title: Modified cap group suberoylanilide hydroxamic acid histone deacetylase inhibitor derivatives reveal improved selective antileukemic activity.
abstract: A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 microM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.
authors.affiliation: Unite 891 INSERM, Centre de Recherche en Cancerologie de Marseille, 27 Bd Lei Roure, 13009 Marseille 09, France.
authors.forename: Chanaz
authors.initials: C
authors.lastname: Salmi-Smail
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
authors.forename: Audrey
authors.initials: A
authors.lastname: Restouin
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.forename: Slaveia
authors.initials: S
authors.lastname: Garbit
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
authors.forename: Xavier
authors.initials: X
authors.lastname: Morelli
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001772:Blood Cell Count; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D036401:Toxicity Tests, Chronic; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D000077337:Vorinostat; C409470:HDAC8 protein, human; D006655:Histone Deacetylases