A team of scientists from the Department of Organic Chemistry at the Faculty of Science, Charles University, Prague, has reported a new and efficient method that simplifies the preparation of complex molecules. The work was published in the prestigious journal Organic Letters. Such molecules are related to natural compounds known for their anticancer and anti-inflammatory effects. The new approach could help scientists prepare different variants of these compounds and study their biological effects.
These natural compounds have a complex three-dimensional structure made up of three connected rings, which makes them very difficult to prepare in the laboratory. One example is galiellalactone, a compound isolated from the fungus Galiella rufa. Galiellalactone shows interesting biological activity – it affects the signalling protein STAT3, which, when misregulated, can contribute to uncontrolled cell growth. For this reason, this natural product is being studied for its potential use in treating prostate cancer resistant to chemotherapy. A similar structural motif can also be found in other naturally occurring compounds, including diocollettines A and rehmaglutin B.
Previous methods for preparing these molecules had several drawbacks. Some important reactions produced only small amounts of the desired product or resulted in mixtures of molecules with different three-dimensional structures. A team led by Eliška Matoušová, has now designed and successfully tested an elegant three-step process that significantly reduces these problems.
Innovative reaction sequence and precise control of molecular structure
The new method combines three consecutive chemical reactions that make it possible to build the complex molecule gradually and precisely. This gives scientists better control over its final three-dimensional structure, which is also important for its potential biological effects.
- High efficiency: In some key steps, up to 98% of the desired product was obtained.
- Precise three-dimensional structure: The reactions are highly selective and mainly produce the desired three-dimensional form of the molecule.
- Use of renewable resources: The method can also be applied using levoglucosenone, a starting material that is derived from biomass.
- Simpler process: Some intermediate products do not need to be isolated and purified separately. This makes the overall process faster and more efficient while reducing the amount of chemicals required.
Structural confirmation and biological testing
Using X-ray crystallography, the scientists confirmed the precise three-dimensional structure of selected molecules they had prepared.
In collaboration with the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (Helena Mertlíková-Kaiserová), the researchers then tested the prepared compounds on four types of human cancer cells as well as healthy human skin cells. Although the compounds did not show a direct toxic effect on cancer cells in the initial tests, the new method makes it easy to further modify their structure. Scientists can therefore prepare additional variants of these molecules and investigate their potential biological effects.
