C5-DNA Methyltransferase Inhibitors: From Screening to Effects on Zebrafish Embryo Development

被引：65

作者：

Ceccaldi, Alexandre ^{[1
]}

Rajavelu, Arumugam ^{[2
]}

Champion, Christine ^{[1
]}

Rampon, Christine ^{[3
]}

Jurkowska, Renata ^{[2
]}

Jankevicius, Gytis ^{[2
]}

Senamaud-Beaufort, Catherine ^{[1
]}

Ponger, Loic ^{[1
]}

Gagey, Nathalie ^{[1
]}

Ali, Hana Dali ^{[1
]}

Tost, Joerg ^{[4
]}

Vriz, Sophie ^{[3
]}

Ros, Sindu ^{[5
]}

Dauzonne, Daniel ^{[5
]}

Jeltsch, Albert ^{[2
]}

Guianvarc'h, Dominique ^{[6
]}

Arimondo, Paola B. ^{[1
]}

机构：

[1] MNHN, UMR 7196, CNRS, INSERM,U565, F-75005 Paris, France

[2] Jacobs Univ Bremen, D-28759 Bremen, Germany

[3] CNRS Chaire Proc, UMR 7233, Morphogenet Coll France, F-75005 Paris, France

[4] CEA Inst Genom, Lab Epigenet, Ctr Natl Genotypage, F-91000 Evry, France

[5] Ctr Rech, CNRS, UMR176, Inst Curie, F-75005 Paris, France

[6] CNRS, UPMC Paris 06, ENS, UMR 7203,FR2769, F-75005 Paris, France

来源：

CHEMBIOCHEM | 2011年 / 12卷 / 09期

关键词：

DNA methylation; DNMT; flavones; high-throughput screening; inhibitors; NOVO DNA METHYLATION; EPIGENETIC MODIFICATIONS; BIOLOGICAL EVALUATION; HUMAN-DISEASE; CANCER; ASSAY; FLAVANONES; GENES; CELLS; POLYPHENOLS;

D O I：

10.1002/cbic.201100130

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

DNA methylation is involved in the regulation of gene expression and plays an important role in normal developmental processes and diseases, such as cancer. DNA methyltransferases are the enzymes responsible for DNA methylation on the position 5 of cytidine in a CpG context. In order to identify and characterize novel inhibitors of these enzymes, we developed a fluorescence-based throughput screening by using a short DNA duplex immobilized on 96-well plates. We have screened 114 flavones and flavanones for the inhibition of the murine catalytic Dnmt3a/3L complex and found 36 hits with IC(50) values in the lower micromolar and high nanomolar ranges. The assay, together with inhibition tests on two other methyltransferases, structure-activity relationships and docking studies, gave insights on the mechanism of inhibition. Finally, two derivatives effected zebrafish embryo development, and induced a global demethylation of the genome, at doses lower than the control drug, 5-azacytidine.

引用

页码：1337 / 1345

页数：9

共 51 条

[1]

ATASSI G, 1985, EUR J MED CHEM, V20, P393

[2] Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13 [J].

Bauvois, B ;

Puiffe, ML ;

Bongui, JB ;

Paillat, S ;

Monneret, C ;

Dauzonne, D .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (18) :3900-3913

[3] An operational definition of epigenetics [J].

Berger, Shelley L. ;

Kouzarides, Tony ;

Shiekhattar, Ramin ;

Shilatifard, Ali .

GENES & DEVELOPMENT, 2009, 23 (07) :781-783

[4] Evaluation of the mutagenicity and antimutagenicity of forty-two 3-substituted flavones in the Ames test [J].

Beudot, C ;

De Méo, MP ;

Dauzonne, D ;

Elias, R ;

Laget, M ;

Guiraud, H ;

Balansard, G ;

Duménil, G .

MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, 1998, 417 (2-3) :141-153

[5] The inducible NO synthase is downregulated during apoptosis of malignant cells from B-cell chronic lymphocytic leukemia induced by flavopiridol and polyphenols [J].

Billard, C ;

Quiney, C ;

Tang, R ;

Kern, C ;

Ajchenbaum-Cymbalista, F ;

Dauzonne, D ;

Kolb, JP .

APOPTOSIS: FROM SIGNALING PATHWAYS TO THERAPEUTIC TOOLS, 2003, 1010 :381-383

[6] Perceptions of epigenetics [J].

Bird, Adrian .

NATURE, 2007, 447 (7143) :396-398

[7] Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases [J].

Brueckner, B ;

Boy, RG ;

Siedlecki, P ;

Musch, T ;

Kliem, HC ;

Zielenkiewicz, P ;

Suhai, S ;

Wiessler, M ;

Lyko, F .

CANCER RESEARCH, 2005, 65 (14) :6305-6311

[8] A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors [J].

Candelaria, M. ;

Gallardo-Rincon, D. ;

Arce, C. ;

Cetina, L. ;

Aguilar-Ponce, J. L. ;

Arrieta, O. ;

Gonzalez-Fierro, A. ;

Chavez-Blanco, A. ;

de la Cruz-Hernandez, E. ;

Camargo, M. F. ;

Trejo-Becerril, C. ;

Perez-Cardenas, E. ;

Perez-Plasencia, C. ;

Taja-Chayeb, L. ;

Wegman-Ostrosky, T. ;

Revilla-Vazquez, A. ;

Duenas-Gonzalez, A. .

ANNALS OF ONCOLOGY, 2007, 18 (09) :1529-1538

[9] Mammalian DNA methyltransferases: A structural perspective [J].

Cheng, Xiaodong ;

Blumenthal, Robert M. .

STRUCTURE, 2008, 16 (03) :341-350

[10] Synthesis of flavanones using nanocrystalline MgO [J].

Choudary, BM ;

Ranganath, KVS ;

Yadav, J ;

Kantam, ML .

TETRAHEDRON LETTERS, 2005, 46 (08) :1369-1371

← 1 2 3 4 5 6 →