Noteworthy Chemistry

August 6, 2012

Chain-growth polymerization forms hyperbranched polyalkynes. Alkyne polymers with hyperbranched structures have unique electronic, optical, and photonic properties. The 3-D, dendrimer-like structures also have low melt and solution viscosities, good solubilities, and abundant reactive sites.

Polymerization processes for hyperbranched polyalkynes currently use coupling or addition reactions of alkyne triple bonds. Z. Dong and Z. Ye* of Laurentian University (Sudbury, ON) developed a chain-growth polymerization method for synthesizing hyperbranched poly(phenylacetylene)s (HBPPAs, 3) in which phenylacetylene (1) and diynes (2; R = alkylidene or arylidene) are copolymerized. The reaction uses an in situ–generated cationic Pd(II) catalyst.

In the polymerization process, diynes act as difunctional comonomers and generate desirable branch-on-branch topologies. The authors produced a series of HBPPAs with tunable degrees of branching and molecular weights from commercially available alkyne monomers under mild reaction conditions.

Because the HBPPAs contain multiple alkyne substituents, they can be used as building blocks for synthesizing core–shell star copolymers with HBPPA cores and multiple polystyrene arms (4). The arms are attached by a copper-catalyzed click reaction with azide-terminated polystyrene chains. (Macromolecules 2012, 45, 5020−5031; Ben Zhong Tang)

Speed up a biocatalytic oxidation process. Amino acids can be deracemized by selectively oxidizing the D-enantiomer with a D-amino acid oxidase and oxygen. Under batch conditions, the reaction time is very scale-dependent: ≈4 h on a 250-mL scale, 24 h on a 1-L scale, and >28 h on a 4-L scale. The scale dependence arises because it is increasingly difficult to get enough oxygen into the reaction mixture to “feed” the reaction.

G. Gasparini and coauthors at AM Technology (Cheshire), Ingenza (Roslin), and C-Tech Innovation (Chester, all in UK) found that using a continuous Coflore ATR reactor solves the problem. The reaction is complete in 8 h on a 1-L scale and in almost the same time on a 10-L scale. (Org. Process Res. Dev. 2012, 16, 1013–1016; Will Watson)

Hydroxybenzoic acids are potential dyslipidemia treatments. Dyslipidemia, or more specifically, hyperlipidemia, is a condition in which the blood contains higher than normal lipid levels. It can lead to the increase of low-density lipoproteins (LDL, “bad cholesterol”) and the decrease of high-density lipoproteins (HDL, “good cholesterol”). Dyslipidemia cases have increased in parallel with the rising trends of obesity and diabetes.

GPR81 and GPR109a are G-protein–coupled receptors (GPCRs) that are involved in reducing triglyceride lipolysis. Stimulating them results in lowered LDL and increased HDL levels, which makes them good targets for dyslipodemia treatments. Niacin (1) is currently used for stimulating the GPCRs, but it can induce flushing and itching in patients, which limit its use considerably. These side effects are attributed to niacin’s strong interaction with GPR109a.

C. A. Dvorak and co-workers at Janssen Research & Development (San Diego) sought to find small-molecule agonists of GPR81 that are selective over GPR109a. Previous work led to the identification of 3-hydroxybenzoic acid (2), which moderately activates GPR81 and GPR109a (Liu, C., at al. J. Pharmacol. Exp. Ther. 2012, 341, 794–801). The authors discovered that substituents at C-5 of 2 increase the molecule’s selectivity toward GPR81.

The researchers then tested the potency of a series of 5-substituted 3-hydroxybenzoic acids and their isosteres. They found that 3-chloro-5-hydroxybenzoic acid (3) was most potent toward GPR81 and had no GPR109a activity. In a mouse model, 3 significantly reduced lipolysis at the same minimum efficacious dose as niacin.

Compound 3 is a good candidate for treating dyslipodemia. Because it does not interact with GPR109a, it should not cause niacin’s side effects. (ACS Med. Chem. Lett.2012, 3, Article ASAP DOI: 10.1021/ml3000676; Chaya Pooput)

Make wound-care dressings from a zwitterionic monomer. R. Lalani and L. Liu* at the University of Akron (OH) prepared electrospun mats of zwitterionic poly(sulfobetaine methacrylate) (PSBMA) to make water-stable functional wound dressings. They made PSBMA stable in water with a three-step production process:

  • free radical polymerizing of SBMA to a spinnable viscosity;
  • low-temperature electrospinning the quenched PSBMA, photoinitiators, and photo-cross-linkers; and
  • cross-linking via UV radiation.

