Chemical Science Blog

In nature, many cellular processes are controlled by structures that are only assembled when they are needed, in response to a chemical energy input. The structure (and hence the action of the structure) is maintained so long as the chemical energy input, or ‘fuel’ for the process is present. For example, microtubules can ‘grow’ or ‘shrink’ depending on the presence of guanosine triphosphate (GTP), and hence GTP serves as a ‘fuel’ for the function of the microtubules.

Inspired by this principle, Tom Fyles and his team from University of Victoria, Canada have used thiol–thioester exchange chemistry to assemble a metastable ion channel that disassembles over time in the absence of a chemical fuel.

In the scheme below, thiol 4 is not an active ion channel, but the addition of thioester 5 causes the formation of 3 by thiol-thioester exchange. 3 forms an active ion channel, but is metastable and therefore over time it disassembles into 4 + 6 which stops the ion transport. Adding more 5 (the fuel) will temporarily regenerate the ion transport as more C is formed.

While this system functions exactly as planned, its design was not without complications, says Fyles: “One setback was that these compounds do not work in vesicles so we had to develop reaction monitoring techniques using the bilayer clamp experiment.  That gives us exquisite sensitivity, but also allows us to detect very minor amounts of impurities.  So another setback was the observation that an oxidation impurity was vastly more active than the compounds we wanted to see.  This problem was easy enough to solve, but it took some time to recognize what was going on.”

This work also opens up exciting new avenues of investigation for the future for Fyles and his team. “The more general insight is that this system depends entirely on kinetic factors.  As chemists we are used to thinking about rates in terms of the reaction order and uniform reactant concentrations in the bulk.  Our system additionally shows the importance of local concentrations as opposed to the bulk concentration.  This introduces additional kinetic components related to diffusion.  The functioning of our system recorded using the bilayer clamp is largely controlled by diffusion processes, rather than the reaction kinetics we control in the design of the system.  This suggests that we might be able to make other systems that deliberately exploit non-uniform concentrations – yet another feature we can see in nature. Stay tuned.”

To download the full article for free*, click the link below:

Dissipative Assembly of a Membrane Transport System
A. K. Dambenieks, P. H. Q. Vu and T. M. Fyles
DOI: 10.1039/C4SC01258E

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Regan Thomson’s group from Northwestern University, Illinois, present the first total synthesis of propolisbenzofuran B. The synthesis has been completed in 17 steps, starting from the phenolic aldehyde, vanillin.

In the natural world propolis is a resin made by bees and used in their hives to preserve a sterile environment. It encases waste and carcasses to prevent the decomposition of proteins and therefore decay.

The beneficial health effects of honeybee products have been hypothesised since ancient Roman times. More recently it has been determined that propolis has many biological and pharmacological properties including antibacterial, antibiotic, anti-oxidant, anti-fungal, anti-cancer and anti-inflammatory activities.

Propolisbenzofuran B is a natural product found in Brazilian propolis, first isolated in 2000 by Banskota and co-workers. Initial biological testing determined that the compound had a cytotoxic effect on murine colon 26-L5 carcinoma and human HT-1080 fibrosarcoma cells.

It was not only the promising range of biological activity which drew the authors’ attention to this particular compound; propolisbenzofuran B has a unique core with an unusual ring-system. The development of an efficient synthesis for this core opens the door to further biological evaluation and possible modifications to the compound.

Highlights of the synthesis include a silicon-tether controlled oxidative ketone-ketone cross-coupling as well as a novel and efficient benzofuran cascade. The cascade was discovered to be induced rapidly with the addition of trimethylsilyl triflate to the 1,4-diketone precursor. The authors believe this methodology will be useful in the synthesis of other complex molecules containing benzofuran groups.

To download the full article for free* click the link below:

Total synthesis of propolisbenzofuran B
Brian T. Jones, Christopher T. Avetta and Regan J. Thomson
DOI: 10.1039/c4sc00356j

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Aristotle’s saying “the whole is more than the sum of its parts” is often well-exemplified in supramolecular chemistry – the result of non-covalent interactions present in a complex assembly of simple building blocks often generate novel properties that would not otherwise be present in a simple mixture of the components. The design of systems that exhibit these emergent phenomena is therefore an aim of many supramolecular chemists, including researchers from India who have achieved the control of supramolecular helicity in a bistable artificial self-assembled system through the addition of either a chiral or achiral component. This example of allosteric regulation in a synthetic system is an interesting analogue of that which occurs in biological systems, and offers an attractive approach to inducing not only conformational change in a pre-formed assembly, but also new chemical properties that could not otherwise be observed.

