Modified cap group suberoylanilide hydroxamic acid histone deacetylase inhibitor derivatives reveal improved selective antileukemic activity.
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.
Salmi-Smail
Chanaz
C
Unite 891 INSERM, Centre de Recherche en Cancerologie de Marseille, 27 Bd Lei Roure, 13009 Marseille 09, France.
Fabre
Aurélie
A
Dequiedt
Franck
F
Restouin
Audrey
A
Castellano
Rémy
R
Garbit
Slaveia
S
Roche
Philippe
P
Morelli
Xavier
X
Brunel
Jean Michel
JM
Collette
Yves
Y
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
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D000077337:Vorinostat; C409470:HDAC8 protein, human; D006655:Histone Deacetylases