Abstract
Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11β-hydroxysteroid dehydrogenase (11β-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11β-HSD1 and 11β-HSD2 as autocrine factors of tumor cell proliferation and differentiation. Herein, we report the synthesis of novel 2-(isopropylamino)thiazol-4(5H)-one derivatives and their inhibitory activity for 11β-HSD1 and 11β-HSD2. The derivative containing the spiro system of thiazole and cyclohexane rings shows the highest degree of 11β-HSD1 inhibition (54.53% at 10 µM) and is the most selective inhibitor of this enzyme among the tested compounds. In turn, derivatives containing ethyl and n-propyl group at C-5 of thiazole ring inhibit the activity of 11β-HSD2 to a high degree (47.08 and 54.59% at 10 µM respectively) and are completely selective. Inhibition of the activity of these enzymes may have a significant impact on the process of formation and course of tumors. Therefore, these compounds can be considered as potential pharmaceuticals supporting anti-cancer therapy.
Highlights
Cancer is a major public health problem and a leading cause of death worldwide
Our research focused on the synthesis of new thiazol-4(5H)-one derivatives and evaluation of their ability to inhibit 11β-HSD1 and 11β-HSD2
We focused on the search for selective 11β-HSD1 inhibitors, among thiazolone and thiazolo [3,2-α]pyrimidin-5-one derivatives [39,40,41]
Summary
Cancer is a major public health problem and a leading cause of death worldwide. Increased investment in basic and clinical research to find the metabolic processes underlying carcinogenesis would help to advance treatment options for patients [1]. In the course of numerous studies carried out over the years, researchers have managed to establish that the formation and development of neoplasms is influenced by psychophysiological factors such as stress, depression, or social isolation. The main physiological pathway related to chronic stress response is the hypothalamic–pituitary–adrenal (HPA) axis. Both acute and chronic stress influence the glucocorticoid response, which leads to changes in diurnal secretion of cortisol. It is the chronic stress, the feeling of anxiety or the overwhelming hopelessness that seems to have a much greater impact on the phenomenon of cancer development than the cases of sudden and short-term events that may Molecules 2020, 25, 4233; doi:10.3390/molecules25184233 www.mdpi.com/journal/molecules
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