In biological systems, allosteric regulation, the binding of a secondary molecule to an enzyme, is employed to modulate the conformation of the active site and thus the effectiveness of an enzyme. This feature allows for communication between remote sites in a cell by providing a control loop in enzymes. It is therefore of interest to scientists to apply this allosteric regulation synthetically as a way of introducing a dynamic component to a molecular system.

Mohit Kumar and Subi George at the Jawaharlal Nehru Centre for Advanced Scientific Research[EB1] (JNCASR) in India have begun to experiment with the use of allostery in synthetic system[EB2] in order to induce [EB3] helicity in a polymeric supramolecular assembly comprised of a perylene bisimide functionalised at either end by a Zinc(II) motif that is known to bind phosphate ligands. In the “off” state this assembly exists as linear stacks of the molecule, such that overall the assembly is achiral. Upon the binding of 0.5 equivalents of chiral adenine trisphospate (ATP), a supramolecular reorganization is observed to form the helically dormant H1 state, which, upon the addition of further equivalents of ATP, results in a second conformational change to the helical H2, whereby the linear stacks are now twisted in nature and exhibit chirality. This example of chiral induction, in which a single molecule can turn “on” its chirality, exemplifies homotropic allosteric regulation. Furthermore, upon the addition of a second achiral pyrophosphate ligand (PPi) to H1, a different helical H2 state is induced in the assembly. The introduction of two chemically different molecules that interact with the assembly in different ways is an example of heterotropic allosteric regulation.

This use of supramolecular chemistry to post-synthetically elicit a change in a molecular assembly is an exciting way of mimicking the allostery observed in biology. Even more remarkable, is the ability of one system to respond in two different ways.

Read this HOT ChemSci article in full for free*!

Homotropic and heterotropic allosteric regulation of supramolecular chirality
Mohit Kumar and Subi B. George
DOI: 10.1039/C4SC00813H

About the Writer

Anthea Blackburn is a guest web writer for Chemical Science. Anthea is a graduate student hailing from New Zealand, studying at Northwestern University in the US under the tutelage of Prof. Fraser Stoddart (a Scot), where she is exploiting supramolecular chemistry to develop multidimensional systems and study the emergent properties that arise in these superstructures. When time and money allow, she is ambitiously attempting to visit all 50 US states before graduation.

*Access is free untill 06.06.14 through a registered RSC account – click here to register

At the mention of DNA most people think of the storage of genetic information, but due to its biocompatibility and the ease with which it can be manipulated, it is becoming increasingly common for DNA to be used as a building material in nanotechnology.

DNA cages have attracted interest in the world of drug delivery as they can encapsulate small molecule drugs and are easily taken up by cells. The precision with which the size and shape of the cages can be controlled is another attractive aspect. Past studies have established that DNA cages can target cells, deliver encapsulated cargo and have a cytotoxic effect in cancer cells. However, specific control of the cellular delivery profile of DNA cages has not yet been achieved.

Sleinman and co-workers, from McGill University based in Montréal, Canada, have created dynamic DNA cubes which ‘unzip’ in a specific cellular environment. The cages are assembled from six DNA strands which make up the six sides of the cube and only disassemble in the presence of a trigger found in prostate cancer cells. The authors tested the uptake and disassembly, or ‘unzipping’, of their DNA cubes in vitro using three different mammalian cell lines.

Hydrophobic and hydrophilic dendritic chains were added to the cube after initial testing. It was determined that these chains coat the exterior of the cube and have a significant effect on the uptake of the structure. While the addition of hydrophobic chains to the cube increase uptake, addition of hydrophilic chains increase the stability of the cube in cellular environments.

One of the exciting aspects about this work is the scope for adaptation; the cubes could potentially be designed to respond to any nucleic acid sequence found specifically in diseased cells. Future work in the group will also look at encapsulating and delivering cargo, such as oligonucleotide drugs, using this new delivery system.

To download the full article for free* click the link below:

Sequence-responsive unzipping DNA cubes with tunable cellular uptake profiles

Katherine E. Bujold, Johans Fakhoury, Thomas G. W. Edwardson, Karina M. M. Carneiro, Joel Neves Briard, Antoine G. Godin, Lilian Amrein, Graham D. Hamblin, Lawrence C. Panasci, Paul W. Wiseman and Hanadi F. Sleiman
DOI: 10.1039/C4SC00646A

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