Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes

Abstract

Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease.

Benzoxaboroles—Novel Autotaxin Inhibitors

“…A recent (2017) publication by Lanier et al [12] reported a fragment based approach used to explore phenylboronic acids as warheads towards ATX inhibitors. They tested more than 650 boronic acid fragments.…”

“…They tested more than 650 boronic acid fragments. combining in silico computational chemistry filters and crystallography, allowing them to identify fragments that were consistent to known SAR against ATX [12].…”

“…Benzoxaboroles have physicochemical properties which are a consequence of the relatively strong Lewis acidic center on the boron atom and the presence of a free hydroxyl group [14]. The sp 2 hybridized boron atom possesses an empty p-orbital which accepts electrons from the hydroxyl group of threonine 209 (Thr209) that explains adduct formation of boronic acids, as in the recent modelling of Lanier [12]. According to Lanier et al [12], a boronic acid motif with this type of interaction may enhance binding affinity up to 1000 fold.…”

Rapid approach to complex boronic acids

“…Other highly useful transformations based on boronic acids include the Petasis reaction ( 4 ), C─N and C─O coupling (Chan-Lam coupling) ( 5 , 6 ), Liebeskind-Srogl coupling ( 7 ), regioselective deuteration, or sulfonamide formation ( 8 ). Boronic acids as mild electrophiles are also investigated as reversible covalent inhibitors ( 9 , 10 ), and thousands of different building blocks are now commercially available. As a result, boronic acids are increasingly being seen in approved drugs, e.g., vaborbactam or bortezomib (Fig.…”

Isocyanide‐Based Multicomponent Reactions of Free Phenylboronic Acids

“…This property facilitates the use of boronic acid derivatives as enzyme inhibitors because they can mimic a tetrahedral sp 3 ‐hybridized carbon atom in the transition state of enzyme‐catalyzed hydrolytic processes. Moreover, based on this prosperity to engage various nucleophiles (alcohols or amines) with the empty p ‐orbital, allows boron to form a dative bond with many molecules of biological interest as carbohydrates and nucleic acids . Despite the increasing interest in boron as an alternative to carbon in drug design the last decade,, boron in general has been overlooked by medicinal chemists even if there are five commercially available and late‐stage clinical trials boronic acid‐based drugs (Bortezomib, Ixazomib, Crisaborole, Tavaborole, Vaborbactam and VNRX‐5133, Figure ) , .…”