N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.

Tandem Amination/Oxetane Ring Opening toward Benzomorpholines.

Herein, a tandem approach that allows rapid access to the benzomorpholine scaffold is reported. This operationally simple method allows for valuable heterocycles to be isolated in moderate to high yields. The overall transformation consists of an initial C-N coupling, demonstrated using traditional Ullmann or Buchwald-Hartwig conditions, followed by an in situ oxetane ring opening. A range of functionality is tolerated on the aryl ring, and the cyclization exposes a pendant hydroxymethyl substituent, providing opportunities for further functionalization.

A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters.

A novel strategy employing cyclohexyl spectator ligands in Stille cross-coupling reactions has been developed as a general solution to the long-standing challenge of conducting stereospecific cross-coupling reactions at nitrogen-containing stereocenters. This method enables direct access to enantioenriched products that are difficult (or impossible) to obtain via alternative preparative methods. Selective and predictable transfer of a single secondary alkyl unit can be achieved under reaction conditions that exploit subtle electronic differences between activated and unactivated alkyl units. Through this approach, enantioenriched α-stannylated nitrogen-containing stereocenters undergo Pd-catalyzed arylation and acylation reactions with exceptionally high stereofidelity in all instances investigated. We demonstrate this process by using α-stannylated pyrrolidine, azetidine, and open-chain (benzylic and non-benzylic) nucleophiles in stereospecific reactions. This process will facilitate rapid and reliable access to enantioenriched compounds possessing nitrogen-substituted stereocenters, which constitute ubiquitous structural motifs in biologically active compounds emerging from the drug-discovery process.

Mild Intramolecular Ring Opening of Oxetanes.

Oxetanes have been increasingly used as stable motifs in medicinal chemistry as well as versatile synthetic intermediates. Herein, an intramolecular ring opening of oxetane carboxamides with mild nucleophiles, such as nitrogen heterocycles, is presented. The reaction proceeds under metal-free basic conditions which is highly unusual in ring opening reactions of oxetanes. Amide formation and oxetane ring opening/cyclization in a one-pot approach affords high levels of molecular complexity in a single step from simple, readily available substrates.

Stereospecific Palladium-Catalyzed Acylation of Enantioenriched Alkylcarbastannatranes: A General Alternative to Asymmetric Enolate Reactions.

We report the development of a Pd-catalyzed process for the cross coupling of unactivated primary, secondary, and tertiary alkylcarbastannatrane nucleophiles with acyl electrophiles. Reactions involving optically active alkylcarbastannatranes occur with exceptional stereofidelity and with net retention of absolute configuration. Because the stereochemistry of the resulting products is entirely reagent-controlled, this process may be viewed as a general, alternative approach to the preparation of products typically accessed via asymmetric enolate methodologies. Additionally, we report a new method for the preparation of optically active alkylcarbastannatranes, which should facilitate their future use in stereospecific reactions.

12b-hydroxy-des-D-garcigerin A enhances glucose metabolism in insulin-resistant HepG2 cells via the IRS-1/PI3-K/Akt cell signaling pathway.

HepG2 cells were induced with a high concentration of insulin to establish an insulin-resistant cell model (HepG2/IR). The effect of 12b-hydroxy-des-D-garcigerin A (DGA) on the glucose consumption (GC) of HepG2/IR cells was analyzed with the glucose oxidase/peroxidase assay. The results showed that DGA significantly stimulated GC by enhancing the activity of hexokinase (HK) and pyruvate kinase (PK) in HepG2/IR cells. The cell signaling pathway by which DGA enhances the GC of HepG2/IR cells was explored. The results showed that DGA promoted the expression of insulin receptor (InsR) protein, and stimulated the expression of insulin receptor substrate 1 (IRS-1), phosphatidylinositol-3 kinase (p-PI3-K), and phospho-protein kinase B Serine(473) (p-AKT ser(473)). Therefore, we concluded that DGA improved the insulin-resistance of HepG2/IR cells by inducing the IRS-1/PI3-K/Akt cell signaling pathway. Interestingly, DGA had no effect on the phosphorylation of threonine(172) (Thr(172)) in AMP-activated protein kinase (AMPK).

Configurationally Stable, Enantioenriched Organometallic Nucleophiles in Stereospecific Pd-Catalyzed Cross-Coupling Reactions: An Alternative Approach to Asymmetric Synthesis.

Several research groups have recently developed methods to employ configurationally stable, enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions. By establishing the absolute configuration of a chiral alkyltin or alkylboron nucleophile prior to its use in cross-coupling reactions, new stereogenic centers may be rapidly and reliably generated with preservation of the known initial stereochemistry. While this area of research is still in its infancy, such stereospecific cross-coupling reactions may emerge as simple, general methods to access diverse, optically active products from common enantioenriched organometallic building blocks. This minireview highlights recent progress towards the development of general, stereospecific Pd-catalyzed cross-coupling reactions using configurationally stable organometallic nucleophiles.

