Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model.

GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gα and Gα heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-ΚB.

Rapid Access to the Structural Core of Aflavinines via Stereoselective Tandem Intramolecular Diels-Alder Cycloaddition Controlled by the Allylic 1,3-Strain.

An expedient route to access the functionalized structural core of aflavinines has been developed starting from three readily available fragments over 12 steps in 29.1% overall yield without using any transition metal catalysis. The key feature of this approach is a tandem intramolecular Diels-Alder cycloaddition to complete the hexacyclic framework with the correct stereochemistry and all the requisite structural elements in place to achieve the total synthesis of aflavinine and its congeners.

Facile ring opening reaction of oxazolone enables efficient amidation for aminoisobutyric acid.

4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examples have been reported to support the utility of other oxazolones in amidation. AIB is an important and strategical synthon in medicinal chemistry but the peptide bond formation of the N-protected urethane derivatives of AIB is known to be often unproductive due to the rapid formation of the stable 4,4-dimethyloxazolone via an intramolecular cyclization. We discovered that the 4,4-dimethyloxazolone of an AIB urethane is in fact an excellent electrophile that enables efficient amidation even with weakly reactive nucleophiles.

An efficient synthetic protocol for amide derivatives of Boc-2-aminoisobutyrate.

Aminoisobutyric acid (AIB) is an important building block widely incorporated by medicinal chemists in molecular design. Owing to the steric challenge, elaborating AIB's carboxylic acid using conventional amidation protocols is often problematic. We discovered that an amidation protocol utilizing methyl Boc-aminoisobutyrate and magnesium amidates of various reactivities produces the corresponding amide derivatives in good to excellent yields.

Selective novel inverse agonists for human GPR43 augment GLP-1 secretion.

GPR43/Free Fatty Acid Receptor 2 (FFAR2) is known to be activated by short-chain fatty acids and be coupled to Gi and Gq family of heterotrimeric G proteins. GPR43 is mainly expressed in neutrophils, adipocytes and enteroendocrine cells, implicated to be involved in inflammation, obesity and type 2 diabetes. However, several groups have reported the contradictory data about the physiological functions of GPR43, so that its roles in vivo remain unclear.

Concise Synthesis of Broussonone A.

A concise and expeditious approach to the total synthesis of broussonone A, a p-quinol natural compound, has been developed. The key features of the synthesis include the Grubbs II catalyst mediated cross metathesis of two aromatic subunits, and a chemoselective oxidative dearomatizationin the presence of two phenol moieties. Especially, optimization associated with the CM reaction of ortho-alkoxystyrenes was also studied, which are known to be ineffective for Ru-catalyzed metathesis reactions under conventional reaction conditions because ortho-alkoxy group could coordinate to the ruthenium center, resulting in the potential complication of catalyst inhibition.

Discovery of a novel class of diacylglycerol acyltransferase 2 inhibitors with a 1H-pyrrolo[2,3-b]pyridine core.

Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TG) synthesis, is a key enzyme associated with hepatic steatosis and insulin resistance. Here, using an in vitro screen of 20000 molecules, we identified a class of compounds with a substituted 1H-pyrrolo[2,3-b]pyridine core which proved to be potent and selective inhibitors of human DGAT2. Of these compounds, H2-003 and -005 exhibited a considerable reduction in TG biosynthesis in HepG2 hepatic cells and 3T3-L1 preadipose cells.

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models.

4-O-methylhonokiol (MH) is known to inhibit inflammation by partially understood mechanisms. Here, the anti-inflammatory mechanisms of MH were examined using enzymatic, cellular, and animal assays. In enzymatic assays, MH inhibited COX-2 activity with an IC50 of 0.

Synthesis of xanthone derivatives based on α-mangostin and their biological evaluation for anti-cancer agents.

A xanthone-derived natural product, α-mangostin is isolated from various parts of the mangosteen, Garcinia mangostana L. (Clusiaceae), a well-known tropical fruit. Novel xanthone derivatives based on α-mangostin were synthesized and evaluated as anti-cancer agents by cytotoxicity activity screening using 5 human cancer cell lines.

Perspectives on the therapeutic potential of short-chain fatty acid receptors.

There is rapidly growing interest in the human microbiome because of its implication in metabolic disorders and inflammatory diseases. Consequently, understanding the biology of short chain fatty acids and their receptors has become very important for identifying novel therapeutic avenues. GPR41 and GPR43 have been recognized as the cognate receptors for SCFAs and their roles in metabolism and inflammation have drawn much attention in recent years.

