Last September, our grant proposal, “Diversity-Oriented Synthesis of Novel Heterocyclic and Natural Product-Like Libraries” was approved by the National Institutes of Health (NIH) as part of their Pilot Scale Libraries for High-Throughput Screening program. This program is part of the NIH Roadmap Molecular Libraries and Imaging Initiative. The NIH defines the goals in this way:
Since the goal of the ML Roadmap is to identify novel small molecule effectors of biological function, it is crucial that library designs be driven by biological considerations, rather than by chemical methodologies. Furthermore, since the goal is to identify effectors of truly novel biological phenotypes and mechanisms, it is important that the compounds produced under this RFA represent chemotypes that are distinct from what is available commercially and in existing compound collections.
We thought that fluorous technology would be a perfect way to access novel chemical libraries and we’re glad that the NIH agreed. This is a 3-year grant with the objective to submit ~800 compounds (>90% pure, 5-20 mg) each year to the NIH Molecular Libraries Small Molecule Repository (MLSMR).
The ~800 compounds per year objective is a tough one and was described by one reviewer as “too aggressive” given the level of effort we were proposing. Our approach combines diversity-oriented library design and fluorous parallel synthesis. Diversity-oriented library design enables us to use common intermediates to generate a series of libraries. Fluorous parallel synthesis provides a fast and simple way to perform library evaluation and production. We felt confident that fluorous techniques would provide a productivity edge that would allow us to meet our aggressive target.
We’re pleased to report that the first year of the grant was a success. We completed 7 libraries and submitted a total of 792 compounds to the MLSMR. In the same time, we also evaluated several additional library proposals which will enter the production phase in year 2. Stay tuned for more details in F-Blog and through other publications.