School of Chemistry Colloquium: Professor Mike Watkinson Targeted small molecule fluorescent probes for the detection of mobile zinc

Zinc mis-regulation is associated with a wide range of disease states and there is an ongoing need to study the behaviour of ‘mobile' or ‘free' zinc to better understand its role in their development and progression. Small molecule fluorescent probes are commonly used for this purpose, and a significant number of probes have been developed by us and many others. Many probes suffer from a number of limitations and a contemporary target remains the development of probes with a high selectivity for Zn2+, displaying a range of Kd values to cover the varying concentrations of zinc present, which are also capable of targeting specific cellular space. To this end, we have developed our first generation “clickate” zinc sensors further and have established a novel one-pot synthetic route towards a library of probes targeted to specific cellular organelles. Following successful in-vitro testing, investigations in murine pancreatic islets demonstrated that each sensor localised in its intended target area and responded to various Zn2+ stimuli. An extracellularly-anchored probe also demonstrated a fluorescent output in-keeping with the known co-release of chelatable Zn2+ when an insulin stimulus was applied to the islets and was further utilized to help differentiate between pacemaker and follower pancreatic β-cells. More recently we have extended this chemistry further to develop probes that are also able to image mobile zinc in the endoplasmic reticulum, Golgi apparatus as well as probes capable of specifically targeting breast cancer cells.