Noteworthy Chemistry

June 29, 2015


Dope superbenzene with a borazine core. Coronene, also called “superbenzene”, consists of six peri-fused benzene rings around a benzene core. Adding another round of fused benzene structures to coronene gives hexa-peri-hexabenzocoronene (HBC, 1 in the figure), a well-known supramolecular material that can be considered a nanosized graphene fragment.

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Hexa-peri-hexabenzocoronene and its borazine analogue

Growing graphene planes with B−N bonds in place of some of the C−C bonds is an established technique, but the precision of this method has not reached the atomic scale. H. F. Bettinger and coauthors at the University of Tubingen (Germany) and the University of St. Andrews (UK) took the state of the art to a higher level by replacing HBC’s core with a borazine (B3N3) ring to form the fundamental BN-HBC structure (4).

To synthesize 4, the authors started with B3N3-hexabenzotriphenylene (2), which they thought could be ring-closed oxidatively by forming three equivalent C−C bonds. This reaction closed only one of the rings, however, to give structure 3. But heating compound 5 (the precursor to 1) to 550 ºC gives 4 as a minor product that can be separated from major product 6.

Compound 4 exhibits a typical B–N stretching vibration in its infrared spectrum. It shows an isotropic 11B chemical shift of 27 ppm in its nuclear magnetic resonance spectrum; the boron signal is shifted upfield under the influence of the surrounding π systems. Scanning transmission microscopy imaging illustrates the 2-D geometry of 4, which lies flat on a gold substrate.

This study provides a new strategy for doping B−N units into extended polycyclic aromatic hydrocarbons with high atomic precision. It should be useful in “bottom-up” strategies for preparing constitutionally well-defined 2-D heteroatomic materials. (Angew. Chem., Int. Ed. DOI: 10.1002/anie.201412165; Xin Su)

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Repurposed drugs are effective against Ebola. Filoviruses such as Ebola cause acute viral hemorrhagic fevers with high fatality rates. As the recent epidemic in Africa showed, easily distributable interventions against Ebola are urgently needed; but none are currently available.

G. G. Olinger and collaborators at Horizon Discovery (Cambridge, MA), the US Army Medical Research Institute of Infectious Diseases (Frederick, MD), the University of Virginia (Charlottesville), and Boston University screened drugs that are approved for other uses for their effectiveness against Ebola. The team identified 80 US Food and Drug Administration–approved drugs that inhibit Zaire ebolavirus activity in vitro by ≥40% with minimal effects on cell viability.

The compounds include antipsychotics, anticholinergics, antidepressants, antihistamines, and receptor modulators. They affect multiple mechanisms of the virus such as ion transport, cell signaling, and protein processing.

The researchers prioritized 30 drugs for further validation, including 17 class II cationic amphiphilic drugs (CADs), which have a hydrophobic tertiary amine with segregated hydrophobic and hydrophilic segments, and 8 amphiphiles with similar hydrophobic–hydrophilic organization. Twenty-five of the compounds, including all of the CADs, inhibit in vitro Z. ebolavirus entry by >90%. The other compounds likely block a postentry step in the infection cycle.

The authors then looked at in vivo drug efficacy in Ebola-infected mice. Animals treated postinfection with bepridil (Vascor), a calcium channel blocker, and sertraline (Zoloft), a selective serotonin reuptake inhibitor, had statistically significant survival benefits. Additional drug studies in nonhuman primates are necessary.

Bepridil and sertraline inhibit a late entry step and are effective against multiple strains of Z. ebolavirus and the related filovirus genus Marburgvirus. The orally available treatments have established human safety and clinical drug profiles that may offer advantages for using them as anti-Ebola therapeutics. (Sci. Transl. Med. DOI: 10.1126/scitranslmed.aaa5597; Abigail Druck Shudofsky)

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A pH-responsive fluorescence system “finds” a drug and shows how it works. Nanoparticles with encapsulated drugs are used to develop controlled drug-delivery systems. Ideally, the drugs are released from the encapsulating nanoparticles when external stimuli are applied. But where drugs go and how they function after they get there is difficult to ascertain.

G. Liu, Y. Wang, and colleagues at Sichuan University (Chengdu, China) developed a “smart system” that provides visual information about the location and pharmacokinetics of doxorubicin (DOX), an anticancer drug, which they encapsulated in nanoparticles.

