ÌÇÐÄTV

Dr Manuela Tosin will be joining ÌÇÐÄTV Chemistry as an Assistant Professor in Organic Chemistry from 1 November 2010. Dr Tosin's research interests are primarily in the area of the discovery and generation of new natural products. Manuela comes to ÌÇÐÄTV Chemistry from the Department of Biochemistry, University of Cambridge where she worked with Dr Joe Spencer and Prof Peter Leadlay.

A Potent Trans-Diimine Platinum Anticancer Complex Photoactivated by Visible Light

N. J. Farrer, J. A. Woods, L. Salassa, Y. Zhao, K. S. Robinson, G. Clarkson, F. S. Mackay, P. J. Sadler

Angew. Chem. Int. Ed, 2010, early view. DOI: 10.1002/anie.201003399

Activating platinum with light: An inert platinum(IV) diazido complex trans,trantrans,trans-[Pt(N₃)₂(OH)₂(py)₂] becomes potently cytotoxic to cancer cells when activated by low doses of visible light.

A review article on linear dichroism (LD) spectroscopy has been published by members of the Biophysical Chemistry Group and is now available online:

Matthew R. Hicks, Jaroslaw Kowalski and Alison Rodger Chem. Soc. Rev., 2010

DOI: 10.1039/b912917k LD spectroscopy of natural and synthetic biomaterials

 

 

In this article in Angewandte Chemie, Rodger and coworkers us metadynamics computer simulations to show that the eggshell protein ovocleidin-17 induces the formation of calcite crystals from amorphous calcium carbonate nanoparticles. Multiple spontaneous crystallization and amorphization events were simulated; these simulations suggest a catalytic cycle that explains the role of ovocleidin-17 in the first stages of eggshell formation (the picture shows one intermediate of this cycle).

Proteins age in many ways, but one of them involves deamidation of asparagine and glutamine to aspartic and glutamic acids respectively.  When this occurs, two isomers of the acidic species are generated.  Glutamine deamidation of proteins is specifically studied by the O'Connor group in a new report in Analytical chemistry, with the result that the two isomers can be readily differentiated with a new fragmentation technique called Electron Capture Dissociation. 

 

 

The team studied the binding mode adopted by picolinamide derivatives in organometallic Os^II and Ru^II half-sandwich complexes and showed that it can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os^II (1, 3−5, 7, 9) and Ru^II (2, 6, 8, 10) complexes [(η⁶-arene)(Os/Ru)(XY)Cl]ⁿ⁺, where arene = p-cymene (1−8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1−5 and 9) hydrolyzed rapidly (t_1/2 ≤ min), exhibited significant (32−70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian, and cisplatin-resistant ovarian human cancer cell lines (3 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic.

Drugs made using unusual metals could form an effective treatment against colon and ovarian cancer, including cancerous cells that have developed immunity to other drugs, according to research at the University of ÌÇÐÄTV and the University of Leeds.

The study, published in the Journal of Medicinal Chemistry, showed that a range of compounds containing the two transition metals Ruthenium and Osmium, which are found in the same part of the periodic table as precious metals like platinum and gold, cause significant cell death in ovarian and colon cancer cells.  

The compounds were also effective against ovarian cancer cells which are resistant to the drug Cisplatin, the most successful transition metal drug, which contains the metal platinum.

  Dr Patrick McGowan, one of the lead authors of the research from the School of Chemistry at the University of Leeds, explains: “Ruthenium and Osmium compounds are showing very high levels of activity against ovarian cancer, which is a significant step forward in the field of medicinal chemistry.

Sabine H. van Rijt, lead researcher in the laboratory of Professor Peter Sadler in the Department of Chemistry at the University of ÌÇÐÄTV, said:

“Most interestingly, cancerous cells that have shown resistance to the most successful transition metal drug, Cisplatin, show a high death rate with these new compounds.”

 Professor Sadler, at the University of ÌÇÐÄTV, commented that he is “excited by the novel design features in these compounds which might enable activity to be switched on and off”.

Cisplatin was discovered in the 1970s and is one of the most effective cancer drugs on the market, with a 95% cure rate against testicular cancer.  Since the success of Cisplatin, chemists all over the world have been trying to discover whether other transition metal compounds can be used to treat cancer.

In this type of anti cancer drug transition metal atoms bind to DNA molecules which trigger apoptosis, or programmed cell death, in the cancerous cells.

The study is a collaboration between the universities of ÌÇÐÄTV and Leeds and was funded by the Engineering and Physical Sciences Research Council  (EPSRC).

