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Marine molecules kill both leukemia cells and resistant bacteria

Pål Rongved og Elvar Örn Viktorsson tilhører forskergruppen Synfas ved UiO.
Professor Pål Rongved with Elvar Örn Viktorsson, who developed more than 100 new drug candidates in the laboratory at UiO's School of Pharmacy. Photo: Bjarne Røsjø, UiO. Bruk bildet.

Marine molecules kill both leukemia cells and resistant bacteria

It has been known for almost 80 years that the small marine molecule iodinin kills bacteria. Unfortunately, natural iodinin is useless as a drug, but new results suggest that analogues of iodinin can be used as effective drugs against both aggressive leukemia cells and antibiotics-resistant bacteria.
Krystaller av iodinin
Crystals of naturally occuring iodinin (picture) are difficult to use, but the synthetic compounds are much more manageable. Photo: Elvar Örn Viktorsson, UiO.

The main results from Elvar Örn Viktorsson’s PhD dissertation, and many long hours in a laboratory at the University of Oslo (UiO), were published in the renowned scientific journal Bioorganic & Medicinal Chemistry already in April 2017, long before Viktorsson’s disputation in October. The message was that Viktorsson and colleagues at the university’s School of Pharmacy had managed to develop highly promising drug candidates based on the molecule iodinin, which other chemists and pharmacists had given up on years ago.

All in all, researcher Elvar Örn Viktorsson at the UiO has produced more than 100 slightly different variants or analogues of the original marine molecule. Some of the new analogues were found to kill blood cancer cells found in acute myeloid leukemia (AML), while others are very efficient in killing bacteria that are resistant to other antibiotics. Viktorsson has even found some compounds that point towards new medicines for treating atherosclerosis and diabetes type 2.

Kills cancer without hurting heart cells

The need for progress in the treatment of AML is urgent, because this cancer has a high mortality and is impossible to cure with surgery. Instead, the cancer must be treated with a powerful chemotherapeutic cocktail that hurts a large portion of the patients. The risk of dying from the treatment increases with the patient’s age, and the chemotherapy can cause serious damage do cells in the musculature of the heart.

"Because of the major problems with today's treatment of AML, there is a great need for new and better methods, and our research has launched some exciting opportunities. Our partners at the University of Bergen have conducted laboratory trials and demonstrated that several of our synthetic iodinin analogues are effective in killing AML cells, while the toxic effect on the heart cells is much less than with the current treatment”, says Viktorsson.

He has worked long hours in the laboratory at the School of Pharmacy, in order to create the more than 100 different variants of iodinin. The next step is to investigate the most interesting AML-fighting iodinin analogues further. But one of the analogues is so efficient in killing antibiotic-resistant bacteria that neither Viktorsson nor his supervisor, Professor Pål Rongved, wants to say too much about it yet.

"We are in the process of patenting, so we need to be a little secretive. But I can tell you that the molecule is called IM37. So far, it has killed all sorts of resistant bacteria we have tested it against”, says Rongved.

Possible new drug against atherosclerosis

As if all this wasn’t enough, Viktorsson has also identified new chemical compounds that can potentially counteract atherosclerosis, which is the first stage in many cardiovascular diseases.

"We have created and tested new cholesterol-derived drugs, which are binding to a receptor (the Liver X receptor) that is central to the body's regulation of fatty acid-, cholesterol- and carbohydrate metabolism. When this receptor is inhibited, the risk of both atherosclerosis, diabetes and obesity is reduced. Medicines that activate this receptor already exist, but they have serious side effects and lead, among other things, to liver failure. Therefore, it is a big step forward that we have found substances that can bind to the same receptor without causing these types of side effects”, says Viktorsson.

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Promising results

Pål Rongved’s research group at the UiO (SYNFAS) has significant support from the Research Council of Norway and cooperates closely with UiO's innovation company Inven2. The company has filed a number of patent applications in these projects, to lay the groundwork for commercial exploitation of the research results.

“At Inven2, we are impressed by the cooperation Rongved has with strong research institutions outside our own university. As for the iodinin project, we think the results are promising. We are still in an early preclinical phase, but we are working closely with Rongved to develop a new drug against AML", says Inven2’s Technology Strategy Manager Jan Solberg.

Almost 80 years in the making

The iodinin molecule at the core of Viktorsson’s work belongs to a group of chemical compounds called phenazines, and was originally discovered in cultures of the marine bacterium Brevibacterium iodinum in 1938. The British researcher J.G. Davis discovered a substance with a cuprous shine, which is used in Brevibacterium’s defence against other microbes. The problem was that iodinin is almost impossible to dissolve in virtually all solvents, so it was considered as unsuitable to handle as a potential medicine.

Thus, the molecule went more or less into oblivion. But suddenly, iodinin was "rediscovered" in 2011 in extracts from actinobacteria in Trondheim Fjord.

“Professor Stein Ove Døskeland and his research group at the University of Bergen were responsible for the discovery, together with Finnish colleagues”, recounts Pål Rongved.