The researchers designed and synthesized an amphiphilic copolymer (1 in the figure) that is susceptible to variations in intracellular pH. Under physiological conditions, the molecules of 1 and DOX self-assemble into nanostructured micelles. The DOX-loaded micelles are internalized by cancer cells, and the drug is steadily released from the micellar nanoparticles at endosomal pH. 

The researchers designed and synthesized an amphiphilic copolymer (1 in the figure) that is susceptible to variations in intracellular pH. Under physiological conditions, the molecules of 1 and DOX self-assemble into nanostructured micelles. The DOX-loaded micelles are internalized by cancer cells, and the drug is steadily released from the micellar nanoparticles at endosomal pH.

The aggregation-induced emission of the tetraphenylethylene substituents attached to the dextran chain of 1 permits the practitioner to observe the intracellular distribution of the drugs and to monitor their pharmacokinetic processes by using fluorescence microscopy. (Polym. Chem. DOI: 10.1039/C5PY00584A; Ben Zhong Tang)

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Slurrying is the key to crystallizing a pharmaceutical. J.-G. Bioteau and co-workers at Galderma R&D Les Templiers (Sophia-Antipolis, France) optimized the synthetic route to a developmental melanocortin 1 receptor (MC1R) agonist that can be used to treat vitiligo, a disease that causes loss of natural skin pigment. Attempts to crystallize the free base were unsuccessful, so the authors carried out a salt screen.

Only the hydrochloric (HCl) and galactaric acid salts gave solid materials, and these were only partially crystalline. The authors focused on the HCl salt, which is hydroscopic and difficult to dry. But when it is subjected to differential scanning calorimetry, an exotherm occurs at 185 ºC, followed by an endotherm at 205 ºC.

The researchers assumed that these events are crystallization and melting. They heated the solid at 190 ºC to produce partially crystalline material that they slurried in ethanol–heptane for 48 h to generate crystalline material that is much easier to dry to a solvent content within International Conference on Harmonization limits. (Org. Process Res. Dev. DOI:10.1021/acs.oprd.5b00097; Will Watson)

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This signal delay is intentional. Pyrotechnic delays prevent launched signal flares from igniting too close to the ground to be useful. Conventional pyrotechnic delays rely on perchlorates, chromates, barium, lead, and other environmentally problematic materials, that burn slowly enough without extinguishing in the large, flat delay housings typical of Army handheld signals.

The figure is a schematic of a signal rocket. The rocket motor (G) and delay element (C) are ignited simultaneously. The delay element burns for several seconds before it ignites the black powder expelling charge (E), which ignites and ejects the pyrotechnic payload (F). The article contains a full description of the signal rocket.

Fluorescent amphiphilic copolymer that signals its location
Schematic of signal rocket

A. P. Shaw and co-workers at the US Army RDECOM-ARDEC* (Picatinny Arsenal, NJ) ran prototype tests of a more environmentally benign pyrotechnic delay based on boron carbide (B4C), sodium periodate (NaIO4), and polytetrafluoroethylene (PTFE) that burns at rates between 1 and 21 s/cm, depending on stoichiometry, particle size, and how tightly the columns are packed.

In dynamic tests on fully assembled signal rockets, the delay time was consistently 46% shorter than for static tests on stand-alone delay elements. The authors attribute this finding to the pressure and heat within the rocket combustion chamber as the propellant burns. Because the B4C–NaIO4–PTFE mixture releases a substantial amount of gaseous combustion products, conductive and convective heat transfer propagate the burn front. Hot combustion gases carry away any condensed-phase products, leaving the housing almost empty and continuously exposing the column burn front. Thus, a slow-burning composition (14–15 wt% B4C) is required to achieve the desired 5–6 s dynamic delay time.

The authors tested their system at –54 and +71 ºC to confirm its reliability and safety at extreme ambient temperatures. Impact, friction, and electrostatic discharge tests confirmed that the B4C-based delay is insensitive to unintended ignition. The ignition temperature is 475 ºC, well above the decomposition temperature of NaIO4 and the melting points of NaIO3 and PTFE. (ACS Sustainable Chem. Eng. DOI: 10.1021/acssuschemeng.5b00254; Nancy McGuire)

*Research, Development and Engineering Command–Armament Research, Development and Engineering Center

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