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Media type:
E-Article
Title:
Melatonin–vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat
Contributor:
Helmi, Youssef Y.;
Papenkordt, Niklas;
Rennar, Georg;
Gbahou, Florence;
El‐Hady, Ahmed K.;
Labani, Nedjma;
Schmidtkunz, Karin;
Boettcher, Stefan;
Jockers, Ralf;
Abdel‐Halim, Mohammad;
Jung, Manfred;
Zlotos, Darius P.
imprint:
Wiley, 2023
Published in:Archiv der Pharmazie
Language:
English
DOI:
10.1002/ardp.202300149
ISSN:
0365-6233;
1521-4184
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (<jats:bold>3a–e</jats:bold>), its indolic nitrogen (<jats:bold>5a–d</jats:bold>), and its ether oxygen (<jats:bold>7a–d</jats:bold>) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, <jats:bold>3e, 5c</jats:bold>, and <jats:bold>7c</jats:bold>, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands <jats:bold>5c</jats:bold> and <jats:bold>7c</jats:bold> were also found to be potent growth inhibitors of MCF‐7, PC‐3M‐Luc, and HL‐60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT<jats:sub>1</jats:sub> receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.</jats:p>