Organic & Biomolecular Chemistry Blog

Researchers from the University of Alberta, Canada, have discovered an antagonist with impressive nanomolar inhibition of cholera toxin (CT) using a novel approach to design and synthesise a small, focused library of CT binding ligands.

David Bundle and co-workers aimed to design a ligand capable of binding to cholera toxin and that could be orally administered.  CT is the most important virulence factor in the disease and deactivating bacterial toxins may reduce the development of antibiotic resistance – a real problem in current cholera treatments.   Binding to CT occurs predominantly at GM₁ receptor, and a multiple binding strategy through weak ligand interactions has been demonstrated to be very effective.

Here, the authors have created a compound library of heterobifunctional ligands, with an invariable ligand, galactose – which is very effective at binding to GM₁ – conjugated to a polymer carrier.  The other, non-galactose ligand fragment was varied to probe a complimentary GM₁ binding site. The polymer scaffold, polyacrylamide or dextran,  provided a framework for the synthesis, purification and assay of the compounds as well as being necessary for the multivalent presentation of the ligands.  The library allowed the authors to identify weak ligands that are capable of complimenting the binding affinity of galactose for the cholera toxin protein.

Read how the authors obtained the nanomolar inhibition activities here – the article is free to access for four weeks!

Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists
Huu-Anh Tran, Pavel I. Kitov, Eugenia Paszkiewicz, Joanna M. Sadowska and David R. Bundle
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB01089H

Brucella spp. are the causative organisms for the zoonotic disease Brucellosis, which in humans may require months of treatment and can kill. As there is no human vaccine, new treatments are needed.

Stephan Köhler and Jean-Yves Winum from CNRS, and their colleagues, have created a new series of inhibitors that are highly active in vitro, and are shown to be active in vivo. Additionally, molecular modelling and competition experiment with NAD+ confirmed the positioning of the inhibitor inside the active site of HDH. As the target HDH has been directly linked to bacterial virulence, and with the results obtained on live extra- and intracellular brucellae, the development of these inhibitors can be considered as a promising step towards novel anti-virulence drugs.

The referees thought this article was very significant, and so do we – so read this HOT article today in OBC. It is free to download until 5th May.

Anti-virulence Strategy against Brucella suis: Synthesis, Biological Evaluation and Molecular Modeling of Selective Histidinol Dehydrogenase Inhibitors
Marie-Rose Abdo, Pascale Joseph, Jérémie Mortier, François Turtaut, Jean-Louis Montero, Bernard Masereel, Stephan Köhler and Jean-Yves Winum
Org. Biomol. Chem., 2011, Advance Article

DOI: 10.1039/C1OB05149K

Cellular oxidative stress is thought to lie behind many disease and ageing processes, so an understanding of its effects is vital to designing strategies to counter such damage. Cynthia J. Burrows et al. from University of Utah have conducted a characterisation study of the nucleoside degradation products of copper-mediated Fenton reactions and determined the major product to be a recently discovered hydantoin, d2Ih. The products contrast with those produced in radiation-induced oxidation and the discovery of a new product, dGh_red, in the double-stranded oligodeoxynucleotide studies points the way for future chemical and biological studies in this vital area.

The referees thought this was a very significant work so read this HOT article today in OBC – it is free to access until 28th April!

Characterization of 2′-deoxyguanosine oxidation products observed in the Fenton-like system Cu(II)/H2O2/reductant in nucleoside and oligodeoxynucleotide contexts
Aaron M. Fleming, James G. Muller, Insun Ji and Cynthia J. Burrows
Org. Biomol. Chem., 2011, Advance Article

DOI: 10.1039/C1OB05112A

The C8 position of guanine is known to be vulnerable to forming adducts that cause damage to DNA,  and these adducts are often used as biomarkers to indicate conditions such as oxidative stress.  Forming guanine adducts synthetically usually occurs via Pd-catalysed coupling reactions, as radical-based approaches generally have poor yields.  Water has also seldom been used as a reaction medium, despite its relevance to biomimetic chemistry.

However, this HOT article from Chryssostomos Chatgilialoglu et al. describes the successful radical-based alkylation of two guanine derivatives in aqueous solution via γ-radiolysis.  The mechanism of α-hydroxylalkyl radical addition to the C8 position of the purine ring, which results in intermolecular C-C bond formation, is discussed in detail and provides useful  insights into the radical chemistry of 8-bromoguanines.

This paper is free to access until 26th April and is part of the forthcoming OBC special web themed issue on radical chemistry.

Radical-based alkylation of guanine derivatives in aqueous medium
Chryssostomos Chatgilialoglu, Clara Caminal and Quinto G. Mulazzani
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB01264E

Alterations in fluid viscosity at the cellular and organismal level can lead to different disorders and diseases such as Alzheimer’s, diabetes, hypertension, infarction and others. This is why, in recent years, there has been an increasing interest in the development of new methods to measure fluid viscosity.

Scientists at University of California, San Diego, and University of Georgia have now developed self-calibrating fluorescent sensors that can be used  for ratiometric measurements of viscosity by covalent linking a reference fluorophore (donor) with a molecular rotor (acceptor). They also present an application of these dyes for the detection of changes of the membrane viscosity in a liposome model and they show that shorter linker length produces a more viscosity sensitive dye.

You can now read this HOT article which is free to access until 26th April. Both the referees and the Editorial Office ranked it as very significant.

Synthesis and evaluation of self-calibrating ratiometric viscosity sensors
Hyung-Jo Yoon, Marianna Dakanali, Darcy Lichlyter, Willy M. Chang, Karen A. Nguyen, Matthew E. Nipper, Mark A. Haidekker and Emmanuel A. Theodorakis
Org. Biomol. Chem.
DOI: 10.1039/C0OB01042A

Read the latest OBC hot paper in which Thorsten Bach and colleagues use a hydrogen bond template to carry out highly enantioselective radical cyclisations.

Bach’s template works as a steric shield preventing the approach of a reagent from one side of the molecule. Using the method Bach was able to demonstrate radical cyclisations of quinolines with 94–99% ee.

This is an important investigation with wide reaching consequences and will be of interest to many organic chemists. Its free to download until 21^st April.   

This paper will be  included in the OBC special web themed issue on radical chemistry that will be published soon. Keep an eye on it!

Enantioselective radical cyclisation reactions of 4-substituted quinolones mediated by a chiral template
Aline Bakowski, Martina Dressel, Andreas Bauer and Thorsten Bach
Org. Biomol. Chem., 2011, DOI: 10.1039/C0OB01272F