Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors.
Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.
Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
Eunhyun
E
Choi
Chulho
C
Lee
Jung Eun
JE
Park
Jeong Jea
JJ
Seo
Misun
M
Cho
Jong Soon
JS
Kang
Hwan Mook
HM
Kim
Song-Kyu
SK
Park
Kiho
K
Lee
Gyoonhee
G
Han
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D021281:Quantitative Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D006655:Histone Deacetylases