Studies on bioisosteric replacement and application to heterocyclic privileged scaffolds

Abstract

Part 1. Development of Bioisosteric Replacement Strategy of $\gamma$-Lactone to NH $\gamma$-Lactam While lactone is a common structural motif found in a variety of biologically active natural products and pharmaceuticals, their cellular and in vivo activities are often significantly labile due to the metabolic instability. In the present investigation, a new synthetic approach has elaborated on the conversion of various $\gamma$-lactones to the corresponding NH $\gamma$-lactams that can serve as $\gamma$-lactone bioisosteres. This approach consists of reductive C–O cleavage of a lactone to a carboxylic acid and then an Ir-catalyzed C–H amidation, offering a powerful synthetic tool for accessing a wide range of valuable NH $\gamma$-lactam building blocks starting from $\gamma$-lactones. The synthetic utility was further demonstrated by the successful late-stage transformation of complex bioactive molecules and the asymmetric transformation.

Part 2. Application of Bioisosteric Replacement for Development of Mutant(d746-750/T790M/C797S) Selective EGFR Inhibitors Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants exhibiting drug resistance. To improve the treatment of NSCLC, it has become urgent to identify the specific inhibitors of triple mutant EGFRs resistant to second- and third-generation EGFR inhibitors. Herein, I report the discovery of potent and selective inhibitors of the delE746-A750/T790M/C797S (d746-750/T790M/C797S) mutant EGFR via a two-track virtual screening and de novo design. A number of nanomolar inhibitors of the d746-750/T790M/C797S mutant were identified using 2-aryl-4-aminoquinazoline as the molecular core which is expected to make interaction with mutated Ser797 and Met790. Intensive medicinal chemistry efforts including bioisosteric replacement enabled development of new EGFR inhibitors showing a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type as well as nanomolar activity against the mutant.