 For more information please contact:

Dr Patrick McGowan  at leeds +44 (0)113 343 6404, or email: p.c.mcgowan@leeds.ac.uk  

Sabine H. van Rijt and Professor Peter Sadler from the University of ÌÇÐÄTV are available for interview via  Professor Peter Sadler +44 (0)24 76 523818 p.j.sadler@warwick.ac.uk

Ann Dixon and collaborators report in Journal of Virology: The bovine papillomavirus E5 protein (BPV E5) is a 44-amino acid homodimeric transmembrane protein that binds directly to the transmembrane domain of the PDGF receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF receptor and transform mouse fibroblasts: a pair of C-terminal cysteines, a transmembrane glutamine, and a juxtamembrane aspartic acid. By using a new genetic technique to screen libraries expressing artificial transmembrane proteins for activators of the PDGF receptor, we isolated much smaller proteins, from 32 to 36 residues, that lack all three of these features yet still dimerize non-covalently, specifically activate the PDGF receptor via its transmembrane domain, and transform cells efficiently. The primary amino acid sequence of BPV E5 is virtually unrecognizable in some of these proteins, which share as few as seven consecutive amino acids with the viral protein. Thus, small artificial proteins that bear little resemblance to a viral oncoprotein can nevertheless productively interact with the same cellular target. We speculate that similar cellular proteins may exist but have been overlooked due to their small size and hydrophobicity.

 

 Professor Gregory Challis has been awarded The 2009 Gabor Medal by the Royal Society, the UK’s independent academy for science.

Greg Challis, Professor of Chemical Biology in the Department of Chemistry, received the medal and £1000 prize for his highly interdisciplinary work exploiting the genomics of Streptomyces coelicolor to identify new natural products and biosynthetic enzymes.

The silver gilt medal is named after Nobel Prize-winner Professor Dennis Gabor FRS and is awarded biennially for acknowledged distinction in interdisciplinary work between the life sciences and other disciplines.

Professor Challis said: “I am delighted that I have been selected to receive the 2009 Gabor Medal. Natural products continue to play important roles in society, for example as life-saving medicines, environmentally benign pesticides and drugs that enhance the quality of our daily lives. It is wonderful that the importance of ongoing research into natural products has been recognised by the Royal Society.

"As is often the case in modern science, many people contributed to the research recognised by this award. It has been my privilege to work with a talented team of postdoctoral researchers, PhD students and collaborators over the past eight years at ÌÇÐÄTV and I am fortunate to have benefited from the support of my family, as well as many colleagues across the University. ÌÇÐÄTV Chemistry has established a reputation for research excellence at the interface of Chemistry and Biology which involves numerous vibrant and dynamic research groups working in several different fields. It is gratifying that this has been recognised by the UK’s premier scientific society.”

Notes to editors

For more information, please contact Kelly Parkes-Harrison, Communications Officer, University of ÌÇÐÄTV, 02476 150483, 07824 540863, k.e.parkes@warwick.ac.uk

Greg Challis wins the RSC Hickinbottom Award for his contributions to the "exploitation of genomics, for the discovery of novel bioactive natural products, and for mechanistic studies on enzymes that catalyse key steps in pathogenicity-conferring siderophore biosynthesis."

Researchers at the University of ÌÇÐÄTV have found how a citric acid-based Achilles heel used by a pathogen that attacks the popular African Violet house plant could be exploited not just to save African Violets but also to provide a potentially effective treatment for Anthrax.The researchers examined how a chemical structure is assembled in a bacterial pathogen called Pectobacterium chrysanthemi (Dickya dadantii) that afflicts plants – particularly the African Violet which often appears in many homes as a decorative houseplant.Like many bacteria Pectobacterium chrysanthemi competes with its host for iron. Without a supply of this essential nutrient the bacterium cannot grow. The University of ÌÇÐÄTV researchers Dr Nadia Kadi, Dr Daniel Oves-Costales, Dr Lijiang Song and Professor Gregory Challis worked with colleagues at St Andrews University to examine how a "siderophore", one of the key tools the bacterium uses to harvest iron is assembled. They discovered how an enzyme catalyst in the assembly of this particular siderophore – called achromobactin – binds citric acid, a vital iron-binding component of the structure. Their findings show that this chemical pathway could be blocked or inhibited to prevent the bacterium from harvesting iron, essentially starving it.

While an interesting piece of science in itself and of even more interest to owners of African Violet houseplants the ÌÇÐÄTV research team found that this work also has major implications for the treatment of several virulent and even deadly mammalian infections including Anthrax.

">A second piece of research conducted by three of the University of ÌÇÐÄTV researchers (Dr Daniel Oves-Costales, Dr Lijiang Song and Professor Gregory L. Challis ) found that the deadly pathogen which causes Anthrax in humans uses an enzyme to incorporate citric acid into another siderophore that is very similar to the one used by the African Violet pathogen. The researchers showed that both enzymes recognise citric acid in the same way. This means a common strategy could be used to block both the Anthrax and African Violet pathogen siderophore synthesis pathways.

Professor Greg Challis from the University of ÌÇÐÄTV said:

"Inhibiting this citric acid-based process could be even more effective in combating an anthrax infection than it would be in combating the African violet pathogen, because the African Violet pathogen has a second siderophore that can harvest iron from the host and could attempt to struggle on with just this, whereas the anthrax pathogen appears not to have such a back up mechanism."