Trithiocarbonates: exploration of a new head group for HDAC inhibitors.
Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn(2+) complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.
Dehmel
Florian
F
Altana Pharma AG, a Member of the Nycomed Group, Byk-Gulden-Strasse 2, D-78467, Germany. florian.dehmel@altanapharma.com
Ciossek
Thomas
T
Maier
Thomas
T
Weinbrenner
Steffen
S
Schmidt
Beate
B
Zoche
Martin
M
Beckers
Thomas
T
D002244:Carbon / Q000737:chemistry; D002254:Carbonates / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D016399:Lymphoma, T-Cell / Q000188:drug therapy; D008956:Models, Chemical; D008968:Molecular Conformation; D012878:Skin Neoplasms / Q000188:drug therapy*; D000077337:Vorinostat; D015032:Zinc / Q000737:chemistry
D002254:Carbonates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D002244:Carbon; D015032:Zinc