Noteworthy Chemistry

May 14, 2012

Ferroquine may overcome malaria drug resistance. Despite much progress, malaria affects more than 200 million people and kills 700,000 worldwide every year. Since World War II, chloroquine (1) has been used extensively to fight malaria, but the rapid emergence and spread of drug-resistant parasites requires constant research for new drugs. Beginning in the mid-1990s, C. Biot and colleagues at the Lille University of Science and Technology (Villeneuve d’Ascq), the Grenoble Institute of Neurosciences, ESRF (Grenoble), and the Pasteur Institute of Lille (all in France) have been designing antimalarial drug candidates. Their efforts resulted in ferroquine (2), a chloroquine analogue that contains the ferrocene moiety. Ferroquine has just completed phase 2 clinical trials.

When Plasmodium falciparum malaria parasites digest hemoglobin, they produce heme, which is toxic to them. They protect themselves against heme by biocrystallizing it into nontoxic hemozoin. Compounds 1 and 2 inhibit this process, but they may have different modes of action.

Researchers believe that resistance to 1 arises when a mutated transporter protein causes it to drain from the digestive vacuole. The authors show that 2 is not recognized or channeled from the digestive vacuole by transporter proteins involved in quinoline resistance. They also found that the ferrocene moiety in 2 may directly or indirectly induce oxidative stress, leading to the parasite’s death.

These findings provide a better understanding of the mechanism of the antimalarial action of ferroquine. (ACS Med. Chem. Lett. 2012, 3, Article ASAP DOI: 10.1021/ml300062q; Chaya Pooput)

How warm and wet should a protein be to function? For many years, researchers have studied the so-called protein dynamical transition, the rapid increase in the atomic mean squared displacements that occurs at ≈220 K for a many proteins and polynucleotides. This rapid increase in dynamics appears to be necessary for some biomolecules to function properly, and it has spurred research into the origin of the change.

The consensus is that the increased displacement originates from the temperature dependence of solvent dynamics at the protein surface. The functional protein motions require the solvent to be mobile. The nature of solvent excitations with this temperature dependence, however, is not well understood.

F. Lipps, S. Levy, and A. G. Markelz* at the Leibniz Institute for Solid State and Materials Research (Dresden, Germany) and the State University of New York at Buffalo used the terahertz time domain spectroscopy technique to investigate the relationship of hydration and temperature to protein picosecond dynamics. They measured the complex dielectric response of myoglobin as a function of hydration and temperature in the 0.2–2.0 THz range. They then used this almost complete set of measurements to determine which motions contribute most strongly to the dielectric response.

The researchers found that in the 100–260 K temperature range, the correlated large-scale structural motions dominate. By examining the combination of hydration, temperature, and frequency dependence, they found that hydration is necessary to achieve the rapid temperature dependence that corresponds to excitations of water clusters of about five molecules at the protein surface.

Whereas subpicosecond motions increase slightly with hydration and temperature, slower motions dramatically increase with solvent concentration. A sharp rise occurs when the hydration is sufficient to completely span the water network over the surface of the protein. The authors believe that this increase arises from the need for the entire protein surface to achieve sufficient plasticity from hydration and temperature to achieve the global motions necessary for functioning. (Phys. Chem. Chem. Phys. 2012, 14, 6375–6381; Gary A. Baker)

Use a porous organic cage for reversible water uptake. Water adsorption has long been dominated by microporous materials based on zeolites, metal–organic frameworks (MOFs), covalent organic frameworks, and organic polymer networks. A. I. Cooper and coauthors at the University of Liverpool (UK) and the Defense Science and Technology Laboratory (Dstl; Salisbury, UK) show that an imine-based porous organic cage (3) takes up water efficiently.

The authors synthesized cage 3 by a one-pot CF3CO2H-catalyzed cycloimination between 4 equiv trialdehyde 1 and 6 equiv diamine 2. The cage is so stable to water that 1H NMR and powder X-ray diffraction analysis show no sign of decomposition or crystal modification after it is refluxed in water for 4 h. It slowly decomposes to the starting materials when it is immersed in concd aq HOAc.

