Conformationally coupled diversity-oriented synthesis (CDOS) using natural product derived fragments

Given the newly recognised role of conformational entropy in conferring additional specificity in protein-ligand interactions, there has been growing interest in taking the approach of congruent conformational selection between the protein receptor and its small molecule ligands for developing more specific bioactive leads for drug discovery. Our group recently introduced the concept of conformationally coupled diversity-oriented synthesis (CDOS) for fragment-based drug design (FBDD). CDOS fragments that possess conformation-tuning handles such as C–F bonds can be utilised in diversity-oriented synthesis to access both chemical and conformational diversity in order to capture protein conformational dynamics for enhanced specificity in ligand recognition. Here synthetic approaches of key fragments for CDOS were investigated for two model systems based on the natural product (–)-balanol and the immunomodulatory (IMiD^®) drug, lenalidomide. Balanol as an ATP mimic consists of three fragments, including the benzamide (adenine mimic); the azepane (ribose mimic), and the substituted benzophenone (triphosphate mimic). A new, scalable and economic route toward the azepane fragment of balanol was developed utilising a chiral aziridinyl intermediate originating from readily available D-serine. This route was utilised to efficiently access new balanoids for future studies toward probing the binding dynamics of the protein kinase C family for enhanced isozyme specificity. Likewise, a key fragment toward a conformationally-biased glutarimide fragment of lenalidomide was accessed, potentially permitting future studies toward accessing CDOS analogues of lenalidomide for enhanced binding to the protein-protein interaction (PPI) targets; CRL4^CRBN and CK1α  or IKAROS transcription factors that are dysregulated in multiple myelmoma.