
Besides providing more efficient synthesis of known drugs, the pathway also opens up wide swaths of interesting chemical space, making possible for the first time the selective synthesis of arabino, ribo, and gem-di-substituted lactones, ribosides, and their polymers.
- *Licensing
- BrianJ. Kellybjk44@cornell.edu212-746-6186
- Country/Region
- USA
