The specialists of the Medical Chemistry Center at Togliatti State University (TSU) in collaboration with colleagues from Saint Petersburg State University (SPbU) and the University of Florence have developed new carbonic anhydrase inhibitors, pharmaceuticals that can inhibit the growth of cancer. The results of the research will be published in the scientific journal European Journal of Medicinal Chemistry (Q1).
Carbonic anhydrases (CAs) is an important class of enzymes in the human body that regulate the level of carbon dioxide (CO2), bicarbonate anion, and protons. There are 16 carbonic anhydrase isoforms that function in regulating various physiological processes maintaining equilibrium within the cell by the concentrations of CO2 and pH – acid-base balance. Unlike a normal cell, a cancer cell has different mechanisms for survival. One of these mechanisms is provided by the increased expression of carbonic anhydrase. CAs can be localized in any part of the cell but scientists are interested in those that are located on the cell surface.
“The tumour behaves like a parasite in our body. It kills everything normal around and frees up space for its own growth. While in an unfavourable environment, the cancer cell intensively expresses (synthesizes) carbonic anhydrase on the surface which acidifies the tumour microenvironment killing healthy cells and creating conditions for tumour growth. At the same time, the cell is still able to multiply in the preserved healthy environment. So, can this mechanism be used to fight the tumour? Our task was to find a chemical compound that can suppress the carbonic anhydrase activity,” explains Professor Mikhail Krasavin, the head of New Synthetic Methods and Chemical Pharmacology Laboratory (Institute of Chemistry, Saint Petersburg State University).
Carbonic anhydrase inhibitors are successfully used by doctors to control eye pressure in glaucoma. Now scientists from all around the world are working on a hypothesis according to which it is possible to suppress cancerous tumour growth by inhibiting the carbonic anhydrase activity.
The world leader in this field is Claudiu Supuran, a professor at the University of Florence (Italy). He is the creator of a unique laboratory where in vitro studies on the carbonic anhydrase activity can be taken. And it was the place where SPbU scientists sent a new set of sulfonamides (potential CAs inhibitors that they created).
“The anti-cancer effect can be achieved by inhibiting two carbonic anhydrase isoforms -CAs IX and CAs XII. Claudiu Supuran’s laboratory confirmed the presence of an inhibitory effect of CAs IX, and it was a great joy for us,” said Mikhail Krasavin. “But it is almost impossible to create an inhibitor of any particular carbonic anhydrase isoform, the search is always conducted by screening*, and this has already become the field of activity of TSU Medical Chemistry Center.”
The OpenHTS project implemented at TSU Medical Chemistry Center is an open platform for high-throughput screening which allowed us to test new sulfonamides on cell lines and select those that showed the desired effect.
“Our task in this research was to study the possibility of translating the inhibitory activity on the protein, which was shown by professor Supuran, to both cancer and healthy cells. After all, making sure that the protein is inhibited in vitro is one thing, and showing the presence of the desired effect on the cell which contains thousands of different proteins is a whole different situation,” says the director of TSU Medical Chemistry Center Alexander Bunev.
“We conducted an extended screening and found that two compounds provided by Professor Krasavin’s group demonstrated the selectivity** on cell lines and high level of activity.”
“The fact that there is such a well-equipped and modern centre providing complex high-throughput screening of chemical compounds for anti-cancer activity in TSU allows us to expect a substantive breakthrough in the development of anticancer agents based on the inhibition of carbonic anhydrase,” claims Mikhail Krasavin. “We should study all sulfonamides as the monoagents and as a combination with known antitumor drugs on a large number of cell lines. Now it is all possible thanks to TSU Medical Chemistry Center.”
TSU Medical Chemistry Center and SPbU are planning to sign a long-term cooperation agreement at the end of April.
The results of the joint work of Togliatti, Saint Petersburg and Florence scientists will be presented in the European Journal of Medicinal Chemistry which publishes research on medical chemistry sections and original research papers.