Abstract
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.
Highlights
Human 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is an enzyme belonging to the superfamily of short-chain dehydrogenases/reductases (SDR) (SDR5C1 in SDR nomenclature) encoded by the HSD17B10 gene
At around the same time, the enzyme was found to be identical to L-3-hydroxyacyl-CoA dehydrogenase [3], denoted as HADH2 or SCHAD and was identified as a novel 17β-hydroxysteroid dehydrogenase localized in mitochondria and responsible for the inactivation of sex hormones [3,4]. 17β-HSD10 is a NAD+-dependent dehydrogenase with a very wide range of substrates and functions, including the metabolism of branched-chain fatty acids, the catabolism of isoleucine [5], and activation or inactivation of potent sex hormones or steroid modulators [6]
We have prepared and in vitro evaluated over 50 novel compounds based on a benzothiazolyl urea scaffold acting as 17β-HSD10 inhibitors
Summary
Human 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is an enzyme belonging to the superfamily of short-chain dehydrogenases/reductases (SDR) (SDR5C1 in SDR nomenclature) encoded by the HSD17B10 gene. At around the same time, the enzyme was found to be identical to L-3-hydroxyacyl-CoA dehydrogenase [3], denoted as HADH2 or SCHAD (short chain to L-3-hydroxyacyl-CoA dehydrogenase) and was identified as a novel 17β-hydroxysteroid dehydrogenase localized in mitochondria and responsible for the inactivation of sex hormones [3,4]. Aβ interacts with 17β-HSD10 via several amino acids within the D-loop region, a unique sequence insertion that is absent in all other members of the SDR family. This interaction was detected in the brains of patients with AD and experimental transgenic mice overexpressing amyloid precursor protein and 17β-HSD10 [12]. Overexpression of the 17β-HSD10 enzyme resulted in mitochondrial matrix condensation and the partial loss of cristae structure [13]
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