A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities.

A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds 12i showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of α-tubulin.

[1]  J. Zuber,et al.  Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies. , 2015, Blood.

[2]  Tao Zhang,et al.  Design and optimization of novel hydroxamate-based histone deacetylase inhibitors of Bis-substituted aromatic amides bearing potent activities against tumor growth and metastasis. , 2014, Journal of medicinal chemistry.

[3]  Wei-Guo Zhu,et al.  Targeting Histone Deacetylases for Cancer Therapy: From Molecular Mechanisms to Clinical Implications , 2014, International journal of biological sciences.

[4]  Mingyao Liu,et al.  Optimization of 2-(3-(arylalkyl amino carbonyl) phenyl)-3-(2-methoxyphenyl)-4-thiazolidinone derivatives as potent antitumor growth and metastasis agents. , 2014, European journal of medicinal chemistry.

[5]  S. Knapp,et al.  Targeting bromodomains: epigenetic readers of lysine acetylation , 2014, Nature Reviews Drug Discovery.

[6]  C. Mercurio,et al.  Towards Selective Inhibition of Histone Deacetylase Isoforms: What Has Been Achieved, Where We Are and What Will Be Next , 2014, ChemMedChem.

[7]  Cheng Huang,et al.  Histone deacetylases in cardiac fibrosis: current perspectives for therapy. , 2014, Cellular signalling.

[8]  Mingyao Liu,et al.  Synthesis and biological evaluation of novel tetrahydro-β-carboline derivatives as antitumor growth and metastasis agents through inhibiting the transforming growth factor-β signaling pathway. , 2014, Journal of medicinal chemistry.

[9]  Yuta Tanaka,et al.  Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins. , 2013, Journal of medicinal chemistry.

[10]  T. Kundu,et al.  Acetyltransferases (HATs) as Targets for Neurological Therapeutics , 2013, Neurotherapeutics.

[11]  M. Soellner,et al.  Development of a chimeric c-Src kinase and HDAC inhibitor. , 2013, ACS medicinal chemistry letters.

[12]  B. Gryder,et al.  Histone deacetylase inhibitors equipped with estrogen receptor modulation activity. , 2013, Journal of medicinal chemistry.

[13]  H. Fu,et al.  Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma. , 2013, Organic & biomolecular chemistry.

[14]  Jim-Min Fang,et al.  Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme A reductase for cancer treatment. , 2013, Journal of medicinal chemistry.

[15]  G. Giannini,et al.  Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives. , 2012, Future medicinal chemistry.

[16]  B. Gryder,et al.  Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. , 2012, Future medicinal chemistry.

[17]  Robert A. Weinberg,et al.  Tumor Metastasis: Molecular Insights and Evolving Paradigms , 2011, Cell.

[18]  G. Giannini,et al.  Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation. , 2011, Journal of medicinal chemistry.

[19]  M. Lübbert,et al.  Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy , 2010, Clinical Epigenetics.

[20]  S. Bates,et al.  Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors , 2010, Expert review of anticancer therapy.

[21]  Zhenxin Zhang,et al.  Association analysis of CβS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer’s disease in Chinese , 2010, Journal of Neural Transmission.

[22]  D. Hart,et al.  Biological and biophysical properties of the histone deacetylase inhibitor suberoylanilide hydroxamic acid are affected by the presence of short alkyl groups on the phenyl ring. , 2010, Journal of medicinal chemistry.

[23]  T. Pollard,et al.  Characterization of two classes of small molecule inhibitors of Arp2/3 complex , 2009, Nature.

[24]  Yong Shen,et al.  Searching for Disease Modifiers—PKC Activation and HDAC Inhibition—A Dual Drug Approach to Alzheimer's Disease that Decreases Aβ Production while Blocking Oxidative Stress , 2009, ChemMedChem.

[25]  W-S Xu,et al.  Histone deacetylase inhibitors: Potential in cancer therapy , 2009, Journal of cellular biochemistry.

[26]  T. Beckers,et al.  Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rbeta, and histone deacetylases. , 2009, Journal of medicinal chemistry.

[27]  Ivars Kalvinsh,et al.  Novel amide derivatives as inhibitors of histone deacetylase: design, synthesis and SAR. , 2009, European journal of medicinal chemistry.

[28]  Robert A. Weinberg,et al.  Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. , 2008, Developmental cell.

[29]  B. Meunier,et al.  Hybrid molecules with a dual mode of action: dream or reality? , 2008, Accounts of chemical research.

[30]  Ken S Lau,et al.  Increased efficiency for performing colony formation assays in 96-well plates: novel applications to combination therapies and high-throughput screening. , 2008, BioTechniques.

[31]  P. Marks,et al.  Histone deacetylase inhibitors: molecular mechanisms of action , 2007, Oncogene.

[32]  P. Wylie,et al.  Determination of cell colony formation in a high-content screening assay. , 2007 .

[33]  P. Marks,et al.  Discovery and development of SAHA as an anticancer agent , 2007, Oncogene.

[34]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[35]  P. Steeg.  Tumor metastasis: mechanistic insights and clinical challenges , 2006, Nature Medicine.

[36]  S. Baylin,et al.  Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? , 2006, Nature Reviews Cancer.

[37]  R. De Francesco,et al.  Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  W. Haq,et al.  Carbodiimide mediated synthesis of 4-thiazolidinones by one-pot three-component condensation , 2002 .

[39]  Ricky W. Johnstone,et al.  Histone-deacetylase inhibitors: novel drugs for the treatment of cancer , 2002, Nature Reviews Drug Discovery.

[40]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[41]  P. Gregory,et al.  Histone acetylation and chromatin remodeling. , 2001, Experimental cell research.

[42]  R Holliday,et al.  The inheritance of epigenetic defects. , 1987, Science.

[43]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[44]  G. Gundersen,et al.  Cell biology (Communication arising): Tubulin acetylation and cell motility , 2003, Nature.