The next thing that happened was that Rongved visited the University of Bergen together with a French colleague. They met Døskeland, who had recently demonstrated that iodinin could kill AML cells. Rongved's research group at the UiO was invited to collaborate because the researchers in Bergen wanted to solve the major problem: Iodinin was almost insoluble except in strong basic aqueous solutions. Moreover, it was difficult to obtain more than tiny amounts of the substance. The researchers at the two universities agreed that it would be a good idea to make an artificial analogue of iodinin with improved characteristics.

The project gets a big grant

Skisse: Slik fremstilles iodinin
The drawing shows how synthetic iodinin analogues can be produced. Illustration: Elvar Örn Viktorsson, UiO.

"At that time, nobody had been able to develop a method for synthesizing iodinin efficiently, but we made a lucky break when Elvar Viktorsson came to us in Oslo in 2013. He had just graduated as an elite student from the University of Iceland”, explains Rongved.

Viktorsson started by delving deeper into the subject of organic synthesis, which is all about creating synthetic molecules consisting of the same building blocks that are found in nature – mainly carbon, hydrogen, nitrogen and oxygen. A new door opened for this research in early 2015, when the Research Council of Norway and the Norwegian Cancer Society launched a new joint call for biotech research.

Pål Rongved in collaboration with the research group wrote an application to meet this call, and the result was a large grant. This was late in 2015, and only two years later, Viktorsson and his supervisors had managed to develop both a method for synthesizing iodinin analogues and a large set of new and promising drug candidates.

More potent, more selective

Elvar Örn Viktorsson i laboratoriet
Iodinin found in nature has a reddish or cuprous shine, like the ones made by Viktorsson in the laboratory. Photo: Bjarne Røsjø, UiO. Download picture.

Elvar Viktorsson has recently selected the most potent analogues from the more than 100 synthetic phenazines, keeping in mind that the goal is to find molecules that can attack cancer cells while having a minimal effect on normal, healthy cells.

“Cancer cells often have lower oxygen levels than normal cells, because they are growing so fast that they don’t have the time to develop a proper supply of blood. We have recently demonstrated that iodinin and a related molecule called myxin are more effective in killing cells that have low levels of oxygen, e.g. cancer cells, without harming normal cells with adequate blood supply”, Viktorsson explains.

The secret behind the AML-killing iodinin analogues is that they contain so-called nitrogen oxide functional groups, that can be unleashed to form highly reactive hydroxyl radicals. These radicals can remove protons from the deoxyribose, which is one of the building blocks in the DNA molecule. This causes the backbone of the DNA to break, and the result is that the cells die quite quickly.

They are flat and dangerous

Pål Rongved adds that the phenazine molecules are aromatic. This means that they contain at least one ring-shaped structure. In addition, they are flat like a sheet of paper.

“Such flat aromatic molecules with functional groups – such as hydroxy groups – are known to have what is called an intercalating effect in DNA. They can literally sneak themselves in between the double-helix of the DNA double strand, where they initially inhibit the replication. The next event is to release the hydroxyl radicals that provide DNA-damaging effects, almost as if they were small scissors", explains Rongved.

From the lab towards clinical testing

Pål Rongved and Elvar Viktorsson have been working in a large project with many partners. One of the important collaborators is the cancer specialist doctor Bjørn Tore Gjertsen, who obtained cells from AML patients being treated at Haukeland University Hospital in Bergen. Professor Lars Herfindal at the University of Bergen tested the more than 100 analogues that came like pearls on a string from Viktorsson’s lab work in Oslo.

An important point is that all research so far has been conducted in test tubes in the laboratory. The researchers have tested iodinin and other phenazines against AML cells from both humans and rats – with promising effects. But new drugs have to be tested both preclinically (in animal models) and clinically (on humans) before they can be launched as new drugs for humans.

"We have already received a grant from the Danish Novo Nordisk Fund's Pre Seed programme, which provides support for important research that has not yet reached what is known as the seed phase. The next milestone is that we are going to test Elvar's best drug candidates in an animal model, says Rongved.

Basic research

The two UiO-based scientists emphasize that their project, named Developing novel anti-leukemic drugs from iodinin analogues, couldn’t have become a success without a lot of basic knowledge in organic chemistry.

“We decided to create a lot of slightly different molecules because we wanted to find out which parts of the molecule is essential for the biological effects. From the whole group of artificial molecules, we selected those that had the best effect and examined them more closely. This is a textbook example of the famous technique called SAR research, concludes Rongved, adding that SAR is the abbreviation for Structure–activity relationship.

Contact:

Researcher Elvar Örn Viktorsson, UiO's School of Pharmacy

Professor Pål Rongved, UiO's School of Pharmacy

Scientific publications:

Elvar Örn Viktorsson et al.: Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives. Bioorganic & Medicinal Chemistry Volume 25, Issue 7, 1 April 2017, Pages 2285-2293.

Elvar Örn Viktorsson et al.: Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations. Steroids Volume 18 2017, Pages 119- 127.

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