ABSTRACT
DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.
Subject(s)
Antitubercular Agents , Enzyme Inhibitors , Mycobacterium tuberculosis , Small Molecule Libraries , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/drug effects , Animals , Mice , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Tuberculosis/drug therapy , Tuberculosis/microbiology , Polyketide Synthases/metabolism , Polyketide Synthases/chemistry , Polyketide Synthases/genetics , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Drug Discovery , Drug Evaluation, Preclinical , Thiolester Hydrolases/antagonists & inhibitors , Thiolester Hydrolases/metabolism , Thiolester Hydrolases/chemistry , Thiolester Hydrolases/genetics , Crystallography, X-Ray , Humans , Disease Models, AnimalABSTRACT
The first total syntheses of (-)-trichorabdal A and (-)-longikaurin E are reported. A unified synthetic strategy is employed that relies on a Pd-mediated oxidative cyclization of a silyl ketene acetal to generate an all-carbon quaternary center and build the bicyclo[3.2.1]octane framework. These studies, taken together with our previous synthesis of (-)-maoecrystal Z, demonstrate that three architecturally distinct ent-kauranoids can be prepared from a common spirolactone intermediate.
Subject(s)
Biological Products/chemical synthesis , Diterpenes, Kaurane/chemical synthesis , Diterpenes/chemical synthesis , Isodon/chemistry , Cyclization , Ethylenes/chemistry , Ketones/chemistry , Octanes/chemistry , Oxidation-Reduction , Palladium/chemistryABSTRACT
The first total synthesis of (-)-maoecrystal Z is described. The key steps of the synthesis include a diastereoselective Ti(III)-mediated reductive epoxide coupling reaction and a diastereoselective Sm(II)-mediated reductive cascade cyclization reaction. These transformations enabled the preparation of (-)-maoecrystal Z in only 12 steps from (-)-γ-cyclogeraniol.
