Design of Dual EP2/EP4 Antagonists through Scaffold Merging of Selective Inhibitors.

Prostaglandin E2 (PGE2) plays a key role in various stages of cancer. PGE2 signals through the EP2 and the EP4 receptors, promoting tumorigenesis, metastasis, and/or immune suppression. Dual inhibition of both the EP2 and the EP4 receptors has the potential to counteract the effect of PGE2 and to result in antitumor efficacy.

Structural Basis of Stereospecific Vanadium-Dependent Haloperoxidase Family Enzymes in Napyradiomycin Biosynthesis.

Vanadium-dependent haloperoxidases (VHPOs) from bacteria differ from their counterparts in fungi, macroalgae, and other bacteria by catalyzing organohalogenating reactions with strict regiochemical and stereochemical control. While this group of enzymes collectively uses hydrogen peroxide to oxidize halides for incorporation into electron-rich organic molecules, the mechanism for the controlled transfer of highly reactive chloronium ions in the biosynthesis of napyradiomycin and merochlorin antibiotics sets the vanadium-dependent chloroperoxidases apart. Here we report high-resolution crystal structures of two homologous VHPO family members associated with napyradiomycin biosynthesis, NapH1 and NapH3, that catalyze distinctive chemical reactions in the construction of meroterpenoid natural products.

Optimization of LpxC Inhibitor Lead Compounds Focusing on Efficacy and Formulation for High Dose Intravenous Administration.

LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as and , which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models.

Discovery of Novel Inhibitors of LpxC Displaying Potent in Vitro Activity against Gram-Negative Bacteria.

UDP-3--(()-3-hydroxymyristoyl)--glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6-thieno[2,3-]pyrrol-6-ones, and (iii) 1,2-dihydro-3-pyrrolo[1,2-]imidazole-3-ones.

A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis.

Bacterial meroterpenoids constitute an important class of natural products with diverse biological properties and therapeutic potential. The biosynthetic logic for their production is unknown and defies explanation via classical biochemical paradigms. A large subgroup of naphthoquinone-based meroterpenoids exhibits a substitution pattern of the polyketide-derived aromatic core that seemingly contradicts the established reactivity pattern of polyketide phenol nucleophiles and terpene diphosphate electrophiles.

Biosynthesis of coral settlement cue tetrabromopyrrole in marine bacteria by a uniquely adapted brominase-thioesterase enzyme pair.

Halogenated pyrroles (halopyrroles) are common chemical moieties found in bioactive bacterial natural products. The halopyrrole moieties of mono- and dihalopyrrole-containing compounds arise from a conserved mechanism in which a proline-derived pyrrolyl group bound to a carrier protein is first halogenated and then elaborated by peptidic or polyketide extensions. This paradigm is broken during the marine pseudoalteromonad bacterial biosynthesis of the coral larval settlement cue tetrabromopyrrole (1), which arises from the substitution of the proline-derived carboxylate by a bromine atom.

Chemoenzymatic Synthesis of Acyl Coenzyme A Substrates Enables in Situ Labeling of Small Molecules and Proteins.

A chemoenzymatic approach to generate fully functional acyl coenzyme A molecules that are then used as substrates to drive in situ acyl transfer reactions is described. Mass spectrometry based assays to verify the identity of acyl coenzyme A enzymatic products are also illustrated. The approach is responsive to a diverse array of carboxylic acids that can be elaborated to their corresponding coenzyme A thioesters, with potential applications in wide-ranging chemical biology studies that utilize acyl coenzyme A substrates.

Total Synthesis of Gelsemoxonine through a Spirocyclopropane Isoxazolidine Ring Contraction.

Plants of the species Gelsemium have found application in traditional Asian medicine for over a thousand years. Gelsemoxonine represents a novel constituent of this plant incorporating a highly functionalized azetidine at its core. We herein report a full account of our studies directed toward the total synthesis of gelsemoxonine that relies on a conceptually new approach for the construction of the central azacyclobutane.

A multitasking vanadium-dependent chloroperoxidase as an inspiration for the chemical synthesis of the merochlorins.

The vanadium-dependent chloroperoxidase Mcl24 was discovered to mediate a complex series of unprecedented transformations in the biosynthesis of the merochlorin meroterpenoid antibiotics. In particular, a site-selective naphthol chlorination is followed by an oxidative dearomatization/terpene cyclization sequence to build up the stereochemically complex carbon framework of the merochlorins in one step. Inspired by the enzyme reactivity, a chemical chlorination protocol paralleling the biocatalytic process was developed.

One-pot enzymatic synthesis of merochlorin A and B.

The polycycles merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH-189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis in vitro.

Amine-selective bioconjugation using arene diazonium salts.

A novel bioconjugation strategy is presented that relies on the coupling of diazonium terephthalates with amines in proteins. The diazonium captures the amine while the vicinal ester locks it through cyclization, ensuring no reversibility. The reaction is highly efficient and proceeds under mild conditions and short reaction times.

Access to the aeruginosin serine protease inhibitors through the nucleophilic opening of an oxabicyclo[2.2.1]heptane: total synthesis of microcin SF608.

Serine proteases play key roles in many biological processes and are associated with several human diseases such as thrombosis or cancer. During the search for selective inhibitors of serine proteases, a family of linear peptides named the aeruginosins was discovered in marine cyanobacteria. We herein report an entry route into the synthetically challenging core fragment of these natural products.

Mechanistic insight into the spirocyclopropane isoxazolidine ring contraction.

A mechanistic study of the ring contraction of spirocyclopropane isoxazolidines to form β-lactams is reported. Based on experimental and computational investigations, we propose a concerted mechanism that proceeds with retention of configuration during cyclopropane cleavage.

Total synthesis of (±)-Gelsemoxonine.

Gelsemoxonine (1) is a Gelsemium alkaloid incorporating an unusual azetidine. Its total synthesis was achieved employing a novel ring contraction of a spirocyclopropane isoxazolidine to furnish a β-lactam intermediate. This β-lactam ring was further elaborated into the azetidine of Gelsemoxonine.

Synthesis of Microcin SF608 through nucleophilic opening of an oxabicyclo[2.2.1]heptane.

The total synthesis of Microcin SF608 is reported. Access to the octahydroindole core structure of Microcin SF608 relies on the TMSOTf/NEt(3)-mediated opening of an oxabicyclic ring system. Additional highlights of the synthetic strategy that is reported include a highly regioselective epoxide reduction and photolytic excision of a 3 degrees alcohol.