Binding mode analysis of 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide: a new synthetic histone deacetylase inhibitor inducing histone hyperacetylation, growth inhibition, and terminal cell differentiation.

The binding mode of 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides 1a-c, belonging to a recently reported class of synthetic histone deacetylase (HDAC) inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072), into the new modeled HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. HDAC1 X-ray coordinates were obtained by virtual "mutation" of those of histone deacetylase-like protein, a bacterial HDAC homologue. In in vitro antimaize HD2 as well as antimouse HDAC1 assay, compounds 1a-c showed inhibitory activities in the low micromolar range. Similarly, 1a-c are endowed with anti-HDAC activity in vivo: on mouse A20 cells, 1a-c induced histone hyperacetylation leading to a highly increased acetylation level of H4 as compared to control histones. Results obtained with acid-urea-triton polyacrylamide gel electrophoresis have been confirmed by Western Blot experiments. Finally, compound 1a, chosen as a representative member of this class of HDAC inhibitors, resulted endowed with antiproliferative (45 and 85% cell growth inhibition at 40 and 80 microM, respectively) and cellular differentiation (18 and 21% of benzidine positive cells at the same concentrations) activities in murine erythroleukemic cells.

[1]  A. Mai,et al.  3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides, a new class of synthetic histone deacetylase inhibitors. , 2001, Journal of medicinal chemistry.

[2]  A. Wolffe,et al.  The origin and utility of histone deacetylases , 1997, FEBS letters.

[3]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[4]  T. Tsuruo,et al.  A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. Eberharter,et al.  A comparative study of histone deacetylases of plant, fungal and vertebrate cells. , 1996, Biochimica et biophysica acta.

[6]  K. Nakahara,et al.  Studies on WF-3161, a new antitumor antibiotic. , 1983, The Journal of antibiotics.

[7]  A. Mai,et al.  A NEW FACILE AND EXPEDITIOUS SYNTHESIS OF N-HYDROXY-N′-PHENYLOCTANEDIAMJDE, A POTENT INDUCER OF TERMINAL CYTODIFFERECNTIATION , 2001 .

[8]  T. R. Hebbes,et al.  A direct link between core histone acetylation and transcriptionally active chromatin. , 1988, The EMBO journal.

[9]  L. Chin,et al.  Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression , 1997, nature.

[10]  Analogues of the cytostatic and antimitogenic agents chlamydocin and HC-toxin: synthesis and biological activity of chloromethyl ketone and diazomethyl ketone functionalized cyclic tetrapeptides. , 1987, Journal of medicinal chemistry.

[11]  J. Kruh.  Effects of sodium butyrate, a new pharmacological agent, on cells in culture , 1981, Molecular and Cellular Biochemistry.

[12]  Jones,et al.  Histone deacetylase inhibitors: novel anticancer agents. , 1999, Expert opinion on investigational drugs.

[13]  C. Van Lint,et al.  Characterization of a human RPD3 ortholog, HDAC3. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  N. Guex,et al.  SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling , 1997, Electrophoresis.

[15]  W. Helliger,et al.  Different types of maize histone deacetylases are distinguished by a highly complex substrate and site specificity. , 1999, Biochemistry.

[16]  M. Yoshida,et al.  Effects of trichostatins on differentiation of murine erythroleukemia cells. , 1987, Cancer research.

[17]  A. Mahowald,et al.  Histones of Drosophila embryos. Electrophoretic isolation and structural studies. , 1974, The Journal of biological chemistry.

[18]  S. Jones,et al.  Histone deacetylase inhibitors as potential anti-skin cancer agents. , 1999, Cancer research.

[19]  T. Suzuki,et al.  Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. , 1999, Journal of medicinal chemistry.

[20]  C. Glass,et al.  A complex containing N-CoR, mSln3 and histone deacetylase mediates transcriptional repression , 1997, nature.

[21]  S. Meng,et al.  p21WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells , 1998 .

[22]  J. Davie,et al.  Rapid Induction of Histone Hyperacetylation and Cellular Differentiation in Human Breast Tumor Cell Lines following Degradation of Histone Deacetylase-1* , 2000, The Journal of Biological Chemistry.

