Rapid sp3-Enriched Scaffold Generation via a Selective Aziridine Amide Ring-Opening Reaction.

Sp3-enriched small molecules play a critical role in developing drug candidates. While designing analogues with greater sp3 character, a methodology utilizing a less explored cyclic-aziridine amide ring-opening reaction to generate sp3-enriched scaffolds has been developed and reported. This methodology enables rapid access to substructures with higher fsp3 values, attracting greater attention within the past few decades. The reaction exhibits a wide reaction scope, featuring a highly sterically hindered phenolic ether, thiophenolic ethers, protected aniline formations, and aliphatic/heteroaromatic ring-containing aziridine amides as substrates. Additionally, this reaction provides access to congested tertiary ether formations through regioselective transformation, applicable to an extensive range of drug discovery targets, construction of complex small molecules, and natural product syntheses. The scaffolds developed show improved physicochemical properties.

Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor.

In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure-activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.

Evaluation of Synthetic Cytochrome P450-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu5 Allosteric Ligands.

Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP450s can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity. We required a higher-throughput approach to assess in vivo metabolic molecular switches, and we turned to a "synthetic liver", a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins) to rapidly survey a broad panel of synthetic CYP450s' ability to oxidize/"metabolize" an mGlu5 PAM (VU0403602) known to undergo an in vivo CYP450-mediated molecular switch. While the synthetic CYP450s did generate a number of oxidative "metabolites" at known "hot spots", several of which proved to be pure mGlu5 PAMs comparable in potency to the parent, the known CYP450-mediated in vivo ago-PAM metabolite, namely, VU0453103, was not formed. Thus, this technology platform has potential to identify hot spots for oxidative metabolism and produce active metabolites of small-molecule ligands in a high-throughput, scalable manner.

DARK Classics in Chemical Neuroscience: Opium, a Historical Perspective.

Opium is the latex from the opium poppy Papaver somniferum L., which humankind has utilized since ancient Mesopotamia all the way to modern times. Opium used to be surrounded in divine mystery or magic-like abilities and was given to cure a wide variety of diseases until its analgesic, antitussive, and antidiarrheal properties were understood, the resulting alkaloids were isolated, and their structure and properties unmasked. Opium went from being sold in any store front in the form of pills or tinctures with no prescription necessary for purchase or smoked in an opium den down the street, to then bringing about consumer advocacy and the right to know what is in a medication. Legislation was created to limit the prescribing and selling of medications to doctors and pharmacists as well as outlawing opium dens and smoking opium. This review focuses primarily on the uses of opium throughout history, the isolation of the principle alkaloids, and their structure elucidation.

Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium.

Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound. Along with 5, two other new and branched compounds 6 and 7 were synthesized as well. Accompanying the five quinolones were two known compounds 2 and 3 which are inactive against Plasmodium falciparum. The isolation, structure elucidation, total synthesis, and biological evaluation of these compounds are discussed in this article.

New potently bioactive alkaloids from Crinum erubescens.

Antimalarial bioassay-guided fractionation of the swamp lily Crinum erubescens led to the isolation of four compounds with potent antiplasmodial activity. Compounds 1 and 2 were determined from their spectroscopic data to be the known pesticidal compound cripowellin A and the known pesticidal and antiproliferative compound cripowellin B. 1D and 2D-NMR techniques were used to determine the identities of 3 and 4 as the new compounds cripowellin C and D. A fifth compound was identified as the known alkaloid hippadine, which was inactive against Plasmodium falciparum. The antiplasmodial IC50 values of compounds 1-4 were determined to be 30±2, 180±20, 26±2, and 260±20nM, respectively, and their antiproliferative IC50 values against the A2780 human ovarian cancer cell line were 11.1±0.4, 16.4±0.1, 25±2, and 28±1nM.

A Synthetic Butenolide Diterpene is now a Natural Product Isolated from Metaporana sericosepala, a Plant from the Madagascar Dry Forest.

Antiproliferative bioassay-guided fractionation of the ethanolic extract of the endemic Madagascan plant Metaporana sericosepala led to the first natural product isolation of a butenolide diterpene, which was synthesized during an anti-inflammatory study in 1988. The structure of the compound was elucidated as 3-homofarnesyl-4-hydroxybutenolide (1) by analysis of its spectroscopic data, including 1D- and 2D-NMR data and chemical evidence. The once synthetic compound can now also be considered as a natural product. Compound 1 had modest antiproliferative activity towards the A2780 ovarian cancer cell line,with an IC50 value of 8 µM.