Organic & Biomolecular Chemistry Blog

Fluorescent bio-probes, polypeptide tags and reporter proteins have become invaluable tools in life science research. So labelling of natural biological molecules with fluorescent organic dyes has become a popular area of research. But while many fluorphores perform well in organic solvents, it’s not so easy to make ones that work well the aqueous media required for biological applications.

Now, Anthony Romieu and colleagues at the University of Rouen, France, have devised an easy and efficient solid-phase synthesis to obtain rapidly water soluble choromophores and fluorophores in a highly pure form. They report the first successful use of N-Fmoc-a-sulfo-b-alanine as a solid-phase peptide synthesis building block, which could open the way to the future development of promising direct protein labelling.

To read more, download the article – it’s free to access for the next four weeks:

N-Fmoc-α-sulfo-β-alanine: a versatile building block for the water solubilisation of chromophores and fluorophores by solid-phase strategy
Anthony Romieu, Thomas Bruckdorfer, Guillaume Clavé, Virgile Grandclaude, Cédrik Massif and Pierre-Yves Renard
Org. Biomol. Chem., 2011, DOI: 10.1039/C1OB05730

Integrastatins display micromolar inhibition of the HIV-1 integrase enzyme, halting replication of the virus.  Medicinal chemists are therefore very interested in being able to synthesise these natural products, and their analogues, to investigate potential HIV therapies.

The total synthesis of either integrastatin A or B is yet to be reported, but several groups have reported the synthesis of the tetracycle core, Brian Stoltz and colleagues Caltech being the latest.   Their synthesis differs from previous reports by utilising a palladium-catalyzed oxidative cyclization.  Their four-step route produces the tetracycle core in 30% overall yield.

This HOT piece of synthesis is free to access for 4 weeks:

A rapid and convergent synthesis of the integrastatin core
Pamela M. Tadross, Pradeep Bugga and Brian M. Stoltz
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB05725A

You may also like to look at the other reports of the integrastatin core synthesis published in RSC journals:

Unexpected Z-stereoselectivity in the Ramberg–Bäcklund reaction of diarylsulfones leading to cis-stilbenes: the effect of aryl substituents and application in the synthesis of the integrastatin nucleus
Jonathan S. Foot, Gerard M. P. Giblin, A. C. Whitwood and R. J. K. Taylor
Org. Biomol. Chem., 2005, 3, 756-763

An expeditious one-step entry to the tetracyclic core of integrastatins
C. V. Ramana, Challa Nageswara Reddy and Rajesh G. Gonnade
Chem. Commun., 2008, 3151-3153

S-glycosides are resistant to hydrolytic cleavage, which gives them a distinct pharmacological advantage over O-glycosides as ligands for lectins, but inherently present different biological activity.  This HOT article evaluates the ability of dithiodigalactoside (DTDG) – which was identified through a dynamic combinatorial library approach in a previous study – to protect human cells from toxin binding.

Jésus Jiménez-Barbero, CSIC, and an international team of researchers show that DTDG is capable of selecting between the mistletoe toxin and human lectins and conclude that glycosyldisulfides have potential as chemical platform for inhibitor design.

Interested? The article is free to download for the next 4 weeks:

Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins
Sonsoles Martín-Santamaría, Sabine André, Eliza Buzamet, Rémi Caraballo, Gloria Fernández-Cureses, Maria Morando, João P. Ribeiro, Karla Ramírez-Gualito, Beatriz de Pascual-Teresa, F. Javier Cañada, Margarita Menéndez, Olof Ramström, Jesús Jiménez-Barbero, Dolores Solís and Hans-Joachim Gabius
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB01235A

Achieving sensitive signal detection in fluorescence-based assays often involves chemically pre-amplifying the signal to detectable levels.   There are currently several methods of achieving amplification, but here Andrei Kutateladze and colleagues at the University of Denver come up with a concept different from previous methods based on photoamplified fluorescence quenching.

They are able to detect molecular recognition events in the biotin-avidin system through the autocatalytic photo-unmasking of benzophenone – which acts as both the amplification chain carrier and the quencher for the reporter fluorophore – achieving attomolar detection limits with a relatively cheap CCD camera.  They even demonstrate the possibility of imaging the binding assay with an ordinary mobile phone camera, showing that sensitive analysis can be carried out when expensive state-of-the-art equipment is not available.

To read more, download the article – it’s free to access for the next four weeks:

Photochemically amplified detection of molecular recognition events: an ultra-sensitive fluorescence turn-off binding assay
Tiffany P. Gustafson, Greg A. Metzel and Andrei G. Kutateladze
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB05289F

Integrins play important roles in cell adhesion and signalling, and crucially are over-expressed in certain cancer cells.  The tripeptide Arg-Gly-Asp (RGD) is known to bind to integrins, and understanding exactly how they bind is obviously of fundamental importance for the development of structures with higher integrin affinities for possible therapeutic applications.

Here, Daniel Welsh and David K. Smith (University of York) investigate different ways in which the peptide ligands can be organised for multivalent binding to integrins. Although integrins only posses a single binding site they often grouped together in cell membranes, so mutlivalent binding to multiple integrins is possible.  They investigate both dendritic (covalent) and self-assembly (non-covalent) strategies, finding both can be used in similar ways to enhance the binding of RGD peptides to integrins, but that the self-assembly approach appears to give rise to slightly higher affinity integrin binding.

To find out more download this article – it’s free for the next four weeks:

Comparing dendritic and self-assembly strategies to multivalency—RGD peptide–integrin interactions
Daniel J. Welsh and David K. Smith
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB05241A

As bacteria continue to resist our efforts to eradicate them, the development of new antibiotics with alternative modes of action are required to augment existing treatments.  Cationic antimicrobial peptides (CAPs) show potential, but are often too cytotoxic to be developed as new antibiotics.  One way to get around the cytotoxic mechanisms is to attach agents to carriers, such as gold nanoparticles which are non-toxic to cells and biocompatible.

In this HOT paper Tushar Kanti Chakraborty and colleagues from the Central Drug Research Institute, India, have synthesised some novel sugar amino acid-containing cyclic cationic peptides and attach them to gold nanoparticles to study their therapeutic effects. The preliminary studies found that the sugar amino acid-containing CAPs retained their antimicrobial activity on conjugation with the nanoparticles, but with significantly reduced cytotoxic effects.

Download the article to discover more about the study and the potential mechanism for these CAPs – it’s free to access for four weeks:

Towards the synthesis of sugar amino acid containing antimicrobial noncytotoxic CAP conjugates with gold nanoparticles and a mechanistic study of cell disruption
Sudip Pal, Kalyan Mitra, Sarfuddin Azmi, Jimut Kanti Ghosh and Tushar Kanti Chakraborty
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB05338H