Chemical biologists seek to explore human biology through the use of small molecule therapeutics and biological probes. One approach to this is fragment-based drug discovery (FBDD), where biologically active molecules are built from core fragment scaffolds. Currently, most of the chemical libraries used in FBDD are dominated by sp2-rich aromatic compounds. Building an expanded library containing sp3-rich chiral fragments would allow the exploration of a larger chemical space which in turn would open avenues for unexplored biological space. In this project, we sought to exploit the power of modern organic chemistry to create a pilot library of sp3-rich, highly soluble chiral fragments derived from 1,2-amino alcohols. These fragments will be synthesized using the principles of Diversity-oriented Synthesis (DOS) to generate a set of molecules diverse in chemical and structural properties. To begin building our sp3-rich chiral fragment library, we focused on optimizing and devising reaction conditions for the synthesis of sulfamidites and sulfamidates fragments derived from 1,2-amino alcohols. The synthesis of free NH sulfamidites was ultimately deprioritized due to their instability. However, a methodology was adapted and optimized for arriving at cyclic sulfamidates from primary and secondary 1,2-amino alcohols. Once synthesized, these chiral fragments were characterized, and their solubility and stability in phosphate-buffered saline (PBS) will be assessed. The results of this pilot study will serve as a blueprint in designing, evaluating and building more focused libraries of chiral fragments. In turn, this will lead to building more structurally diverse fragment libraries which will expand the scope of fragment-based drug discovery.
PROJECT: Building small molecule fragments from chiral or sp3-rich 1,2-amino alcohols
The second I stepped foot inside the Broad, I felt like this was the place where the future of research was headed, and I wanted to be a part of it. I spent my summer working with some of the most motivated and ambitious students and scientists I have ever met. The Broad community is extremely welcoming; by the end of my first week I felt part of a scientific family dedicated to improving the collaborative quality of scientific research. One of the most rewarding aspects of working at the Broad is the level of respect demonstrated for members at all levels. At group meetings or seminars, I was never afraid to speak my mind and ask any question I had, and I knew even the highest ranked scientist in the room would be engaged and eager to answer. Working with my fellow Broadies, my mentor, and my PI at the Broad has guided and enriched my research career in a way I could not have imagined.