Francesca Burgoyne – Page 7 – Organic & Biomolecular Chemistry Blog

Author Archive

HOT: multivalent strategies for RGD peptide-integrin binding

24 May 2011

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

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HOT: sweet but not sickly – non-cytotoxic sugar amino acid-containing antimicrobial agents

24 May 2011

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

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Emerging area: unlocked nucleic acids

27 Apr 2011

The continuing search for modified nucleic acids with improved properties for use in molecular diagnostics, gene- and RNA-targeting therapies has now lighted on unlocked nucleic acids monomers – which act as acyclic RNA mimics. Unlocked nucleic acids monomers (UNA) were first synthesised over a decade ago, but only now has their potential for therapeutics really been explored.

Structure of a UNA monomer

In this Emerging Area article, Anna Pasternak and Jesper Wengel (University of Southern Denmark) find that UNA monomers inserted into oligonucleotides can modulate the thermodynamic stability of DNA and RNA structures such as duplexes, quadruplexes and i-motifs. This, they hope, will open up new options for designing new quadruplex-based aptamer drugs and superior siRNA constructs due to their high silencing activity and low toxicity.

Download the article to read the full details:

Unlocked nucleic acid – an RNA modification with broad potential
Anna Pasternak and Jesper Wengel
Org. Biomol. Chem., 2011, 9, 3591-3597
DOI: 10.1039/C0OB01085E

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HOT article: upping the TEMPO-H

19 Apr 2011

The stable radical TEMPO is an an important molecule for organic catalysis, and its protonated cousin TEMPO-H is an excellent chemical source of hydrogen. However, Jason Masuda and Jason Clyburne (Saint Mary’s University, Canada) were concerned that, due to the current synthetic route, water present in TEMPO-H could lead to unwanted side reactions.

In this HOT paper they overcome this problem by reporting the first anhydrous route to TEMPO-H (2,2,6,6-tetramethylpiperidin-1-ol), by treating the sodium salt of TEMPO with triethylamine hydrochloride. They show that the anhydrous form is not only more stable during synthesis, but that it has a different structure and reactivity patterns as well. They tested their anhydrous compound against several molecules with low valence carbon centres such as carbenes and ketenes, demonstrating the use of the anhydrous form in avoiding side reactions and creating different complex structures.

: Preparation of anhydrous TEMPO-H

You can read the full details of the synthesis and characterisation for free until 14th May:

Anhydrous TEMPO-H: reactions of a good hydrogen atom donor with low-valent carbon centres
Nick A. Giffin, Miller Makramalla, Arthur D. Hendsbee, Katherine N. Robertson, Cody Sherren, Cory C. Pye, Jason D. Masuda and Jason A. C. Clyburne
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB00999G, Paper

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HOT article: success in a time of cholera

07 Apr 2011

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

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HOT article: radical alkylation of guanosines in water

29 Mar 2011

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

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HOT article: 2,3-diarylquinoline derivative potential new lead for anticancer drug

24 Mar 2011

Researchers from Kaohsiung Medical University, Taiwan, have synthesised and tested a number of 2,3-diarylquinoline derivatives for anticancer activities, one of which showed significant potential preventing cell growth in certain cancer cell lines.

Cherng-Chyi Tzeng and colleagues synthesised the 2,3-diarylquinoline derivatives as part of a continuing study to explore potent anticancer drug candidates. The quinoline skeleton is prevalent in many natural and synthetic heterocycles with a wide range of biological effects, including antitumor activity. The structures of tamoxifen and combretastatin A-4, two potent anticancer agents, were modified to include the quinoline moiety and various side chains to improve their activity.

Testing against six cancer cell lines, including human hepatocelluar carcinoma, non-small cell lung cancer and breast cancer, revealed one compound that was more active than tamoxifen. 6-fluoro-2,3-bis{4-[2-(piperidin-1-yl)ethoxy]phenyl}quinoline-otherwise known in this paper as the more manageable 16b-was shown to induce cell cycle arrest at the G2/M phase, resulting ultimately in cell death in half of the tested cell lines. Work is ongoing to optimise the structure.

This HOT article is free to access for the next month – download it today!