The crystal structure of 3 consists of homochiral cages with tetrahedral symmetry. It has four 5.8 Å–diam windows per cage that are packed in a window-to-window manner. Desolvated crystals of 3 adsorb water when they are exposed to water vapor or immersed directly into water. Water adsorption–desorption cycles can be reproduced three times at 25 °C without decomposition of 3.

The crystal structure of water-saturated 3 shows that its tetrahedral symmetry is conserved. There are ≈12 water molecules per cage. This result is consistent with gravimetric measurements that showed that 12.5 water molecules are adsorbed by one molecule of 3, corresponding to a mass fraction of water of 20.1% (11.2 mmol/g). (Chem. Commun. 2012, 48, 4689–4691; Xin Su)

Which amide is the best substrate for a Grignard reaction? In the course of screening acyl protecting groups for converting 2-fluoro-3-methyl-4-acylaminoiodobenzene to 2-fluoro-3-methyl-4-acylaminobenzoic acid, X.-j. Wang and co-workers at Boehringer Ingelheim (Ridgefield, CT, and Laval, QU) made an unexpected discovery. The reaction was carried out by using Knochel I–Mg exchange conditions followed by quenching with CO2.

With a standard acetyl protecting group, the yield of the desired product was 62%. The major byproduct was 34% 3-fluoro-2-methylaniline, which presumably forms when the acidic acetyl protons quench the Grignard reagent internally. When a trifluoroacetyl group was used, the desired carboxylic acid was formed in 92% yield; and when an isobutyryl protecting group was used, a 90% yield was obtained with 5–6% of the side product.

The authors believe that steric factors suppress the internal quenching process. The isobutyryl substrate was chosen for scale-up on the basis of cost. (Org. Process Res. Dev. 2012, 16, 561–566; Will Watson)

Use emissive aggregates in bioelectronics and chemoionics. The recently discovered luminescent phenomenon aggregation-induced emission enhancement (AIEE) is observed in many arylolefin luminogen systems in which multiple aromatic rotors are linked by an olefinic stator. A team led by V. Bhalla and M. Kumar at Guru Nanak Dev University (Amritsar, India) reports a fully aromatic AIEE luminogen system (1) in which six aromatic rotors are connected by a benzene stator.

The weak luminescence of 1 is enhanced when its molecules aggregate (i.e., 1 is AIEE-active). The aggregates’ fluorescence responds to three proteins—bovine serum albumin, cytochrome c, and lysozyme—and to ionic species Pb2+ and Pd2+. By using the differences among the emission responses, the researchers prepared integrated logic circuits to demonstrate the potential of the aggregates for producing bioelectronic and chemoionic devices. (Chem. Eur. J. 2012, 18, 3765–3772; Ben Zhong Tang)

Nature inspires stretchable, conductive nanowire coatings. T. Akter and W. S. Kim* at Simon Fraser University (Surrey, BC) developed a way to make extensible, transparent, conductive coatings for optoelectronics. They modified the surface of poly(dimethylsiloxane) (PDMS) with a small amount of bioderived polydopamine to produce an elastomeric, hydrophilic substrate. They then spray-deposited silver nanowires (AgNWs) on the functionalized PDMS to prepare homogeneously distributed, strongly adherent nanowires.

Patterned AgNWs on stretched or unstretched masked dopamine-modified PDMS were highly conductive. Transparent coatings (formed by 2-s sprays) with <15% elongation had relatively constant sheet resistance.

Denser coverage of AgNWs produced opaque coatings with sheet resistance that decreased as elongation increased. The stretching was reversible and, with some hysteresis, was accompanied by corresponding changes in conductivity. The polydopamine-derived stretchable coatings show promise for flexible electrodes. (ACS Appl. Mater. Interfaces 2012, 4, 1855–1859; LaShanda Korley)

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