Visible-Light-Induced Organophotocatalytic Difunctionallization: Open-Air Hydroxysulfurization of Aryl Alkenes with Aryl Thiols.

Herein, we report a regioselective visible-light-induced organophotoredox catalytic difunctionalization method to prepare ß-hydroxysulfides using aryl alkenes and aryl thiols as substrates. The reaction provides a wide substrate scope of aryl alkenes (from simple styrene to complex bioactive compounds) and aryl thiols (from diverse heteroaromatic thiols to nonheteroaromatic thiols) (total 45 examples, up to 88% yield). Based on the combined experimental and computational studies, we demonstrate that in situ generated hydroperoxyl radicals from O2 in air react with benzylic radicals, which restrains the reaction between benzylic radicals and the acidic form of thiols in a classical thiol-ene radical reaction. We show that difunctionalization is possible due to the choice of bases, diluted substrate concentrations, increment in catalyst loading, and selection of suitable aryl thiols under aerobic conditions. Considering the biological importance of heteroaromatic thiols and the lack of methods to install them, our approach offers a platform to derive various ß-hydroxysulfides that contain aromatic elements.

Enhanced anti-angiogenic activity of novel melatonin-like agents.

Hypoxia-inducible factor-1 (HIF-1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N-acetyl-5-methopxytryptamine, is produced naturally by the pineal gland and has anti-angiogenic effects in cancer through its ability to modulate HIF-1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half-life. Here, we synthesized melatonin-like molecules with enhanced HIF-1α targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, N-butyryl-5-methoxytryptamine (NB-5-MT) showed the most potent HIF-1α targeting activity. This molecule was able to (a) reduce the expression of HIF-1α at the protein level, (b) reduce the transcription of HIF-1α target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB-5-MT showed improved anti-angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB-5-MT is thus a promising lead for the future development of anticancer compounds with HIF-1α targeting activity. Given that HIF-1α is overexpressed in the majority of human cancers, the melatonin derivative NB-5-MT could represent a novel potent therapeutic agent for cancer.

Single-Step Approach toward Nitrones via Pyridinium Ylides: The DMAP-Catalyzed Reaction of Benzyl Halides with Nitrosoarenes.

A single-step approach is reported for the preparation of nitrones from benzyl halides and nitrosoarenes via pyridinium ylides, utilizing 4-dimethylaminopyridine (DMAP) catalyst and mild reaction conditions (Li2CO3, dimethylacetamide, and room temperature). The reaction provides both keto- and aldonitrones in high yields with a wide scope for benzyl halides and nitrosoarenes. In the same reaction system, 2-methyl-2-nitrosopropane, which does not have an aryl group, also affords the corresponding N-tert-butyl nitrones from primary benzyl bromides that have an electron-withdrawing group. As an application of the reaction, methyl 2-bromo-2-phenylacetate was used to prepare the corresponding isoxazolidine by a sequential one-pot synthesis.

4-Dimethylaminopyridine-Catalyzed Metal-Free Aerobic Oxidation of Aryl α-Halo Esters to Aryl α-Keto Esters.

A novel, metal-free aerobic oxidation method is described. 4-Dimethylaminopyridine (DMAP) successfully catalyzed the oxidation of aryl α-halo esters to corresponding aryl α-keto esters (up to 95% yield) under mild reaction conditions (Li2CO3, dimethylacetamide, air, and room temperature). A mechanism has been proposed where the oxidation proceeds through a [3 + 2] cycloaddition between O2 in an air atmosphere and pyridinium ylides. The ylides are supposedly generated from aryl α-halo esters and DMAP in the presence of carbonates. Based on the plausible mechanism, the potential of DMAP as a catalyst in oxidation reactions was extended.

Highly Selective Synthesis of Hydrazoarenes from Nitroarenes via Polystyrene-Supported Au-Nanoparticle-Catalyzed Reduction: Application to Azoarenes, Aminoarenes, and 4,4'-Diaminobiaryls.

A selective synthesis of hydrazoarene from nitroarene and its application are reported. Using polystyrene (PS) resins as solid supports for Au nanoparticles (AuNPs), polystyrene-supported Au nanoparticles (AuNPs@PS) were synthesized and characterized. In the presence of AuNPs@PS (1.0 mol %) as a catalyst, nitroarenes afforded corresponding hydrazoarenes (up to 99%) with high selectivity (up to 100%) under mild reaction conditions (NaBH4, 50% aq. EtOH, and room temperature). Depending on the reaction conditions (the amount of NaBH4, the substituent of nitroarenes, and the sequential addition of HCl), nitroarenes were converted to corresponding azoarenes (up to 95%), aminoarenes (up to 99%), and 4,4'-diaminobiaryls (up to 99%). Our easily recyclable catalytic system using a solid-phase reaction vessel provides an attractive synthetic method in an eco-friendly and sustainable manner.

A synthetic Nitraria alkaloid, isonitramine protects pancreatic ß-cell and attenuates postprandial hyperglycemia.

OBJECTIVE: The extracts of Nitraria genus are composed of Nitraria alkaloids and have been used traditionally as a hypoglycemic medicine. However, the efficacy and precise mechanism of Nitraria alkaloids remain largely unknown. METHODS: Previously, we reported the total synthesis of (+)-isonitramine, one of Nitraria alkaloids. In this study, we investigated the anti-diabetic potential of isonitramine in diabetes mellitus and its underlying molecular mechanism in carbohydrate catabolism in vitro and in vivo. RESULTS: Isonitramine exerted significant inhibitory effect on α-glucosidases but not α-amylase in vitro. In zebrafish, isonitramine alleviated the streptozotocin (STZ)-induced postprandial hyperglycemia and protected the pancreatic damages against alloxan-induced oxidative stress in vivo. Also, isonitramine induced insulin without any toxicities and downregulated phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first committed step in gluconeogenesis. CONCLUSION: Taken together, isonitramine inhibited α-glucosidase activity and PEPCK expression, while increased insulin expression, resulting in attenuating the postprandial hyperglycemia. Also, isonitramine protected the pancreas from ROS-mediated toxicities. Therefore, isonitramine may be a new drug candidate for the treatment of diabetes mellitus.