Mike Shipman, Tiffany Walsh and co-workers have recently published a new method for detecting and quantifying noncovalent interactions.  They have discovered that the rate of nitrogen inversion in aziridine derivatives is dependent on intramolecular interactions between attached functional groups.  For example, the ortho-substituted pyridine undergoes faster inversion than its para-substituted analogue as a result of the formation of an intramolecular amide–pyridine (NH⋅⋅⋅N) hydrogen bond in the transition state (see graphic).  Using simple NMR methods, it is possible to quantify the strength of these interactions in the transition state, and compare them with those predicted using computational methods.  This work is expected to have applicability to a range of other important noncovalent interactions.  It was conducted in collaboration with the Tucker group at the University of Birmingham. 

The paper is published in the 17 January 2011 issue of Angewandte Chemie.

http://onlinelibrary.wiley.com/doi/10.1002/anie.201005580/abstract

When it comes to health care blue lights, are usually most useful on the top of ambulances but now new research led by the University of Warwick has found a way to use blue light to activate what could be a highly potent platinum-based cancer treatment.

Research led by the University of Warwick, along with researchers from Ninewells Hospital Dundee, and the University of Edinburgh, have found a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use “light activation” to kill cancer cells in a much more targeted way than similar treatments.

The University of Warwick team had already found a platinum-based compound that they could activate with ultra-violet light but that narrow wave length of light would have limited its use. Their latest breakthrough has discovered a new platinum based compound known as trans,trans,trans-[Pt(N₃)₂(OH)₂(py)₂] that can be activated by normal visible blue, or even green, light. It is also stable and easy to work with, and it is water soluble so it can simply dissolve and be flushed out of the body after use.

The University of Warwick researchers passed the new compound to colleagues at Ninewells Hospital Dundee, who tested it on oesophageal cancer cells cultivated within lab equipment. Those tests show that once activated by blue light the compound was highly effective requiring a concentration of just 8.4 micro moles per litre to kill 50% of the cancer cells. The researchers are also beginning to examine the compound’s effectiveness against ovarian and liver cancer cells. Early results there are also excellent but that testing work is not yet complete.

Professor Peter Sadler, from the Department of Chemistry from University of Warwick, who led the research project, said:

“This compound could have a significant impact on the effectiveness of future cancer treatments. Light activation provides this compound’s massive toxic power and also allows treatment to be targeted much more accurately against cancer cells.”

“The special thing about our complex is that it is not only activated by ultra-violet light, but also by low doses of blue or green light. Light activation generates a powerful cytotoxic compound that has proven to be significantly more effective than treatments such as cisplatin.”

We believe that photoactivated platinum complexes will make it possible to treat cancers that have previously not reacted to chemotherapy with platinum complexes,” says Sadler. “Tumors that have developed resistance to conventional platinum drugs could respond to these complexes and with less side-effects.”

This research has been supported by the EPSRC, MRC, ERC and Science City (ERDF/AWM).

Note for editors: The research has just been published in Angewandte Chemie, under the title “A Potent Trans Diimine Platinum Anticancer Complex Photoactivated by Visible Light”. The authors are – Project leader Professor Peter Sadler, (University of Warwick) and Nicola J. Farrer, Julie A. Woods, Luca Salassa, Yao Zhao, Kim S. Robinson, Guy Clarkson, and Fiona S. Mackay.

For more information please contact:

Professor Peter Sadler
University of Warwick, Department of Chemistry
Tel: +44 (0)7913 944357
P.J.Sadler@warwick.ac.uk

Peter Dunn, Head of Communications, University of Warwick,
44 (0)24 76 523708
mobile/cell +44 (0)7767 655860
p.j.dunn@warwick.ac.uk

PR171 9th December 2010

A new class of highly active zirconium catalyst for the synthesis of chiral heterocycles from aminoalkenes is shown to operate via a Zr=N bonded (imido) species. Peter Scott and group members Laura Allan and Andrew Gott, in collaboration with David Fox and Guy Clarkson at Warwick, report in Journal of the American Chemical Society a detailed EPSRC-funded study which for the first time excludes the conventional Zr-N (amido) mechanism.

Dr Manuela Tosin will be joining Warwick 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 Warwick Chemistry from the Department of Biochemistry, University of Cambridge where she worked with Dr Joe Spencer and Prof Peter Leadlay.

Angew. Chem. Int. Ed, 2010, early view (DOI: 10.1002/anie.201002721)

http://onlinelibrary.wiley.com/doi/10.1002/anie.201002721/abstract

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.

http://0-www3.interscience.wiley.com.pugwash.lib.warwick.ac.uk/cgi-bin/fulltext/123597042/PDFSTART

Sarah Crosby, working in Jon Rourke's group, has identified a number of new Pt(IV) complexes containg dmso ligands.

Oxidation of cyclometalated Pt(II) complexes with S-bound DMSO ligands initially results in Pt(IV) complexes which retain the S-bound DMSO ligands in the same relative position. Isomerisation reactions result in a rearrangement of the ligands to give O-bound DMSO complexes, with the DMSO trans to a cyclometalated carbon. X-ray structures representing the only two known examples of Pt(IV) complexes with O-bound DMSO ligands have been solved. The rate of isomerisation of complexes without a pendant alkyl chain is strongly solvent dependent, consistent with the need to stabilise a coordinatively unsaturated intermediate. Pt(IV) complexes with a pendant alkyl chain show little dependence on isomerisation rate with solvent, with solution NMR data strongly suggesting the presence of agostic complexes. DFT calculations provide support for the presence of agostic complexes, with the same interactions being used to account for the loss of DMSO from the O-bound DMSO complexes.

See http://pubs.acs.org/doi/pdf/10.1021/om901087m

Jon Rourke and collaborators report in ACS nano on the structural analysis of graphene oxide (GO) by transmission electron microscopy (TEM). Electron diffraction shows that on average the underlying carbon lattice maintains the order and lattice-spacings of graphene; a structure that is clearly resolved in 80 kV aberration-corrected atomic resolution TEM images. These results also reveal that single GO sheets are highly electron transparent and stable in the electron beam, and hence ideal support films for the study of nanoparticles and macromolecules by TEM. We demonstrate this through the structural analysis of physiological ferritin, an iron-storage protein. http://dx.doi.org/ 10.1021/nn900694t

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. http://dx.doi.org/10.1021/jm900731j

2-tert-Butyl-6-(4-fluorophenyl)pyridine reacts with K₂PtCl₄ via the activation of an sp² C−H bond to give a cyclometalated complex that contains a bifurcated agostic interaction. Rearrangement of this complex results in the activation of an sp³ C−H bond, and reaction eventually leads to a doubly cyclometalated complex where both sp² and sp³ C−H bonds have been activated. Deuterium exchange studies show that a delicate balance exists between the two cyclometalations.

http://dx.doi.org/10.1021/ja905046n