Scheuerer, Simon and Motlova, Lucia and Schaeker-Huebner, Linda and Sellmer, Andreas and Feller, Felix and Ertl, Fabian J. and Koch, Pierre and Hansen, Finn K. and Barinka, Cyril and Mahboobi, Siavosh (2024) Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 276: 116676. ISSN 0223-5234, 1768-3254
Full text not available from this repository. (Request a copy)Abstract
Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) 4 ) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S) S )-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, 29b , which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b S- 29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTONE DEACETYLASE 6; FRIEDEL-CRAFTS REACTION; RACEMIZATION; CATALYSIS; CONSTRUCTION; ACETYLATION; METABOLISM; INDOLES; TUBULIN; DESIGN; Histone deacetylase inhibitors; HDAC selectivity; Enantiomers; Tetrahydro-beta-carboline; Phenylhydroxamate; Chemical structure |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Jan 2026 09:20 |
| Last Modified: | 22 Jan 2026 09:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/64104 |
Actions (login required)
 |
View Item |
