Researchers from Tomsk Polytechnic University together with colleagues from the United States have synthesized 21 new inhibitor compounds to block or slow down the functioning of a class of enzymes that trigger the process of cell death in the heart and in the brain at a stroke and heart attack. The study outcomes were published in the European Journal of Medical Chemistry (IF 4.816; Q1). Some of the substances demonstrated high biological activity. For example, a derivative of tryptanthrin, which is a natural alkaloid out of the fruits of a cannon tree in South America, has already sparked the interest of pharmacologists.
In the humane body, enzymes serve as catalysts accelerating biochemical processes. Almost all the reactions in the cells occur with the participation of specific enzymes. However, in some cases, it is necessary to block or slow down enzyme functioning. Such blockers are inhibitors. For each enzyme or a group of them, you can choose a unique inhibitor as a key to a lock. A group of researchers from TPU Kizhner Research Center together with foreign colleagues is working with kinase enzymes, in particular, with JNK3 enzyme which works in the brain and in the heart. It participates in inflammatory processes and in the cell death during the heart attack and stroke. To reduce the negative consequences of heart attack and stroke it is necessary to block the enzyme.
A co-author of the study Igor Shchepetkin, SRF from the Kizhner Research Center, a leading researcher from the Department of Microbiology and Immunology, Montana State University, Bozeman, says:
‘Earlier we have already found pronounced anti-ischemic properties of the compound under the code name IQ1, to which a number of publications were devoted. Based on this compound an anti-stroke drug is developing at the Tomsk Research Institute of Pharmacology.
Currently, we are purposefully searching the analogs of this compound with more higher biological activity and better bioavailability indicators, in particular, better solubility in water.’
The search of new compounds was not random. At first, the researchers modeled the compounds that can theoretically become such a key blocking the JNK3 enzyme, synthesized them and then tested their compatibility performing molecular docking.
As one of the co-authors of the study Andrey Khlebnikov, a professor of the Kizhner Research Center, clarifies: ‘The comparison of enzymes and their inhibitors with locks and keys describes well the mechanism of their interaction. An inhibitor enters the enzyme cavity where biochemical reactions occur, which we want to block, and just physically takes up this space. In the case of JNK3, the inhibitor molecule must be coplanar and with oxygen and nitrogen atoms on the poles. During this study, we synthesized 21 compounds which meet these parameters. In any case, all of them will expand the variety of organic compounds. We recorded high activity in two compounds, one of which even higher than IQ1. This is tryptanthrin oxime, i.e. a derivative of tryptanthrin. The inhibiting activity of this compound has never been studied.’
The study showed that tryptanthrin oxime inhibits JNK3 well and does not practically bind to other enzymes.
‘If this compound becomes a basis for an anti-stroke drug in the future, it will be very specific. In turn, it means fewer side effects.
This compound has already sparked the interest of the Tomsk Research Institute of Pharmacology and Regenerative Medicine (as part of the Tomsk National Research Medical Center of RAS – ed.) for further research,’ says Andrey Khlebnikov.
The study was supported by the Russian Science Foundation.