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Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Vise andre og tillknytning
2010 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 23, s. 8387-8399Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society , 2010. Vol. 53, nr 23, s. 8387-8399
Identifikatorer
URN: urn:nbn:se:umu:diva-38059DOI: 10.1021/jm101092uISI: 000284738400018PubMedID: 21073160Scopus ID: 2-s2.0-78649876797OAI: oai:DiVA.org:umu-38059DiVA, id: diva2:372792
Tilgjengelig fra: 2010-11-29 Laget: 2010-11-24 Sist oppdatert: 2023-03-23bibliografisk kontrollert

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