Pseudocannabinoid H4CBD improves glucose response during advanced metabolic syndrome in OLETF rats independent of increase in insulin signaling proteins.

Cannabidiol (CBD) use has grown exponentially more popular in the last two decades, particularly among older adults (>55 yr), though very little is known about the effects of CBD use during age-associated metabolic dysfunction. In addition, synthetic analogues of CBD have generated great interest because they can offer a chemically pure product, which is free of plant-associated contaminants. To assess the effects of a synthetic analogue of CBD (H4CBD) on advanced metabolic dysfunction, a cohort of 41-wk-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered 200 mg H4CBD/kg by oral gavage for 4 wk. Animals were fed ad libitum and monitored alongside vehicle-treated OLETF and Long-Evans Tokushima Otsuka (LETO) rats, the lean-strain controls. An oral glucose-tolerance test (oGTT) was performed after 4 wk of treatment. When compared with vehicle-treated, OLETF rats, H4CBD decreased body mass (BM) by 15%, which was attributed to a significant loss in abdominal fat. H4CBD reduced glucose response (AUCglucose) by 29% (P < 0.001) and insulin resistance index (IRI) by 25% (P < 0.05) compared with OLETF rats. However, H4CBD did not statically reduce fasting blood glucose or plasma insulin, despite compensatory increases in skeletal muscle native insulin receptor (IR) protein expression (54%; P < 0.05). H4CBD reduced circulating adiponectin (40%; P < 0.05) and leptin (47%; P < 0.05) and increased ghrelin (75%; P < 0.01) compared with OLETF. Taken together, a chronic, high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of the profound loss of visceral adiposity.NEW & NOTEWORTHY Cannabis product use has grown in the last two decades despite the lack of research on Cannabidiol (CBD)-mediated effects on metabolism. Here, we provide seminal data on CBD effects during age-associated metabolic dysfunction. We gave 41-wk-old OLETF rats 200 mg H4CBD/kg by mouth for 4 wk and noted a high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of loss of visceral adiposity.

Confirmation of the Revised Structure of Samoquasine A and a Proposed Structural Revision of Cherimoline.

The identity of the natural product samoquasine A has remained obscure since its isolation from custard apple seeds in 2000. One of the proposed structures, benzo[ f]phthalazin-4(3 H)-one, was prepared in two steps by regioselective ortho-lithiation/formylation of N, N-diisopropyl-2-naphthylamide, followed by cyclization with hydrazine, but was shown to be different from the natural product. Perlolidine, another candidate structure, was synthesized by a novel route involving a ß-selective Heck reaction of butyl vinyl ether. Both perlolidine and samoquasine A are converted by trimethylsilyldiazomethane into the same N-methyl derivative. In addition, the 13C NMR spectra of perlolidine and another structurally mis-assigned natural product, cherimoline, are almost identical. Thus, both samoquasine A and cherimoline are actually perlolidine.

Stereoselective formation of quaternary stereogenic centers via alkylation of α-substituted malonate-imidazolidinones.

A new stereoselective alkylation methodology is presented for formation of chiral, nonracemic quaternary centers via a chiral auxiliary protocol involving α-alkylated malonate imidazolidinones. Based on two X-ray structures of quaternized products, the diastereoselectivity observed may be rationalized via a transition-state involving an s-transC-N conformation of the C-N bond of the auxiliary, with the metal cation (K(+)) chelated into the malonate six-membered hole as a Z-enolate. A deprotection protocol involving ethanethiolate exchange of the imide to the corresponding thioester, followed by a standard Fukuyama reduction and a borohydride reduction, furnishes α,α'-quaternized ß-hydroxypropionates in high ee overall.

Toward the Total Synthesis of Alpkinidine: Synthesis of Haloquinone CE Ring System Synthons and Attempted Nucleophilic Bisannulation.

Model chemistry involving the bisannulation of 2,3-dichloro-1,4-naphthoquinone with the ester enolate derived from ethyl o-nitrophenylacetic acid, which rapid assembled the ABCD ring system of a pentacyclic pyrroloacridine, has been applied to the attempted synthesis of the marine natural product alpkinidine. The reaction of ethyl o-nitrophenylacetic acid with 6,7-dichloro-2-methylisoquinoline-1,5,8(2H)-trione, required to extend the model strategy to alpkinidine, was unfruitful, giving only complex mixtures. Efforts to direct the regiochemistry of the key Michael substitution step using 6-bromo-2-methylisoquinoline-1,5,8(2H)-trione afforded an adduct sharing the complete carbon skeleton of alpkinidine, but this could not be elaborated to the natural product.

Toward the Total Synthesis of Alpkinidine: Michael Addition to Isoquinolinetrione CE Ring-System Synthons.

Strategies toward the total synthesis of the marine pyrroloacridine alkaloid alpkinidine have been explored, focusing on linking quinonoid CE ring-system synthons with the A ring, followed by condensation to form the B and D rings. The key Michael addition of the ester enolate derived from ethyl o-nitrophenylacetate to 2-methylisoquinoline-1,5,8(2H)-trione proceeded with the wrong regiochemistry. This issue was addressed by incorporating the D-ring nitrogen at an earlier stage, affording advanced intermediates possessing the complete carbon skeleton of alpkinidine. However, attempts to close the D and B rings were unsuccessful. The novel isoquinolinetriones reported here, and the general strategy of connecting CE- and A-ring synthons through Michael additions, may be useful in the synthesis of other pyrrolo- and pyridoacridines, in particular the anticancer lead neoamphimedine and analogues.

Interrupted Nazarov cyclization on silica gel.

Exposure of a mixture of propargyl vinyl ketone and a nucleophilic primary or secondary amine to activated dry silica gel in the absence of solvent leads to a cascade of reactions that results in the formation of an aminocyclopentenone. The reaction with triethylamine leads to a cross-conjugated cyclopentadienone.