Ulven Group

Our research activities are within medicinal chemistry, drug discovery. Our main focus is on G protein-coupled receptors (GPCRs) and we have especially interested in the free fatty acid receptors, a group of receptors that has great potential as drug targets.

The FFARMED project is an international project that focus on exploring the activity of food constituents on free fatty acid receptors and take advantage of these to counteract type 2 diabetes.

We are also interested in various other targets within inflammation and metabolic diseases, including chemokine receptors and the energy level monitoring kinase AMPK.

Our medicinal chemistry projects revolved design – synthesis – evaluation to map structure-activity relationships and efficiently identify compounds with desired properties. Much of our effort go into synthesis and we continuously aim at developing simpler and more efficient, as well as greener, synthetic methods that can be useful to medicinal chemistry.

 

 

 

 

 

 

 

 

The free fatty acid receptors (FFARs) make up a sub-class of GPCRs that are activated by free fatty acids (FFAs, broadly defined as a carboxylic acid attached to a saturated or unsaturated hydrocarbon chain – a definition that also includes compounds such as acetic acid) and respond to FFAs in physiological settings.

FFA1 (GPR40)

FFA1 is activated by saturated and unsaturated medium- and long-chain FFARs. The receptor is highly expressed in pancreatic β-cells, where it enhances glucose-stimulated insulin secretion, intestinal enteroendocrine cells, where it can promote release of glucose- and appetite-regulating hormones, and in the CNS, where its function is less well characterized.

FFA2 (GPR43)

FFA2 is activated by short-chain fatty acids (SCFAs), including acetic and propionic acid, a compound class that is produced in large amounts by bacterial fermentation of dietary fiber in the lower intestines and colon. The receptor is therefore likely to be an important mediator of the effects of dietary fiber, perhaps the most healthy of all food constituents, and the gut microbiota, which has in recent years been found to have important effects on human health. FFA2 is expressed in immune cells, primarily neutrophils, intestine, pancreas and fat, and is an interesting target for treatment of metabolic and inflammatory conditions.

FFA3 (GPR41)

FFA3 is also activated by SCFAs and is, like FFA2 also a likely mediator of effects from dietary fiber and the gut microbiota. The receptor also has other properties that overlap with FFA2 but has been difficult to study due to the lack of high-quality tool compounds.

FFA4 (GPR120)

FFA4 is activated by long-chain FFARs and is expressed in various organs, including intestines, lung, fat, taste buds and the CNS, as well as on on certain immune cells. The receptor is linked to regulation of metabolism and inflammation, and is a very interesting therapeutic target in these areas.

GPR84

Medium-chain fatty acids are able to activate GPR84 but it is doubted that they are sufficiently potent to make this effect relevant in the physiological setting, and the receptor is therefor still considered to be an orphan (i.e. its natural activator has not been unambiguously identified). GPR84 is found to promote inflammation and is an interesting potential target for treatment of fibrosis and other inflammatory conditions.

 

 

 

 

 

 

 

 

 

 

 

 

Some say that organic chemists these days can make any molecule. But can they be made easily? Our ideal is to develop practical, safe and environmentally benign synthetic methods where improved methods are needed. Naturally, we focus on methods that we need in our medicinal chemistry projects.

Copper-catalyzed N-arylation reactions

Copper is an abundant transition metal that can have excellent catalytic properties under the right conditions. We used copper in combination with a nucleophilic phenanthrolin ligand for the development of an efficient method for arylation of nitrogen in aqueous medium.

(Engel-Andreasen et al. Green Chem. 2012, 15, 336-340)

Purines make up an extremely important compound class, e.g. represented in two of the four nucleic acid bases. They are also ligands for several important receptors with caffeine probably as the most famous example.  On this background, our method was developed further into the first efficient method for N-arylation of purines with aryl iodies.

(Larsen & Ulven Chem. Commun. 2014, 50, 4997-5000)

Simple, safe and stoiciometric production of carbonmonoxide from oxalyl chloride

Carbon monoxide (CO) is a fabulous small building block, but its properties as a highly toxic odorless gas has made many chemists reluctant to bring a cylinder of CO into the lab. Our method makes pure CO in exactly the desired amount easily and cheaply available to anybody with standard equipment and a fume hood.

