Histone deacetylase inhibitors from the rhizomes of Zingiber zerumbet.
Histone acetylation and deacetylation play fundamental roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase (HDAC) inhibitors that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models have been identified. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. In the context of our natural product chemistry program dealing with the development of new potent anticancer agents, we have examined the isolation from Zingiber zerumbet as leads for novel HDAC inhibitors. Zingiber zerumbet (L.) J. E. Smith (Zingiberaceae) is a wild ginger that typically grows widely in Southeast Asia. Isolation of the n-hexane soluble fraction from Zingiber zerumbet yielded two major sesequiterpenoids, 6-methoxy-2E,9E-humuladien-8-one (1) and zerumbone (2). The structures were elucidated on the basis of spectroscopic data. The histone deacetylase (HDAC) activities of compounds 1 and 2 were determined in vitro against HDAC enzyme assay. Compound 1 exhibited growth inhibitory activity on six human tumor cell lines, and showed potential inhibitory activity in histone deacetylase (HDAC) enzyme assay (GI50 = 1.25 microM). It also exhibited growth inhibitory activity on five human tumor cell lines and more sensitive inhibitory activity on the MDA-MB-231 breast tumor cell line (IC50 = 1.45 microM). Further structure-activity relationships of position C-6 and C-7 from aromatic ring will be reported in due course.
Chung
Ill-Min
IM
Department of Applied Life Science, Kon Kuk University, Seoul, South Korea.
Kim
Min-Young
MY
Park
Won-Hwan
WH
Moon
Hyung-In
HI
D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D020939:Zingiber officinale / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018517:Plant Roots / Q000737:chemistry; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012717:Sesquiterpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue