A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α: a potential role for targeting HIF-2α to prevent and treat reflux esophagitis.

Traditionally, reflux esophagitis was assumed to develop as a caustic, chemical injury inflicted by refluxed acid. Recently, however, studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2α playing a major role. In response to the reflux of acid and bile, HIF-2α in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus. Recent studies have identified small molecule inhibitors of HIF-2α that demonstrate exquisite isoform selectivity, and clinical trials for treatment of HIF-2α-driven kidney cancers are ongoing. It is conceivable that a HIF-2α-directed therapy might be a novel approach to prevention and treatment of reflux esophagitis.

Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block.

The stereoselective oxidation of hydrocarbons is one of the most notable advances in synthetic chemistry over the past fifty years. Inspired by nature, enantioselective dihydroxylations, epoxidations and other oxidations of unsaturated hydrocarbons have been developed. More recently, the catalytic enantioselective allylic carbon-hydrogen oxidation of alkenes has streamlined the production of pharmaceuticals, natural products, fine chemicals and other functional materials. Allylic functionalization provides a direct path to chiral building blocks with a newly formed stereocentre from petrochemical feedstocks while preserving the olefin functionality as a handle for further chemical elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic carbon-hydrogen oxidation of simple alkenes with cyclic or terminal double bonds. However, a general and selective allylic oxidation using the more common internal alkenes remains elusive. Here we report the enantioselective, regioselective and E/Z-selective allylic oxidation of unactivated internal alkenes via a catalytic hetero-ene reaction with a chalcogen-based oxidant. Our method enables non-symmetric internal alkenes to be selectively converted into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the resulting multifunctional chiral building blocks highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be used in the synthesis of complex target molecules.

Catalytic Asymmetric Intermolecular Allylic Functionalization of Unactivated Internal Alkenes.

The asymmetric allylic functionalization of unactivated internal alkenes is an emerging strategy for the conversion of simple unsaturated starting materials into a diverse range of enantioenriched products. This Perspective summarizes the development of reactions wherein a chiral catalyst facilitates the intermolecular stereoselective reaction between an achiral unactivated internal alkene and a reagent.

Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2.

Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2α subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.

Regioselective and Diastereoselective Aminoarylation of 1,3-Dienes.

The 1,4-functionalization of dienes is a synthetically useful strategy for incorporating molecular complexity into a class of simple substrates. We report the aminoarylation of acyclic and cyclic 1,3-dienes via the sequential [4+2] cycloaddition with a sulfurdiimide reagent and copper-catalyzed allylic substitution with Grignard reagents. The regioselective and diastereoselective aminoarylation of unsymmetrical dienes is also presented, which highlights the utility of this method for generating products with multiple functional groups and stereocenters.

Allylic functionalization of unactivated olefins with Grignard reagents.

New advances in the functionalization of unactivated olefins with carbon nucleophiles have provided more efficient and practical approaches to convert inexpensive starting materials into valuable products. Recent examples have been reported with stabilized carbon nucleophiles, tethered carbon nucleophiles, diazoesters, and trifluoromethane donors. A general method for functionalizing olefins with aromatic, aliphatic, and vinyl Grignard reagents was developed. In a one-pot process, olefins are oxidized by a commercially available reagent to allylic electrophiles, which undergo selective copper-catalyzed allylic alkylation with Grignard reagents. Products are formed in high yield and with high regioselectivity. This was utilized to synthesize a series of skipped dienes, a class of compounds that are prevalent in natural products and are difficult to synthesize by known allylic alkylation methods.

Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks.

Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl-alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure-activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 <500 nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC50=164 nM. All of the compounds evaluated were inactive (IC50 >10,000 nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.

Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor.

Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2α-ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.

Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.

The presence of nitrogen atoms in most chiral pharmaceutical drugs has motivated the development of numerous strategies for the synthesis of enantioenriched amines. Current methods are based on the multi-step transformation of pre-functionalized allylic electrophiles into chiral allylic amines. The enantioselective allylic amination of unactivated olefins represents a more direct and attractive strategy. We report the enantioselective synthesis of ent-sitagliptin via an allylic amination of an unactivated terminal olefin.

Synthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L.

A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure-activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L.