Histone deacetylase inhibitors through click chemistry.
Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5 g (NSC746457) was discovered that inhibited HDAC1 at an IC(50) value of 104 +/- 30 nM and proved quite potent in the cancer cell line screen with GI(50) values ranging from 3.92 microM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach.
Shen
Jie
J
Department of Biochemistry, The Ohio State University, 876 Biological Sciences Building, 484 West 12th Avenue, Columbus, Ohio 43210, USA.
Woodward
Robert
R
Kedenburg
James Patrick
JP
Liu
Xianwei
X
Chen
Min
M
Fang
Lanyan
L
Sun
Duxin
D
Wang
Peng George
PG
D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C539552:3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; D000480:Alkynes; D001386:Azides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014230:Triazoles