A Proline-Squaraine Ligand Framework (Pro-SqEB) for Stereoselective Rhodium(II)-Catalyzed Cyclopropanations.

A proline-squaraine ligand (Pro-SqEB) that demonstrates high levels of stereoselectivity in olefin cyclopropanations when anchored to a Rh2II scaffold is introduced. High yields and enantioselectivities were achieved in the cyclopropanation of alkenes with diazo compounds in the presence of Rh2(Pro-SqEB)4. Notably, the unique electronic and steric design of this catalyst enabled the use of polar solvents that are otherwise incompatible with most RhII complexes.

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System.

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic in vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This in vivo assay substantiated the in vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.

Polyphenols from the sagebrush Artemisia tridentata ssp. tridentata affect the redox state of cultured hepatocytes by direct and indirect mechanisms.

Basin big sagebrush (Artemisia tridentata Nutt. ssp. tridentata (Asteraceae)), is a widespread North American shrub which produces a variety of polyphenolic compounds. Although sagebrush has been used as a traditional remedy by natives and settlers to the region, the polyphenols in Artemisia tridentata ssp. tridentata have not been highly investigated for their bioactive properties. To determine whether these polyphenols affect the intracellular redox state, we measured their ability to neutralize radicals in vitro and in a human liver carcinoma cell line (HepG2), and their effects on intracellular glutathione levels. Extracts from Artemisia tridentata ssp. tridentata decreased the oxidation of 2'7'-dichlorofluorescin in vitro and in cultured cells. Cells treated with polyphenolic extracts showed increased levels of glutathione in a time and dose-dependent manner. Approximately 48 polyphenolic compounds were distinguishable in extracts, by HPLC/UV absorbance detection. Mass spectroscopy was used to identify thirteen compounds as aesculin, aesculetin, apigenin, apigenin-7-O-glucoside, axillarin, casticin, chlorogenic acid, isoscopoletin, kaempferol, luteolin, methyl-axillarin, quercetin, and scopoletin. These results indicate that polyphenols produced in Artemisia tridentata ssp. tridentata affect the redox state of living cells by multiple mechanisms.

Aroyl Isocyanates as 1,4-Dipoles in a Formal [4 + 1]-Cycloaddition Approach toward Oxazolone Construction.

A formal phosphine-mediated [4 + 1]-cycloaddition between a 1,2-dicarbonyl and an aroyl isocyanate to provide oxazolones bearing a disubstituted C5 center is described. By exploiting the carbene-like reactivity of oxyphosphonium enolates as C1 synthons and aroyl isocyanates as formal 1,4-dipoles, oxazolones and spiroooxindole oxazolones are constructed in high yields (39-99%).

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.

The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting. Cancer Res; 77(11); 2844-56. ©2017 AACR.