Odd-even effects in charge transport across self-assembled monolayers

This paper compares charge transport across self-assembled monolayers (SAMs) of n-alkanethiols containing odd and even numbers of methylenes. Ultraflat template-stripped silver (Ag(TS)) surfaces support the SAMs, while top electrodes of eutectic gallium-indium (EGaIn) contact the SAMs to form metal/SAM//oxide/EGaIn junctions. The EGaIn spontaneously reacts with ambient oxygen to form a thin (～1 nm) oxide layer. This oxide layer enables EGaIn to maintain a stable, conical shape (convenient for forming microcontacts to SAMs) while retaining the ability to deform and flow upon contacting a hard surface. Conical electrodes of EGaIn conform (at least partially) to SAMs and generate high yields of working junctions. Ga(2)O(3)/EGaIn top electrodes enable the collection of statistically significant numbers of data in convenient periods of time. The observed difference in charge transport between n-alkanethiols with odd and even numbers of methylenes--the "odd-even effect"--is statistically discernible using these junctions and demonstrates that this technique is sensitive to small differences in the structure and properties of the SAM. Alkanethiols with an even number of methylenes exhibit the expected exponential decrease in current density, J, with increasing chain length, as do alkanethiols with an odd number of methylenes. This trend disappears, however, when the two data sets are analyzed together: alkanethiols with an even number of methylenes typically show higher J than homologous alkanethiols with an odd number of methylenes. The precision of the present measurements and the statistical power of the present analysis are only sufficient to identify, with statistical confidence, the difference between an odd and even number of methylenes with respect to J, but not with respect to the tunneling decay constant, β, or the pre-exponential factor, J(0). This paper includes a discussion of the possible origins of the odd-even effect but does not endorse a single explanation.     

Inhibition of phospholipase D2 induces autophagy in colorectal cancer cells

Autophagy is a conserved lysosomal self-digestion process used for the breakdown of long-lived proteins and damaged organelles, and it is associated with a number of pathological processes, including cancer. Phospholipase D (PLD) isozymes are dysregulated in various cancers. Recently, we reported that PLD1 is a new regulator of autophagy and is a potential target for cancer therapy. Here, we investigated whether PLD2 is involved in the regulation of autophagy. A PLD2-specific inhibitor and siRNA directed against PLD2 were used to treat HT29 and HCT116 colorectal cancer cells, and both inhibition and genetic knockdown of PLD2 in these cells significantly induced autophagy, as demonstrated by the visualization of light chain 3 (LC3) puncta and autophagic vacuoles as well as by determining the LC3-II protein level. Furthermore, PLD2 inhibition promoted autophagic flux via the canonical Atg5-, Atg7- and AMPK-Ulk1-mediated pathways. Taken together, these results suggest that PLD2 might have a role in autophagy and that its inhibition might provide a new therapeutic basis for targeting autophagy.     

Ion transport in polymerized lyotropic liquid crystals containing ionic liquid

In this work, we investigate the effect of morphology and segmental dynamics on ion transport in polymerized lyotropic liquid crystals (polyLLCs) containing 1-butyl-3-methylimidazolium tetrafluoroborate as ionic liquid (IL). We demonstrate that two important factors, which affect ion conduction in polyLLCs, are grain size and chain density at the interface. The polyLLC with large grain size (70 nm) shows significant reduction in ion conductivity (one order of magnitude) compared to its homopolymer/IL mixture. However, the polyLLC with small grain size (20 nm) has little difference in ion conductivity compared to its homopolymer/IL mixture. It is observed that decreasing the chain density enhances the interaction of IL with polymer chains and consequently slows the relaxation of polymer chains. In addition, comparing the dynamics of polymer chains in mixtures of homopolymer/IL and templated LLC mesophases shows that the confinement in LLC structure prolongs the relaxation of polymer chains.     

Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I,and the Chemotherapeutic Drug,Temozolomide against Glioblastoma Tumorspheres

Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.     

Synthesis of 3-substituted-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

The reaction of the Baylis-Hillman adducts 1b-f derived from o-nitrobenzaldehydes in trifluoroacetic acid in the presence of triflic acid (0.2 equiv.) afforded 3-substituted-4-hydroxyquinoline N-oxides 2b-e and 2a in good to moderate yields. The reaction mechanism was evidenced by the experiment with 1f, the Baylis-Hillman adduct of 2-nitrobenzaldehyde N-tosylimine, as the one involving N-hydroxyisoxazoline as the key intermediate.     

Synthesis of 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitriles and -6-carboxylic acid esters

Dieckmann ring closure reactions of 4-[(2-cyanoethyl)substituted amino]-2-phenyl-5-pyrimidinecarboxylates (Ha-f) afforded several 5,6,7,8-tetrahydro-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitriles (IIIa-f). The open-chain intermediates (IIa-f) were prepared by dechloroamination of 5-carbethoxy-4-chloro-2-phenylpyrimidine (1a) with several 3-substituted amino- propionitriles. Alkylation of the sodium salt of 5,6,7,8-tetrahydro-8-methyl-5-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6- carbonitrile (IIIa) with methyl iodide in DMF resulted in methylation at C-6 to afford IV. Tosylation of IIIa in pyridine gave the corresponding tosyl ester (V) of the enolic form. Oxidative dehydrogenation at the 6,7-position resulted when IIIa reacted with thionyl chloride, affording 5,8-dihydro-8-methyl-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitrile (VII). Dechloroamination of la or 5-carbethoxy-4-chloro-2-methylthiopyrimidine (Ib) with ethyl 3-ethylaminopropionate followed by Dieckmann cyclization of the resulting open-chain intermediates gave the corresponding ethyl 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates IX'a and IX'b, respectively. These exist predominately in the enol form and undergo alkylation and oxidation reactions similar to IIIa.     

Thieno[2,3-d]pyrimidines. I. A new method for the preparation of esters and amides of thieno[2,3-d] pyrimidine-6-carboxylic acids

A novel method for the preparation of esters and amides of thieno[2,3-d]pyrimidine-6-carb-oxylic acids was described. A typical example was the direct formation of ethyl 5-amino-2-methylthiothieno[2,3-d]pyrimidine-6-earboxylate(IIIa) from 4-chloro-2-methylthio-5-pyrimidine-carbonitrile (Ia) and ethyl mercaptoacetate in refluxing ethanol containing sodium carbonate. Displacement of the methylthio group in IIIa by various amines gave the corresponding amino derivatives. The reactions of IIIa and related compounds with acetylating agents such as acetic anhydride or chloroacetyl chloride gave various products. Treatment of 5-carbethoxy-4-chloro-2-phenylpyrimidine(IV) with methyl mercaptoacetate afforded the dechloro intermediate diester Va, which cyclized on reaction with sodium ethoxide to form methyl 5-hydroxy-2-phenylthieno-[2,3-d]pyrimidine-6-carboxylate (Vla). The synthesis was expanded to include the preparation of various new 2,4,5-trisubstituted thieno[2,3-d]pyrimidine-6-carboxylic acid esters and amides (Charts I-V).