Scientists from St. Petersburg State University, Immanuel Kant Baltic Federal University (Kaliningrad), Togliatti State University, together with foreign colleagues, have synthesized a number of compounds for the targeted destruction of cancer cells.
This was reported to RT in the press service of the Russian Science Foundation (RNF).
The study, the results of which were published in the European Journal of Medicinal Chemistry, was supported by a grant from the Russian Science Foundation.
The molecular method of fighting cancer is considered one of the most promising.
The essence of the method lies in the selective destruction of specific proteins that are vital for the functioning of cancer cells.
To do this, scientists use the natural mechanism of intracellular purification from damaged proteins.
Normally, such proteins that can disrupt the normal functioning of the cell are detected by a special enzyme - ubiquitinase.
It attaches another protein, ubiquitin, to the protein chain, which becomes a “black mark” for it.
Such a "labeled" protein molecule is quickly destroyed by special cell organelles - proteasomes.
The idea to use this mechanism to destroy specific proteins of cancer cells arose in the scientific community back in the early 2000s.
Its essence lies in the fact that with the help of an intermediary molecule to connect the enzyme ubiquitinase with the protein that needs to be destroyed.
The resulting structure is called a chimeric molecule.
The substance that serves as a “coupler” between an enzyme and a protein is called a “ligand”, and the entire technology for the targeted destruction of proteins is called PROTAC (PROteolysis TArgeting Chimeras).
“Today, billions of dollars are being invested in the development of drugs based on chimeric molecules, and almost any large pharmaceutical company is striving to get them into their portfolio.
Chimeric constructs of this type are an ideal "killer", since they can be made for almost any desired target protein.
At the same time, they work in the cell at extremely low concentrations, which helps to avoid side effects, ”said project manager Mikhail Krasavin, Doctor of Chemistry, head of the Laboratory for the Synthesis of Bioactive Small Molecules at St. Petersburg State University, in an interview with RT.
To date, research in this area is underway in a number of countries, some developments are at the stage of clinical trials.
Most often, molecules of already known immunomodulatory drugs, thalidomide and its close analogues, act as a "bridge" for protein binding.
However, as it turned out earlier, the use of these substances by pregnant women led to severe developmental disorders in children.
© KATERYNA KON/SCIENCE PHOTO LIBRARY
However, Russian scientists, together with foreign colleagues, have found an alternative to potentially dangerous compounds.
Chemists synthesized 20 different molecules based on glutarimide, an organic nitrogen-containing substance that is non-toxic and readily binds to enzymes and proteins inside the cell.
Glutarimide is already used in pharmacology as a component of drugs with sedative and psychostimulant effects.
The authors of the work tested the resulting molecules in vitro during experiments on live cancer cells.
Compounds containing sulfur proved to be the best: they bound to the enzyme and target protein twice as efficiently as existing analogues.
New molecules were able to suppress the activity of bone marrow cancer cells without causing a toxic effect.
“In the future, we will study in more detail the antitumor effect of the molecules we obtained in order to find out why the compounds containing sulfur turned out to be the most active,” says Mikhail Krasavin.
According to the scientists, the obtained compounds can become the basis for a number of anti-cancer drugs in the future.