Organic & Biomolecular Chemistry Blog

An international team of scientists has synthesised a cholera inhibitor that matches both the valency and target sugar of the cholera toxin. The molecule is 100,000 times better at trapping the cholera toxin than inhibitors based on the target sugar alone.

Cholera is an acute intestinal infection that can be fatal in severe cases. It is caused by the cholera toxin, a protein with a disease causing A subunit, surrounded by five B subunits. The B subunits bind to GM1, a pentasaccharide sugar, on the cell membrane of intestinal cells. Once attached, the cholera toxin can inject its toxic A subunit into the cell.

‘Optimally, one would bind all 5 B subunits to one inhibitor that uses this natural GM1 sugar,’ explains Han Zuilhof, from Wageningen University, the Netherlands, who led the work. ‘This should yield the strongest one-on-one complex. Previous work combined either pentavalent scaffolds with simpler sugars, or non-pentavalent scaffolds with the real deal sugar.’ Now, Zuilhof and colleagues have created the first inhibitor that is both pentavalent and uses GM1.

Read the full article in Chemistry World

And read the OBC paper here:
Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene
Jaime Garcia-Hartjes, Silvia Bernardi, Carel A. G. M. Weijers, Tom Wennekes, Michel Gilbert, Francesco Sansone, Alessandro Casnati and Han Zuilhof

Synthetic indirubin derivatives can selectively inhibit cyclin-dependent kinases, stalling cancer growth and proliferation.
Peter Langer and co-workers hypothesised that selenoindirubins could have similar anti-proliferative effects. Selenoindirubins are scarcely reported in the literature, with only three examples known. This HOT article details an optimized synthesis for a series of selenoindirubins, alongside the first report of spectroscopic data for this class of compounds. A glycosyl moiety increased the pharmacological activity of indirubin derivatives and was incorporated into the selenoindirubin series to improve their solubility in DMSO and water. Members of this series had an anti-proliferative effect in lung cancer cells. Apoptosis was enhanced by combination treatment with the death ligand TRAIL, suggesting that selenoindirubins may have potential applications as anti-tumour agents.

Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides
Friedrich Erben, Dennis Kleeblatt, Marcel Sonneck, Martin Hein, Holger Feist, Thomas Fahrenwaldt, Christine Fischer, Abdul Matin, Jamshed Iqbal, Michael Plötz, Jürgen Eberle and Peter Langer
DOI: 10.1039/c3ob40603b

Free to access for 4 weeks

In this HOT paper, John Pezacki and co-workers report novel rearrangement and addition reactions of biarylazacyclooctynone (BARAC) leading to tetracyclic products. This behaviour may limit the practical applications of azacyclooctynones as bioorthogonal probes for biological systems.

Bioorthogonal reactions, i.e. reactions which can occur inside of a living system without interfering with native chemical processes, allow for the study of molecules such as proteins and lipids in vivo and in real time. The 1,3-dipolar cycloaddition between azides and octynes is an example of such a reaction. This copper-free variant of the Huisgen cycloaddition (better known as the click reaction) has been applied within cultured cells, live zebrafish and mice.

John Paul Pezacki and his research group at National Research Council Canada have been looking into these reactions and their application in biological probes and sensors. During their studies into the cycloaddition of azacyclooctynones such as BARAC (biarylazacyclooctynone), they noticed some interesting and unexpected results.

These molecules are able to undergo novel intramolecular cyclisation reactions which lead to the formation of tetracyclic products. Pezacki has performed some neat kinetics studies and computer-modelling, which have revealed that this rearrangement is accelerated by the presence of acid and that the linker side-chain also influences the rate of rearrangement.

This elegant, but rather unhelpful, reaction may limit the effectiveness of these molecules in biological systems, and this fascinating study illustrates how challenging it is to design effective bioorthogonal reactions.

Rearrangements and addition reactions of biarylazacyclooctynones and the implications to copper-free click chemistry
Mariya Chigrinova, Craig S. McKay, Louis-Philippe B. Beaulieu, Konstantin A. Udachin, André M. Beauchemin and John Paul Pezacki.
DOI: 10.1039/C3OB40683K

Free to access for 4 weeks

In this HOT article Bräse and co-workers report the synthesis of eight new rhodamine fluorophores with fluorous ‘ponytails’, dubbed rhodamine F dyes. Rhodamine derivatives are widely used as fluorescent labels for biomolecules and characteristically have high absorption coefficients and high absorption and emission maxima in the visible region combined with high chemical and photostability.

The ‘ponytails’ are fluorous alkyl residues that are deliberately not cleaved during synthesis. They facilitate fluorous solid-phase extraction, utilising the strong, specific nature of fluorine-fluorine interactions. During this purification process a fluorous solid phase is used to bind fluorous molecules and separate them from non-fluorous compounds.

The fluorine content of the rhodamine F dyes is below 50% of the total molecular weight, preserving solubility in organic solvents. Conjugation with a peptide mediates cellular uptake may have potential applications in live cell imaging; clear, bright images were obtained in human cervix carcinoma cells incubated with rhodamine F dyes at concentrations as low as 1 µM.

Rhodamine F: a novel class of fluorous ponytailed dyes for bioconjugation
Dominik K. Kölmel, Birgit Rudat, Delia M. Braun, Christin Bednarek, Ute Schepers and Stefan Bräse
DOI: 10.1039/c3ob40267c

Free to access for 4 weeks

Published on behalf of Steve Moore, Organic & Biomolecular Chemistry web science writer.

In this HOT article, Dave Smith, Sabrina Pricl and co-workers report the synthesis of 4 different RGD-peptide derivatives, which spontaneously self-assemble into nanoscale architectures. They used multiscale modelling to understand the self-assembly of these ligands and they demonstrated that by modifying the building blocks through organic synthesis on the molecular scale, they could control the morphology of the resulting self-assembled nanostructures. The multivalent binding of the assemblies to integrin proteins was shown to be highly dependent on the morphology of the assemblies. The paper elegantly showcases the importance of nanoscale morphology on binding events and highlights the advantages of employing a self-assembly approach. 

Self-assembled multivalent RGD-peptide arrays – morphological control and integrin binding
Daniel J. Welsh, Paola Posocco, Sabrina Pricl and David K. Smith
DOI: 10.1039/c3ob00034f

Free to access for 4 weeks

… and presently in the Top 10 most read articles in OBC –  check the full list here