Organic & Biomolecular Chemistry Blog

The power of multivalency against cholera

Marie Cote, Deputy Editor — Thu, 23 May 2013 14:53:59 +0000

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

The 21st Lakeland meeting on Heterocyclic Chemistry and Synthesis, 40 years since the first meeting, was not to be missed!

Marie Cote, Deputy Editor — Mon, 20 May 2013 15:24:55 +0000

Were you there? Or you might have been following the live tweets from @Grasmere2013, updated by @APDobbs & @AzaPrins?

For a round up of the meeting and some highlight pictures, why not read below for a summary by this year’s organisers!

Grasmere 2013

The Heterocyclic Group began in 1967 and first held a Heterocyclic Conference in the Lake District village of Grasmere in May 1973. This meeting has been repeated every two years since, and the latest in this series took place 9-13th May 2013 and organised by Professors Adrian Dobbs (University of Greenwich) and David Knight (Cardiff University).

This was a landmark for the meeting, marking 40 years since the first such meeting and the 21st meeting in the series – the ‘coming of age’ symposium! The original founder of the meeting, Professor Otto Meth-Cohn was in attendance and one member of the group, Professor Gurnos Jones has attended all 21 meetings. As ever, lectures were held in Grasmere Village Hall and the conference booked-out two local hotels, as well as numberous B&B’s. Excellent science and food were in abundance during the meeting, as was the Lakeland rain, but a good time was had by all.

Highlights of the meeting included the presentations of two RSC Medals and their associated lectures: to Professor Scott Rychnovsky (UC Irvine, Pedler Medal) and Professor Chris Moody (University of Nottingham, Charles Rees Medal and Lecture).

Group photo outside Grasmere village Hall

Dr Robin Attrill (GSK); Prof Adrian Dobbs (Uni of Greenwich & Sec/Treasurer Heterocycli & Synthesis Group); Prof Scott Rychnovsky (recipient of the RSC Pedler Medal Award); Dr David Rees (Org Div President); Dr Marie Cote (Deputy Editor, OBC)

Prof Keith Jones (ICR); Prof Chris Moody (Uni of Nottingham, recipient of the RSC Charles Rees Award); Dr David Rees (Astex Pharmaceuticals)

HOT – New selenium compounds combat cancer

Alessia Millemaggi, Development Editor — Wed, 15 May 2013 14:08:47 +0000

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

HOT – Unexpected Rearrangements of Biarylazacyclooctynones

Annabella Newton — Mon, 13 May 2013 09:12:19 +0000

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

Chemical Biology and Medicinal: Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria

Aliya Anwar — Thu, 09 May 2013 09:08:09 +0000

Pathogen-associated lectins are considered to be attractive targets for the development of antiadhesive drugs. It is of great importance to design sugar-based derivatives able to selectively bind to specific pathogen-associated lectins with the aim of fighting bacterial infections without interfering with human lectins involved in physiological processes.

The stereoselective synthesis of the new fucose-based derivative 1, as the first example of glycomimetic selectively recognized by the fucose-binding lectin BambL from Burkholderia ambifaria is described.

Scientists in Italy report the first example of a synthetic ligand able to selectively bind, in the micromolar range, the pathogen-lectin BambL. BambL is a fucose-specific lectin from Burkholderia ambifaria, a bacterium member of the Burkholderia cepacia complex (BCC), a closely related group of Gram-negative bacteria responsible for cepacia syndrome in immunocompromised patients.

The fucose-based mimetic is therefore a promising candidate for the development of antibacterial agents against infection by B. ambifaria.

Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria
Barbara Richichi, A Imberty, Emilie Gillon, Rosa Bosco, Ieva Sutkeviciute, Franck Fieschi and Cristina Nativi
Org. Biomol. Chem., 2013, Accepted Manuscript
DOI: 10.1039/C3OB40520F

OBC poster prizes at the 5th Chemical Protein Synthesis

Richard Kelly — Wed, 01 May 2013 07:32:42 +0000

Congratulations to Stijn Agten and Claudia Bello who both received OBC poster prizes at the 5th Chemical Protein Synthesis meeting in Vienna last month.

