Intern
Prof. Dr. U. Schatzschneider

CO-releasing Molecules

CO-releasing molecules (CORMs)

CO-releasing molecules either release the carbon monoxide "payload" outside the cell or first get internalized and then release the bioactive small molecule.

Biological activity of carbon monoxide

To the general public, carbon monoxide is usually only known as a highly toxic air pollutant resulting from the incomplete combustion of carbon materials. However, it is in fact also enzymatically generated in higher organisms, including humans, by the activity of heme oxygenase (HO) on heme. Over the last decade or so, a wide range of biological processes were demonstrated to be influenced by such endogenously produced carbon monoxide and researchers have now also started to explore its therapeutic potential in human medicine.

468 nm blue light LED light source for the illumination of samples in standard 96-well plates, constructed in-house by the Electronics Workshop

Carbon monoxide delivery systems

Since carbon monoxide gas is difficult to dose and distributes in the body solely based on the partition ratio between different body fluids and tissues, researchers have started to explore organic and metal carbonyl compounds as carbon monoxide delivery systems, commonly referred to as CO-releasing molecules (CORMs).

For almost a decade, the Schatzschneider group has been involved in the development of metal-carbonyl complexes as CO-releasing molecules, with a particular focus on the use of light to initiate the release of carbon monoxide from the carrier molecule, which enables spatial and temporal control of the release process. Such photoactivatable CO-releasing molecules (PhotoCORMs) are now explored for their biological potential in the context of wound healing and antibacterial chemotherapy.

In addition to optimization of the CO release parameters, such as excitation wavelength and release kinetics, which are controlled by proper metal-coligand combinations (called the CORM sphere), the focus of our research has now increasingly shifted towards the improvement of the bioavailability of our CO-releasing molecules, which involves systematic variation of the outer ligand periphery (called the drug sphere).

A relatively new approach we have started to explore only recently is the encapsulation of CO and CORMs in solid nanomaterials for slow release and retention of metal-coligand byproducts of the release process.

Reviews

For some general reviews from the Schatzschneider group on the biological activity of CO as well as NO and H2S as the other two small signaling molecules, and the use of metal complexes as delivery systems for carbon monoxide, see for example:

Biological activity of CORMs

In a number of studies, the Schatzschneider group has investigated the antitumor and antibacterial activity of CO-releasing molecules (CORMs). A particularly useful tool to study the CO release in living human cells is the use of the COP-1 fluorescent probe developed by the laboratory of Prof. Dr. Chris Chang at the University of California at Berkeley (UCB):

UV/Vis excitation (red arrow) leads to release of one CO ligand with the structure of the follow-up product probed by IR interrogation (blue arrow)

Advanced spetroscopy on CORMs

A wide range of advanced spectroscopic methods was utilized to investigate the primary photophysical and photochemical processes on light-triggered CO release and localization of CORMs in biological systems based on their inherent spectroscopic signature. For example, in cooperation with the group of Prof. Dr. Patrick Nürnberger at the Ruhr-Universität Bochum (RUB), UV/Vis pump-IR probe spectroscopy on the femtosecond timescale was used to study the initial excited states of a PhotoCORM when triggered at 264 nm. Together with Prof. Dr. Martina Havenith-Newen, also at RUB, Raman microspectroscopy allowed us to image the intracellular distribution of a CORM in livinig human cells.

CO- and NO-releasing molecules

A wide range of metal-carbonyl and nitrosyl complexes has been investigated as CO- and NO-releasing molecules. The focus of our work has been on manganese(I) tricarbonyl complexes of the general formula fac-[MnBr(CO)3(N^N)] and fac-[Mn(CO)3(N^N^N)]+ with bi- and tridentate chelating coligands. However, other metal carbonyl moieties, such as Ir(CO)2, Ru(CO)2, and Fe(CO)3 was also investigated with a number of collaboration partners:

CORM bioconjugates

The target affinity of CO-releasing molecules can be modulated by attachment to bio(macro)molecules. Over the last couple of years, the Schatzschneider group has utilized different bioorthogonal Click reactions such as Sonogashira, CuAAC, and oxime ligation reactions to attach manganese(I) tricarbonyl and molybdenum(0) tetracarbonyl moieties to a range of carrier peptides:

Transmission electron microscopy (TEM) was utilized to visualize silica nanoparticles prepared by the Stöber process and decorated with CO-releasing molecules (CORMs) using CuAAC "click" chemistry

CORM nanomaterials

Surface modification of organic and inorganic hard nanomaterials such as nanodiamond or silica particles with CO releasing-molecules (CORMs) allows precise spatial and temporal control of the release process, while potentially cytotoxic byproducts remain bound to the surface. Alternatively, a porous nanomaterial can be directly loaded with CO gas coordinating to the metal building blocks, for example in metal-organic frameworks (MOFs):