Change search
ReferencesLink to record
Permanent link

Direct link
Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Show others and affiliations
2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 23, 8387-8399 p.Article in journal (Refereed) Published
Abstract [en]

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.

Place, publisher, year, edition, pages
American Chemical Society , 2010. Vol. 53, no 23, 8387-8399 p.
URN: urn:nbn:se:umu:diva-38059DOI: 10.1021/jm101092uISI: 000284738400018PubMedID: 21073160OAI: diva2:372792
Available from: 2010-11-29 Created: 2010-11-24 Last updated: 2010-12-02Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Larsson, Andreas
By organisation
Department of Chemistry
In the same journal
Journal of Medicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 130 hits
ReferencesLink to record
Permanent link

Direct link