Stijn Agten, from the group of Professor Tilman Hackeng at Maastricht University, The Netherlands won for a poster entitled “Chemoselective reactions in proteins and peptides using an optimized oxime strategy: the demise of levulinic acid”, while Claudia Bello from the Institute of Biological Chemistry at University of Vienna presented a poster entitled “A Chemoenzymatic Approach for the Preparation of Site-Specifically O-Glycosylated MUC1 variants for Proteomic Studies”.

Both winners receive a year’s subscription to OBC.

HOT – Dyes with fluorinated ponytails

Alessia Millemaggi, Development Editor — Fri, 26 Apr 2013 08:53:49 +0000

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.

PERSPECTIVE – A Brief History of Molecular Sensors

Annabella Newton — Mon, 22 Apr 2013 14:33:05 +0000

In this HOT article, Julius Rebek Jr presents a fascinating insight into the design of molecules which can detect and destroy organophosphorus compounds.

Organophosphorus (OP) compounds are primarily used as pesticides, and can be a useful alternative to more traditional chlorinated hydrocarbon-based pesticides. However, due to OP compounds’ ability to inhibit acetylcholine esterase (AChE), they can be extremely toxic to humans and they have therefore found use as nerve agents and chemical weapons. For these reasons, their toxicity is an area of intense research focus and new methods for their detection and treatment are always welcome.

Rebek and his research group at The Scripps Research Institute have been looking into molecular sensors for OPs for several years, and this paper highlights some of the significant developments in the field. Their interest in the area was sparked by a carefully crafted pyridine structure discovered by Swager, which upon reaction with an OP undergoes a subsequent cyclisation reaction to create a fluorescent dye. This is a useful premise for the sensing of OPs. The Rebek group have expanded upon this premise and developed a series of molecular sensors that employ similar mechanisms. They have used their established expertise in cavitand chemistry to develop specially-tailored vase-shaped molecules, which are able to fold around OP-based nerve agents and isolate them from the surrounding medium. This paper provides a whistle-stop tour of an exciting and important area of organic chemistry.

Chemical approaches for detection and destruction of nerve agents
Dariush Ajami and Julius Rebek, Jr.
DOI: 10.1039/c3ob40324f

Free to access for 4 weeks

Bursary opportunity for final year PhD students and postdocs to attend the Sao Paulo Advanced School Bioorganic Chemistry

Alessia Millemaggi, Development Editor — Tue, 16 Apr 2013 16:22:29 +0000

The RSC is delighted to announce a fantastic bursary opportunity for PhD students/post docs to attend the Advanced School Bioorganic Chemistry taking place in Araraquara, Brazil, 30 June – 05 July 2013. The school includes talks and discussion sessions from highly qualified scientists (including Professor Steven V. Ley from the University of Cambridge) and leaders in the field covering bioorganic chemistry, involving aspects of natural products, medicinal chemistry, synthesis and spectroscopic methods. The full programme can be viewed here: http://www.bioorgchemespca.iq.unesp.br/nodes/view/program

FAPESP (Sao Paulo Research Foundation) have invited the RSC to select 2 UK students to participate in the meeting. The bursary will cover international and domestic transportation, hotel accommodation, meals, registration fee and welcome reception. To apply please complete the form which is available download here and at the end of this post. Return to science@rsc.org by 19 April 2013 at 4pm.

Closing date for application is 4pm on 19 April 2013

For any queries please contact science@rsc.org

Application Form for the Advanced School Bioorganic Chemistry

HOT – Self-assembled multivalent RGD-peptide arrays – morphological control and integrin binding

Alessia Millemaggi, Development Editor — Tue, 16 Apr 2013 15:44:06 +0000

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