Azetidinones as zinc-binding groups to design selective HDAC8 inhibitors.
2-Azetidinones, commonly known as beta-lactams, are well-known heterocyclic compounds. Herein we described the synthesis and biological evaluation of a series of novel beta-lactams. In vitro inhibition assays against HDAC isoforms showed an interesting isoform-selectivity of these compounds towards HDAC6 and HDAC8. The isoform selectivity changed in response to modification of the azetidinone-ring nitrogen atom substituent. The presence of an N-thiomethyl group is a prerequisite for the activity of these compounds in the micromolar range towards HDAC8.
Galletti
Paola
P
Dipartimento di Chimica G. Ciamician, Università of Bologna, Via Selmi 2, 40126 Bologna, Italy.
Quintavalla
Arianna
A
Ventrici
Caterina
C
Giannini
Giuseppe
G
Cabri
Walter
W
Penco
Sergio
S
Gallo
Grazia
G
Vincenti
Silvia
S
Giacomini
Daria
D
D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*
C116379:2-azetidinone; D001384:Azetidines; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D006655:Histone Deacetylases; D015032:Zinc