3 years ago

Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups

Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups
Finn K. Hansen, Frank J. Dekker, Viktoria Krieger, Thomas Kurz, Holger Gohlke, Manfred Jung, Johanna Senger, Alexandra Hamacher, Martijn R. H. Zwinderman, Matthias U. Kassack, Christophe Romier, Christoph G. W. Gertzen, Martin Marek
In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy activity in the cellular HDAC assays, four compounds were further screened for their inhibitory activity against recombinant HDAC1–3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1–3 as well as significant inhibition of HDAC6 with IC50 values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head–neck cancer cell line Cal27CisR by almost 7-fold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00197

DOI: 10.1021/acs.jmedchem.7b00197

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.