Histone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activities.
In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results show that representative compounds can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, (S)-4-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-phenylacetamido)-N-hydroxybenzamide (D17) showed better performance than SAHA in blocking U937 tumor growth. Western blot analysis revealed that representative molecules can block the function of both class I HDACs and HDAC6. More importantly, our western blot results reveal that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by our compounds in the U937 cell line rather than MDA-MB-231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA-MB-231 cell line.
Department of Pharmacy, School of Medicine, Qingdao University, 308 Dengzhou Road, Qingdao, Shandong 266071 (China). lei@qdu.edu.cn.
Lei
L
Zhang
Yingjie
Y
Zhang
C James
CJ
Chou
Elizabeth S
ES
Inks
Xuejian
X
Wang
Xiaoguang
X
Li
Jinning
J
Hou
Wenfang
W
Xu
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020298:U937 Cells
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D054852:Small Molecule Libraries; D006655:Histone Deacetylases
antitumor agents; cancer; epigenetics; histone deacetylases; inhibitors; structural optimization