Glycoborinine induces apoptosis through mitochondrial pathway in HepG2 cells.

Glycoborinine (GB), a natural carbazole alkaloid isolated from Glycosmis pentaphylla, has been shown to be a potential molecule against cancer cells. In this study, the cell-signaling pathway of its anti-tumor activity was investigated. MTT assay result showed that GB inhibited HepG2 cell proliferation in a dose- and time-dependent manner and 50% inhibiting concentration (IC50) of GB-induced cell death was 39.7 µM for a period of 48 h. GB-induced HepG2 apoptosis was confirmed by Hochest 33258 staining and PI staining. The level of reactive oxygen species (ROS) was measured with H2DCF-DA staining and the change of mitochondrial membrane potential (△Ψ(m)) was analyzed with tetrechloro-tetraethylbenzimidazolcarbocyanine iodide (JC-1) probe. Results showed that GB at 12.5, 25, and 50 µM promoted ROS production. GB induced HepG2 apoptosis through a mitochondrial apoptotic pathway, which was demonstrated by GB-induced increase in the ratio of Bax/Bcl-2, cytochrome C release, the ratio of cleaved caspase-3/procaspase-3, and the ratio of cleaved poly ADP-ribose polymerase (cleaved PARP)/poly ADP-ribose polymerase (PARP). To summarize, this study demonstrated that GB could induce HepG2 apoptosis through the mitochondrial-dependent pathway, which might provide a promising approach to cure liver cancer with GB.

Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides.

The development of transition metal-catalysed cross-coupling reactions has greatly influenced the manner in which the synthesis of complex organic molecules is approached. A wide variety of methods are now available for the formation of C(sp(2))-C(sp(2)) bonds, and more recent work has focused on the use of C(sp(3)) electrophiles and nucleophiles. The use of secondary and tertiary alkyl nucleophiles in cross-coupling reactions remains a challenge because of the propensity of these alkyl groups to isomerize under the reaction conditions. Here, we report the development of a general Pd-catalysed process for the stereoretentive cross-coupling of secondary alkyl azastannatrane nucleophiles with aryl chlorides, bromides, iodides and triflates. Coupling partners with a wide range of electronic characteristics are well tolerated. The reaction occurs with minimal isomerization of the secondary alkyltin nucleophile, and with retention of absolute configuration. This process constitutes the first general method to use secondary alkyltin reagents in cross-coupling reactions.

Palladium-catalyzed borylation of primary alkyl bromides.

A mild Pd-catalyzed process for the borylation of alkyl bromides has been developed using bis(pinacolato)diboron as a boron source. This process accommodates the use of a wide range of functional groups on the alkyl bromide substrate. Primary bromides react with complete selectivity in the presence of a secondary bromide. The generality of this approach is demonstrated by its extension to the use of alkyl iodides and alkyl tosylates, as well as borylation reactions employing bis(neopentyl glycolato)diboron as the boron source.

Nickel-catalyzed Kumada cross-coupling reactions of tertiary alkylmagnesium halides and aryl bromides/triflates.

We report a Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides. This process is extremely general for a wide range of electrophiles and generally occurs with a ratio of retention to isomerization >30:1. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component.

Efficiency of slightly acidic electrolyzed water for inactivation of Salmonella enteritidis and its contaminated shell eggs.

The efficiency of slightly acidic electrolyzed water (SAEW) at different temperatures (4, 20 and 45 degrees C) for inactivation of Salmonella enteritidis and it on the surface of shell eggs was evaluated. The bactericidal activity of SAEW, sodium hypochlorite solution (NaClO) and acidic electrolyzed water (AEW) to inactivate S. enteritidis was also compared. SAEW with a pH value of 6.0-6.5 used was generated by the electrolysis of a dilute hydrochloric acid (2.4 mM) in a chamber without a membrane. Although the pH value of SAEW was greatly higher than that of AEW (pH2.6-2.7), SAEW had a comparative powerful bactericidal activity at the same available chlorine concentrations. The efficiency of SAEW for inactivation of pure S. enteritidis cultures increased with increasing the available chlorine concentration and treatment time at the three different temperatures. The S. enteritidis counts decreased to less than 1.0 log(10) CFU/ml at available chlorine of 2 mg/l and 100% inactivation (reduction of 8.2 log(10) CFU/ml) was resulted in using SAEW with available chlorine more than 4 mg/l at 4, 20 and 45 degrees C after 2 min treatment, whereas no reduction was observed in the control samples. Moreover, SAEW was also effective for inactivating the S. enteritidis inoculated on the surface of shell eggs. A reduction of 6.5 log(10) CFU/g of S. enteritidis on shell eggs was achieved by SAEW containing 15 mg/l available chlorine for 3 min, but only a reduction of 0.9-1.2 log(10) CFU/g for the control samples. No survival of S. enteritidis was recovered in waste wash SAEW after treatment. The findings of this study indicate that SAEW may be a promising disinfectant agent for the shell egg washing processing without environmental pollution.