17β-HSD10 is a mitochondrial enzyme that catalyzes the steroidal oxidation of a hydroxy group to a keto group and, thus, is involved in maintaining steroid homeostasis. The druggability of 17β-HSD10 is related to potential treatment for neurodegenerative diseases, for example, Alzheimer's disease or cancer. Herein, steroidal derivatives with an acidic hemiester substituent at position C-3 on the skeleton were designed, synthesized, and evaluated by using pure recombinant 17β-HSD10 converting 17β-estradiol to estrone. Compounds 22 (IC50 = 6.95 ± 0.35 μM) and 23 (IC50 = 5.59 ± 0.25 μM) were identified as the most potent inhibitors from the series. Compound 23 inhibited 17β-HSD10 activity regardless of the substrate. It was found not cytotoxic toward the HEK-293 cell line and able to inhibit 17β-HSD10 activity also in the cellular environment. Together, these findings support steroidal compounds as promising candidates for further development as 17β-HSD10 inhibitors.

• Publikační typ
• časopisecké články MeSH

Multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a potential drug target for the treatment of various pathologies. The most discussed is the pathology associated with Alzheimer's disease (AD), where 17β-HSD10 overexpression and its interaction with amyloid-β peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17β-HSD10 inhibitors were designed based on the structure-activity relationship analysis of formerly published inhibitors. A set of enzyme-based and cell-based methods were used to evaluate the inhibitory potency of new compounds, their interaction with the enzyme, and their cytotoxicity. Most compounds exhibited significantly a higher inhibitory potential compared to published benzothiazolyl ureas and good target engagement in a cellular environment accompanied by low cytotoxicity. The best hits displayed mixed-type inhibition with half maximal inhibitory concentration (IC50) values in the nanomolar range for the purified enzyme (3-7, 15) and/or low micromolar IC50 values in the cell-based assay (6, 13-16).

• Publikační typ
• časopisecké články MeSH

Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson's disease, or Alzheimer's disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1-2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.

• Klíčová slova
• 17β-hydroxysteroid dehydrogenase type 10, ABAD, Alzheimer’s disease, benzothiazole, inhibitor, neurodegeneration,
• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   chemie   MeSH
• aktivace enzymů MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• benzothiazoly chemie   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• močovina chemie   farmakologie   MeSH
• molekulární struktura MeSH
• rekombinantní proteiny MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-hydroxyacyl-CoA-dehydrogenasy MeSH
• benzothiazoly MeSH
• HSD17B10 protein, human MeSH Prohlížeč
• inhibitory enzymů MeSH
• močovina MeSH
• rekombinantní proteiny MeSH

: It has long been established that mitochondrial dysfunction in Alzheimer's disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.

• Klíčová slova
• 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), amyloid binding alcohol dehydrogenase (ABAD), benzothiazole, Alzheimer’s disease (AD), amyloid-beta peptide (Aβ), mitochondria,
• MeSH
• 17-hydroxysteroidní dehydrogenasy antagonisté a inhibitory   chemie   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• benzothiazoly chemie   MeSH
• buněčné linie MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• močovina chemie   MeSH
• molekulární struktura MeSH
• racionální návrh léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 17-hydroxysteroidní dehydrogenasy MeSH
• amyloidní beta-protein MeSH
• benzothiazoly MeSH
• močovina MeSH