Because PSBMA is superhydrophilic, the photo-treated electrospun mat (with ≈1.1-μm diam nanofibers) exhibited varying degrees of stiffness, reversible water uptake, and hydration-influenced transparency. The PSBMA nanofiber mat resisted bacteria and proteins; cell attachment was minimal after 96 h because of the absence of adhesion promoters.

Homogeneously incorporating silver ions via ionic interactions with the PSBMA mat provided a significant inhibition zone when the mat was exposed to bacteria. The electrospun PSBMA mats have the potential to overcome such challenges to wound-care dressings as infection, hydration, and removal. (Biomacromolecules 2012, 13, 1853–1863; LaShanda Korley)

Build supramolecular vesicles to target cholinesterase. Drug delivery is a constant concern for pharmaceutical chemists. Targetability and efficiency are the main objectives of drug-delivery vehicle research. Y. Liu and co-workers at Nankai University (Tianjin, China) developed a noncovalent interaction strategy for making superamphiphiles that specifically and efficiently target cholinesterase, a key overexpressed protein involved in Alzheimer’s disease.

The authors first selected myristoylcholine, a cholinesterase substrate, which itself is not ideal for enzyme-responsive vesicles because of the slight change in its critical aggregation concentration (CAC) before and after reacting with the enzyme. When it complexes with p-sulfonatocalix[4]arene (SC4A), a biocompatible macrocycle that strongly binds choline derivatives, however, the myristoylcholine’s CAC drops drastically. In addition, hollow, 90–200-m diam binary vesicles form between SC4A and myristoylcholine. Their surface is a bilayer membrane that consists of SC4A and myristoylcholine.

Treating the binary vesicles with butyrylcholinesterase (BChE) almost completely disassembles the vesicles because myristoylcholine decomposes BChE. Other enzymes, such as exonuclease (Exo I) and glucose oxidase (GOx), do not dissemble the vesicles.

When the vesicles are loaded with a hydrophobic guest molecule, the trisodium salt of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS), they react with BChE to release almost all of the HPTS in 4 h. But when the vesicles are loaded with tacrine, a common cholinesterase inhibitor, they do not undergo complete disassembly in the presence of BChE. This shows that the released tacrine inhibits BChE activity. Initial cell tests showed no evidence of vesicle cytotoxicity. (J. Am. Chem. Soc. 2012, 134, 10244–10250; Xin Su)

Use isothermal microcalorimetry to monitor drug action. Isothermal microcalorimetry is a technique for measuring heat flow that has applications in physical, chemical, and biological processes. T. Wenzler and co-workers at the Swiss Tropical and Public Health Institute (Basel) and the University of Basel used this technique to estimate the inhibition of microorganism growth by chemical compounds.

When a microorganism grows, it generates heat. If a drug inhibits growth, heat generation is lowered. The authors chose the microorganisms Trypanosoma brucei rhodesiense and Plasmodium falciparum to test their microcalorimetry method because they cause human African trypanosomiasis (sleeping sickness) and malaria.

For each parasite, the authors optimized the parameters for obtaining heat-flow curves without inhibitors. They then chose pentamidine, melarsoprol, and suramin as inhibitors of T. b. rhodesiense and chloroquine, artemether, and dihydroartemisinin as inhibitors of P. falciparum. Each compound was tested in two concentrations.

With microcalorimetry, the authors determined the drug action onset time and the time until the parasites stopped producing heat (time to kill) for each compound. The technique is simple, and it allows continuous parasite action monitoring and parallel measurements of 48 samples. It can be expanded to other microorganisms.

A drawback is the requirement for sealed ampoules. CO2 produced by the microorganisms cannot escape and lowers the acid content of the medium, which can affect drug action. (PLoS Negl. Trop. Dis. 2012, 6, e1668; DOI: 10.1371/journal.pntd.0001668; JosÉ C. Barros)

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