In our fragment-based drug discovery projects, we constantly think about new ways of stitching together heterocycles. It is particularly satisfying if we find a way to make completely new, previously unexplored, chemistry matter. As you might imagine, herein lies a dilemma. On the one hand, we want high ligand efficiency, which goes implies relatively small size. On the other hand, try to plug something completely new (for instance, a 6-membered ring) that is composed of common heteroatoms into SciFinder. Good luck with that. Chances are, your composition of matter has been disclosed in a patent or, worse yet, published in peer-reviewed literature. Challenges notwithstanding, we recently bravely embarked on a journey that has sought the discovery and development of new kinds of small and medium rings. One of our favorite examples is the so-called boromorpholinone, which is obtained by plugging a boron atom into the framework of a well-familiar morpholinone scaffold. You see a model of a representative member of this class of compounds in the graphic below (boron is green). Earlier this year, Aleksandra Holownia (pictured below) joined our efforts as a Summer undergraduate student. Under the direction of my graduate student Adam Zajdlik, Aleksandra not only helped us understand the boromorpholinone area better, but earlier today won one of the AstraZeneca poster awards. I applaud her dedication to this project. As you might imagine, the boron atom in these sorts of rings is not going to be an innocent bystander. There are, in fact, many applications that await these compounds, which is something we are engaged in together with Ben Cravatt at Scripps. Speaking of Adam, he just came back from a one month internship at Anacor in California, where he further learned about the use of boron. Anacor is the pioneer in the deployment of boron-containing molecules in drug design. There are myriad reasons to like boron and I will give you just one: boric acid, the main metabolite of organoboron therapeutics, has LD50 of 2.7 g/kg. This toxicity is comparable to that of table salt. Once again, congratulations, Aleksandra!
