Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F24%3A00598294" target="_blank" >RIV/86652036:_____/24:00598294 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0223523424005567?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523424005567?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2024.116676" target="_blank" >10.1016/j.ejmech.2024.116676</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/LUAUS23247" target="_blank" >LUAUS23247: Charakterizace a vývoj nových epigenetických modulátorů určených pro léčbu nádorů</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

276

Číslo periodika v rámci svazku

OCT 5 2024

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

11

Strana od-do

116676

Kód UT WoS článku

001283375500001

EID výsledku v databázi Scopus

2-s2.0-85199348983