Modification of cap group in delta-lactam-based histone deacetylase (HDAC) inhibitors.
Novel delta-lactam-based HDAC inhibitors which have various substituted benzyl, bi-aromatic cap groups were prepared using ring closure metathesis reaction, and evaluated their HDAC inhibitory activities and anti-proliferative effects. Among prepared analogues, 11m and 11o have very strong HDAC enzymatic inhibition and showed the most potent growth inhibitory activity to five human tumor cell lines including PC-3, ACHN, NUGC-3, HCT-15, and MBA-MB-231 tumor cell lines. Compounds 11m and 11o also showed good tumor growth inhibition of MDA-MB-231 cells in in vivo xenograft model. Structure-activity relationship study using docking model explained the significance of hydrophobic aromatic cap groups for their in vitro activities.
Kim
Hwan Mook
HM
Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon 305-333, Republic of Korea.
Hong
Sung Hee
SH
Kim
Myung Sook
MS
Lee
Chang Woo
CW
Kang
Jong Soon
JS
Lee
Kiho
K
Park
Song-Kyu
SK
Han
Jeung Whan
JW
Lee
Hee Yoon
HY
Choi
Yongseok
Y
Kwon
Ho Jeung
HJ
Han
Gyoonhee
G
D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D006655:Histone Deacetylases