Synthesis and antiproliferative evaluation of 2,3-diarylquinoline derivatives
Chih-Hua Tseng, Yeh-Long Chen, Kuin-Yu Chung, Chi-Huei Wang, Shin-I Peng, Chih-Mei Cheng and Cherng-Chyi Tzeng
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB01225D

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HOT article: nitrate radical real culprit in respiratory diseases?

24 Mar 2011

Although the presence of ozone and NO_x gases (i.e. NO^. and NO₂^.) are often linked to an increase in respiratory conditions such as asthma, the mechanism by which these pollutants cause respiratory distress is still not clear. Interestingly, the highly reactive NO₃^. (formed in the atmosphere at night by reaction of O₃ and NO₂^.) has been somewhat overlooked as a possible respiratory irritant despite numerous studies on its role in the atmosphere.

In this HOT paper Uta Wille and colleagues at the University of Melbourne follow up a previous study published in Chem. Comm. which identified the products of the reaction of the NO₃ radical with amino acids. Now, they have simulated the exposure of proteins present at the surface of the respiratory tract to a number of environmental pollutants, determining clear reaction pathways resulting in aromatic ring nitration of the amino acids studied. They note that nitrated aromatic amino acids are often observed in a wide range of inflammatory-immune responses such as asthma and cystic fibrosis, leading them to suggest that the NO₃ radical could actually be the real culprit in certain pollution-related diseases.

You can read the full details of this interesting study online here (it’s free to access for the next month!).

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

Damage of aromatic amino acids by the atmospheric free radical oxidant NO3˙ in the presence of NO2˙, N2O4, O3 and O2
Catrin Goeschen, Natalia Wibowo, Jonathan M. White and Uta Wille
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB01186J

And the previous Chem. Comm. paper can be found here:

Can the night-time atmospheric oxidant NO3˙damage aromatic amino acids?
Duanne C. E. Sigmund and Uta Wille
Chem. Commun., 2008, 2121-2123
DOI: 10.1039/B803456G

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Issue 7 cover article – an efficient iron-mediated approach to pyrano[3,2-a]carbazole alkaloids

16 Mar 2011

The article highlighted on the cover of Issue 7 is a communication from Hans-Joachim Knölker and co-workers describing the syntheses of O-methylmurrayamine A and 7-methoxymurrayacine and first asymmetric synthesis of (−)-trans-dihydroxygirinimbine.

Pyrano[3,2-a]carbazole alkaloids are an interesting class of molecule with pharmacological potential, which has lead to an effort to develop efficient synthetic routes towards them. Here the authors report an iron-mediated route to the pyrano[3,2-a]carbazole skeleton with high efficiencies.

The article comes highly recommended by our referees, so why not download the article today – it’s free to access for 6 weeks!

Efficient iron-mediated approach to pyrano[3,2-a]carbazole alkaloids—first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine, first asymmetric synthesis and assignment of the absolute configuration of (−)-trans-dihydroxygirinimbine
Konstanze K. Gruner, Thomas Hopfmann, Kazuhiro Matsumoto, Anne Jäger, Tsutomu Katsuki and Hans-Joachim Knölker
Org. Biomol. Chem., 2011, 9, 2057-2061
DOI: 10.1039/C0OB01088J

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HOT article: neutral species from “non-protic” ionic liquids

16 Mar 2011

This computational study addresses the possible isomerisation of 1,2,3-trialkylimidazolium and 1-alkylpyridium ion pairs through proton transfer. The formation of neutral species in protic room temperature ionic liquids has been well studied, but the mechanism in other, “non-protic” species has been subject to less investigation.

Oldamur Hollóczki and László Nyulászi from Budapest University of Technology and Economics carried out the DFT study after observing that the “protic nature” of an ionic liquid depends not only on the cation, but on the cation/anion assembly. Their investigations determined that the formation of neutral species is a viable possibility for ion pairs containing sufficiently basic anions, such as organic acids . This, they say, means that the description of imidazolium or pyridinium based ionic liquids with basic anions as pure ionic substances is oversimplified. The presence of trace amounts of neutral species could affect the physical properties of the ILs and any basic anions present could result in unexpected reactions in “inert” IL solvents.

Neutral species from “non-protic” N-heterocyclic ionic liquids
Oldamur Hollóczki and László Nyulászi
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB00007A

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