Exhaustive fluorine scanning toward potent p53-Mdm2 antagonists.

The unmatched properties of the element fluorine are reflected in organic fluorine compounds. The richness of modern fluorine chemistry allows for the regioselective introduction of this element at virtually every position of a given molecule.[1, 2] Thus the introduction of fluorine has been especially valuable in the process of drug discovery to fine tune many different target and off-target related properties.[3–6] For example, fluorine has been used to increase the binding affinity of small molecules to its target,[7] to tune the pKB and logD,[8] to improve target selectivity,[9] to improve oral absorption and exposure,[10] to prevent from metabolism[11] or to increase the antibacterial spectrum.[12] Not surprisingly, an estimated 20% of all pharmaceuticals contain fluorine.[4] Additionally, 18F is often used as a positron emission tomography (PET) active element to perform time and space resolved distribution studies of drugs in animals and humans.[13, 14] Last but not least, 19F is very useful in NMR of complex biological systems due to its high sensitivity and zero natural background.[15] Herein, we report the systematic F-scanning of a scaffold derived from the Ugi four-component reaction (Ugi-4CR) for the synthesis, optimization and biophysical characterization of potent p53-Mdm2 antagonists.