Dr Alexis Perry

About me:

Molecules that can be used to detect biologically significant chemicals and provide a visual output (e.g. a colour change or fluorescence) are vital tools in elucidating fundamental biological processes and their impact upon disease. Our research seeks to develop novel methods in organic chemistry for the discovery and preparation of new sensors, fluorescence probes and light-controllable ligands, both as biomedical tools and as potential therapeutics. In order to achieve this, our research is focussed upon molecules called spiropyrans. Spiropyrans are well-known for their ability to change between colourless and coloured forms in response to light irradiation; however, they can also be tuned to respond to specific molecules of interest (e.g. they can be designed to change colour if they encounter a specific metal). In our research we exploit this property in several related ways:

• We wish to understand how and why specific spiropyrans can detect specific analytes, and hence be able to design spiropyran-based sensors for biomedically significant chemicals (e.g. to understand the role of metals in Alzheimer’s Diseaese).

• The process of “detection” typically involves binding of a spiropyran to an analyte, and this process can be reversed with light. Consequently, we design spiropyrans for light-controlled capture, transport and release of specific molecules, and this is important in chemical synthesis and targeted drug delivery.

• We design spiropyrans that, when irradiated with light, will sequester chemicals that are vital to cellular function – hence causing cell death. This enables targeted cell death to be achieved simply by focussing light as required, and this has potential for the treatment of several cancer types.

Current methods for preparing spiropyrans are somewhat antiquated and inefficient. Correspondingly, rapid, effective discovery of new spiropyrans exists hand-in-glove with development of new methods for their synthesis, and chemical synthesis shares equal prominence with applied research in our laboratory.

Interests:

New methodology for spiropyran synthesis = new opportunities in applied spiropyran research

For over five decades, researchers have uncovered many fascinating spiropyrans with extensive, exciting and important applications. In recent years, however, progress has slowed, principally because synthetic methodology for spiropyran synthesis has not kept pace with the needs of spiropyran discovery. Current synthetic methods for spiropyran synthesis are frequently inefficient, and are strikingly ineffective in generating structural diversity and non-racemic products. This presents a limitation for spiropyran discovery chemistry, wherein new structures with genuinely new properties are rare, and development of spiropyran-based applications is becoming increasingly constrained.

As a synthetic organic chemist by background, my focus in spiropyran chemistry is to address the key deficiencies in current methods for spiropyran synthesis through development of new methodologies, and these then underpin our endeavours in applied spiropyran research. The approaches that we are developing include:

• Multicomponent reaction sequences for efficient synthesis of structurally-diverse spiropyrans

• Combinatorial methods for spiropyran discovery chemistry

• Desymmetrisation methodologies for asymmetric spiropyran synthesis

• New methods for ligation of spiropyrans onto biomolecules of interest

As alluded to above, our development of applied spiropyran research is intrinsically linked to our advances in methodology for spiropyran synthesis. We have previously developed a graphene-spiropyran hybrid material as a platform for sensing for Zn(II), and spiropyran-based sensors for generic M(II) cations and hydrogen sulfide. Our current interests include:

• Light-controlled enantioselective receptors for amino acids

In recent years, the biological importance of D-amino acids has been firmly established against the background of common, genetically-coded L-isomers. D-amino acids are now regarded as essential in mammalian CNS and endocrine function – dysregulation is a feature of neurological diseases such as Alzheimer’s, Parkinson’s, Huntington’s and schizophrenia – and they are found in several important drugs. Consequently, we are designing enantioselective spiropyran-based tools with which to elucidate and manipulate amino acid behaviour comprehensively on a single enantiomer basis, and to facilitate straightforward synthesis of D-amino acids, which are hard to access with current methods

• Light-activated metal chelators for investigating metal dyshomeostasis

The role of metal dyshomeostasis in neurological conditions such as Alzheimer’s disease has been the subject of considerable debate and controversy, and the involvement of metals such as zinc, copper and iron in disease progression remains unclear. To help clarify this situation, we are developing spiropyran-based metal chelators to enable quantification, imaging and transport of each specific metal cation within affected tissues.

• Photodynamic therapy through light-activated iron capture

Qualifications:

PhD (University of Leeds, 2005; supervised by Prof. Adam Nelson)

MSci Chemistry with Medicinal Chemistry (University of Glasgow, 2001)

Career:

2014-present: Lecturer in Organic Chemistry, University of Exeter

Post-doctoral research:

• 2009-2014, University of Exeter (with Dr Mark Wood and Dr Steve Green)
• 2007-2009, University of York (with Prof. Richard Taylor)
• 2005-2006, University of Sydney (with Prof. Max Crossley)