High-Speed Medicinal Chemistry
Status
Established Project
Background
Today there is an ever growing demand for new lead-like organic molecules for biological evaluation in the pursuit of new drugs. The combinatorial or high-throughput chemist is therefore under constant pressure to increase the compound production. In this reality, not only purification speed, but also reaction rate is of essence. Convenient methods to promote rapid reactions then become important. New automatic microwave synthesizers constitute robust high-speed tools with the potential to help meet these demands, and to become efficient "superheating" devices in the combinatorial laboratory.
Aim
To explore microwaves as an efficient energy source for rapid solution phase combinatorial chemistry. To utilize high-density microwave irradiation for controlled release of gases from solids and liquids, and to use the liberated gases as a central building block in high-speed metal-catalyzed synthesis. To apply the microwave "flash-heating" methodology in the synthesis of discrete and well characterized, high quality libraries of biologically interesting lead molecules. To employ a new concept for rapid lead optimization based on metal-catalysis target-assisted selection and preformed building blocks.
Method
The presented research project brings together investigations of new robust and very rapid microwave heated metal-catalyzed organic reactions for use in combinatorial chemistry, including reactions with carbon monoxide, with a general rational for optimization of lead structures. Microwave flash-heating with a computer-controlled, dedicated single-mode microwave cavity, designed for high-speed sequential synthesis, is exploited as a combinatorial niche technology. All transformations are monitored with GC/MS or LC/MS, and purified by MS-triggered preparative LC/MS or automatic flash-chromatography.