Synthesis of fluorinated natural product analogues for probing selectivity toward AGC protein kinases

<p dir="ltr">The AGC kinases are highly conserved proteins and validated drug targets. (–)-Balanol, a fungal metabolite, is a potent protein kinase A (PKA) and protein kinase C (PKC) antagonist but exhibits limited selectivity across the superfamily. With the recent recognition of conformation entropy following the discovery of Imatinib (Gleevec), there has been a growing interest in taking the approach of congruent conformation induction between a protein and its ligand for developing specific drug leads. </p><p dir="ltr">We investigated this conformational induction using C–F bond as a tuning motif on (–)-balanol as a model system for enhanced selectivity towards AGC protein kinases. (–)-Balanol (Scheme 1) is an ATP mimic and consists of three fragments, including adenine mimic (benzamide), ribose mimic (azepane); and triphosphate mimic (substituted benzophenone). Here in this work, a new efficient route towards stereoselective C–N bond formation in (–)-balanol azepane involving hypervalent silicates was developed. A series of fluorinated benzophenones (triphosphate mimics) were accomplished in 13–15 steps involving key reactions including Lithium halogen exchange for CO₂ trapping, intra molecular Fries rearrangement and chemo selective Swern and Pinnick oxidations. The benzophenones were coupled to balanol benzamide and azepane fragments to access four fluorinated balanoids for probing their selectivity in protein binding that could come from fluorine substituents in protein pockets. The binding affinity profile of fluorinated balanoids showed that fluorination in triphosphate mimic retains affinity for prototype AGC kinase, PKA, with enhanced selectivity (>600-fold) in one balanoid (Scheme 1).</p>