(Hansen & Ulven, Org. Lett. 2015, 17, 2832-2835)

Synthesis of difficult amides

Amides are everywhere since they link amino acids to form peptides and proteins, and synthesis of amides have often been considered a solved problem. However, most organic chemists have probalby encountered amides that they were unable to synthesize (even if they don’t talk about it…). Electron poor amines such as anilines can be quite difficult substrates for amide coupling, and often impossible if the substrates also are sterically hindered. We encountered one such amide in the synthesis of an FFA2 ligand. We solved the problem by converting the carboxylic acid to a minimally hindered acyl fluoride and performing the coupling with gentle heating. (The challenging nature of this particular amide was illustrated by its clean hydrolysis back to the starting material with only weak acid – in fact, since the FFA2 lignad also contained a carboxylic acid, it was unstable towards itself in neutral form.)

(Due-Hansen et al, Org. Biomol. Chem. 2016, 14, 430-433)

Improved Sonogashira coupling

Our first FFA1 series required assembly by Sonogashira coupling. Unfortunately, the unusually sluggish and unpredictable reactions with our substrate put a serious brake on the progress in the project. This was solved by adopting a ligand developed in the Beller group and performing the reaction under aqueous conditions.

Synthesis of functionalized phenanthrolines

Phenanthrolines are efficient metal chelators that have a variety of used. We have used them as scaffolds in design of G-quaruplex stabilizing ligands and as ligands in transition metal catalyzed reactions.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Luminescent tools enable accurate real-time tracking of molecular entities in biological systems and have become ubiquitous in molecular biological research. We are especially interested in developing small-molecule fluorescent tools for studies of GPCRs. Ongoing project fall in two general categories: The first is tools for microscopy, where probes that emit long-wave light in the red or near-infrared bands are preferred for maximal tissue penetration and minimal interference from cellular autofluorescence. The second is tools designed to communicate with other molecules, such as tagged proteins. One way to do this is to tag the protein of interest (for us, typically a GPCR) with an enzyme that is able to convert a chemical substrate to light with a particular wavelength. If a fluorescent compound that is excited at the same wavelength comes nearby, the light is transferred from the enzyme to the probe in a process known as bioluminescence resonance energy transfer (BRET), and the probes emits light at a new wavelenght. For example, nanoluciferase (NLUC) consumes coelantrazine and produces light with 460 nm wavelenght.

A fluorescent ligand that is excited at this wavelength will then shine in a different color when binding to a receptor that is tagged with NLUC. It turns out that the small fluorophore NBD (green star below) has an excitation band that overlaps almost perfectly with the emission band of NLUC.

This is a principle that we have used for the generation of BRET-based binding assays for FFA1 and FFA2:


(Christiansen, Hudon, et al. J. Med. Chem. 2016, 59, 4849-4858)


(Hansen, Sergeev, et al. J. Med. Chem. 2017, 60, 5638-5645)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Our body has multiple receptors that detect nutrients and ensure that the body responds appropriately to convert nutrients to energy or use them as building materials. Many of these receptor has potential as drug targets. For example, the medium- and long-chain fatty acid receptors FFA1 and FFA4 are recognized as promising targets for treatment of metabolic diseases such as type 2 diabetes and metabolic dysfunction-associated steatohepatitis (MASH), and activation of the receptors is expected to give the therapeutic effect. This implies that medium and long-chain fatty acids has therapeutic potential through activity on these receptors. Our FFARMED project was set up to explore this potential.

 

 

 

 

 

 

 

 

 

 

 

 

Group leader

Group leader

Trond Ulven
Professor

E-mail: tu@sund.ku.dk
Phone: +45 3533 6487

Publications
Google Scholar

Group members

Name Title Phone E-mail
Anette Lundskov Eriksen Laboratory Technician +4535336245 E-mail
Asmita Manandhar Postdoc E-mail
Jakob Bjerregaard Jeppesen Research Assistant E-mail
Katrine Schultz-Knudsen Postdoc +4535325516 E-mail
Lasse Brokmose Poulsen Postdoc E-mail
Trond Ulven Professor +4535336045 E-mail