β-Arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor-κB.

G-protein coupled receptor 43 (GPR43) serves as a receptor for short-chain fatty acids (SCFAs), implicated in neutrophil migration and inflammatory cytokine production. However, the intracellular signaling pathway mediating GPR43 signaling remains unclear. Here, we show that β-arrestin 2 mediates the internalization of GPR43 by agonist.

Identification and validation of a selective small molecule inhibitor targeting the diacylglycerol acyltransferase 2 activity.

Diacylglycerol acyltransferase 2 (DGAT2) is one of two distinct DGAT enzymes that catalyze the last step in triacylglycerol (TG) synthesis. Findings from previous studies suggest that inhibition of DGAT2 is a promising strategy for the treatment of hepatic steatosis and insulin resistance. Here, we identified compound 122 as a potent and selective inhibitor of human DGAT2, which appeared to act competitively against oleoyl-CoA in vitro.

A novel therapeutic target, GPR43; where it stands in drug discovery.

With growing interest in human microbiome for its implication in metabolic disorders, inflammatory diseases, immune disorders and so forth, understanding the biology at the interface of the gut flora and the host becomes very important for identifying novel therapeutic avenues. GPR43 has been deorphanized and the metabolites of microbiome, such as short-chain fatty acids, serve as its natural ligands. There are numerous reports that GPR43 might be a crucial link to the novel therapies for the unmet medical needs and many drug discovery organizations are making their moves in response.

Design and synthesis of 4-O-methylhonokiol analogs as inhibitors of cyclooxygenase-2 (COX-2) and PGF₁ production.

A series of novel 4-O-methylhonokiol analogs were synthesized in light of revealing structure-activity relationship for inhibitory effect of COX-2 enzyme. The key strategy of the molecular design was oriented towards modification of the potential metabolic soft spots (e.g.

Synthesis of grandisol, the sexual attracting insect pheromone.

In this issue, Suh's group reported a new formal total synthesis of (±)-grandisol featuring a palladium-catalyzed 4-exo-trig cyclization. Grandisol's interesting cyclobutane structure has been a popular test model for various cyclization methods over the years. This report summarizes Suh's formal synthesis of grandisol along with a concise review of the four-membered ring cyclization strategies employed in the synthesis of grandisol.

Syntheses of sulfur and selenium analogues of pachastrissamine via double displacements of cyclic sulfate.

Bioisosteric analogues of pachastrissamine that contain sulfur and selenium atoms replacing the oxygen in the ring system, were efficiently prepared from a cyclic sulfate intermediate by sequential intermolecular and intramolecular S(N)2 displacement reactions of the dianions. The analogues exhibited cytotoxicities comparable to that of pachastrissamine.

Synthesis and anti-platelet activity of obovatol derivatives.

Obovatol derivatives were synthesized and evaluated for anti-platelet activity. Three derivatives (1, 2, 4i) displayed equipotent activity to obovatol in arachidonic acid-induced platelet aggregation. An initial SAR study revealed that the introduction of alkoxy group in B ring could enhance inhibitory activity.

Efficient and convenient preparation of 3-aryl-2,2-dimethylpropanoates via Negishi coupling.

An efficient and convenient Negishi coupling protocol was developed for the preparation of 3-aryl-2,2-dimethylpropanoates providing easy access to key pharmaceutical intermediates that often require multi-step synthesis using conventional enolate chemistry.

Synthesis of pachastrissamine from phytosphingosine: a comparison of cyclic sulfate vs an epoxide intermediate in cyclization.

[reaction: see text] The syntheses of the cytotoxic natural product pachastrissamine and its unnatural 4-epi-congener were accomplished starting from a natural phytosphingosine. The relatively unstrained cyclic sulfate intermediate smoothly underwent the 5-endo cyclization to yield the 2,3,4-trisubstituted tetrahydrofuran ring system of pachastrissamine. The corresponding epoxy alcohol afforded the 4-epi-congener via a tosylate-mediated double inversion process.

Catalytic enantioselective conjugate addition of trimethylsilylacetylene to 2-cyclohexen-1-one.

[reaction: see text] The first example of catalytic asymmetric conjugate addition of TMS-acetylene to a cyclic alpha,beta-enone has been accomplished using the chiral bisoxazoline-Ni complex 9 as catalyst and dimethylalumino TMS-acetylide and 2-cyclohexen-1-one as reactants.