[23]  Adrian Bird,et al.  Alternative chromatin structure at CpG islands , 1990, Cell.

[24]  H. W. Lee,et al.  Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. , 2000, Cancer research.

[25]  J. Walton,et al.  Inhibition of maize histone deacetylases by HC toxin, the host-selective toxin of Cochliobolus carbonum. , 1995, The Plant cell.

[26]  A. Mai,et al.  Synthesis and antimicrobial and cytotoxic activities of pyrrole-containing analogues of trichostatin A. , 1990, Journal of medicinal chemistry.

[27]  G Brosch,et al.  Amide analogues of trichostatin A as inhibitors of histone deacetylase and inducers of terminal cell differentiation. , 1999, Journal of medicinal chemistry.

[28]  P. Marks,et al.  Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors , 1999, Nature.

[29]  D. Cohen,et al.  Histone Deacetylase Inhibition Selectively Alters the Activity and Expression of Cell Cycle Proteins Leading to Specific Chromatin Acetylation and Antiproliferative Effects* , 1999, The Journal of Biological Chemistry.

[30]  K. Struhl.  Histone acetylation and transcriptional regulatory mechanisms. , 1998, Genes & development.

[31]  G. Brosch,et al.  Biochemical methods for analysis of histone deacetylases. , 1998, Methods.

[32]  G. Brandner,et al.  Butyrate modulates DNA-damage-induced p53 response by induction of p53-independent differentiation and apoptosis , 1997, Oncogene.

[33]  P. Loidl.  Histone acetylation: facts and questions , 1994, Chromosoma.

[34]  M. Yoshida,et al.  Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. , 1993, The Journal of biological chemistry.

[35]  Andrew J. Bannister,et al.  The TAFII250 Subunit of TFIID Has Histone Acetyltransferase Activity , 1996, Cell.

[36]  Garland R. Marshall,et al.  VALIDATE: A New Method for the Receptor-Based Prediction of Binding Affinities of Novel Ligands , 1996 .

[37]  L. Franco,et al.  Characterization of pea histone deacetylases , 1988, Plant Molecular Biology.

[38]  E. Bradbury,et al.  Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Andrew J. Bannister,et al.  The CBP co-activator is a histone acetyltransferase , 1996, Nature.

[40]  Wen‐Ming Yang,et al.  Histone Deacetylases Associated with the mSin3 Corepressor Mediate Mad Transcriptional Repression , 1997, Cell.

[41]  Peter A. Kollman,et al.  AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules , 1995 .

[42]  L. Magnaghi-Jaulin,et al.  The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[44]  P. Rowley,et al.  Inducers of erythroid differentiation in K562 human leukemia cells. , 1981, Experimental hematology.

[45]  M. Grunstein.  Histone acetylation in chromatin structure and transcription , 1997, Nature.

[46]  S. Schreiber,et al.  Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Rolf Apweiler,et al.  The SWISS-PROT protein sequence data bank and its supplement TrEMBL , 1997, Nucleic Acids Res..

[48]  P. Parsons,et al.  Histone Hyperacetylation Induced by Histone Deacetylase Inhibitors Is Not Sufficient to Cause Growth Inhibition in Human Dermal Fibroblasts* , 2001, The Journal of Biological Chemistry.

[49]  S. Schreiber,et al.  Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase , 1997, Cell.

[50]  P. Marks,et al.  A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  G. Brosch,et al.  Purification and characterization of a high molecular weight histone deacetylase complex (HD2) of maize embryos. , 1996, Biochemistry.

[52]  M. Okuhara,et al.  FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. , 1994, The Journal of antibiotics.

[53]  S. Tamura,et al.  Mass spectrometric determination of amino acid sequence in Cyl-2, a novel cyclotetrapeptide from Cylindrocladium scoparium. , 2005, Biomedical mass spectrometry.

[54]  P. Stiegler,et al.  The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin A promoter. , 1998, Cancer research.

[55]  C. Allis,et al.  Tetrahymena Histone Acetyltransferase A: A Homolog to Yeast Gcn5p Linking Histone Acetylation to Gene Activation , 1996, Cell.

[56]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[57]  James J. P. Stewart,et al.  MOPAC: A semiempirical molecular orbital program , 1990, J. Comput. Aided Mol. Des..