Preparation of phenylethylbenzamide derivatives as modulators of DNMT3 activity Anzhelika Kabro, a Hugo Lachance, ab Iris Marcoux-Archambault, a Val´ erie Perrier, a Vicky Dor´ e, a Christina Gros, c V´ eronique Masson, c Jean-Marc Gregoire, c Fr´ ed´ eric Ausseil, c David Cheishvili, d Nathalie Bibens Laulan, e Yves St-Pierre, be Moshe Szyf, d Paola B. Arimondo * c and Alexandre Gagnon * ab DNA-methyltransferases (DNMTs) are a class of epigenetic enzymes that catalyze the transfer of a methyl moiety from the methyl donor S-adenosyl-L-methionine onto the C5 position of cytosine in DNA. This process is dysregulated in cancers and leads to the hypermethylation and silencing of tumor suppressor genes. The development of potent and selective inhibitors of DNMTs is of utmost importance for the discovery of new therapies for the treatment of cancer. We report herein the synthesis and DNMT inhibitory activity of 29 analogues derived from NSC 319745. The effect of selected compounds on the methylation level in the MDA-MB-231 human breast cancer cell line was evaluated using a luminometric methylation assay. Molecular docking studies have been conducted to propose a binding mode for this series. Introduction Epigenetics is dened as the changes that occur on chromo- somes without alteration of the DNA sequence and that lead to a stable phenotype. 1 Epigenetic information is regulated by chromatin modications, which involve histones and DNA. 2 DNA methylation is a stable epigenetic modication leading to the installation of a methyl group at the C5 position of cytosine. 3 This reaction is catalyzed by DNA methyltransferase (DNMT) enzymes, which use S-adenosyl-L-methionine (SAM) as methyl donor. The products of the reaction are 5-methylcytosine in DNA and S-adenosyl-L-homocysteine (SAH). 4 Five DNMTs have been identied: DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. However, only DNMT1 and DNMT3A/B are catalyti- cally active on DNA. In fact, DNMT2 has a very weak DNA methylation activity and rather performs the methylation of tRNA Asp . 5 DNMT3L is catalytically inactive since it lacks the necessary catalytic domain. However, DNMT3L has been found to associate with DNMT3A/B to modulate its activity. DNMT3A/ B are involved in de novo methylation of DNA, initiating meth- ylation on a strand of DNA that is complementary to either the unmethylated or methylated DNA template. Thus, DNMT3A/B can generate new DNA methylation sites irrespective of the pattern of methylation of template DNA. 6 DNMT1 is implicated in the maintenance of methylation patterns during cell division and methylates hemimethylated DNA. Therefore, DNMT1 copies the pattern of methylation from the parental strand to the nascent strand. 7 In cancer cells, abnormal DNA methylation of the genome is observed with both hypomethylation and hypermethylation of critical genes 8 as well as global reduction in the level of DNA methylation across the genome 9 and hypermethylation of CpG islands in the promoter regions of some specic genes such as tumor suppressor genes. This process leads to silencing of those genes due to poor recognition by transcription factors and recruitment of proteins involved in the chromatin remodeling such as the methyl-binding proteins (MBD). 10 Contrary to sequence aberrations, DNA methylation is a reversible process. 11 More importantly, DNA methyltransferases are aber- rantly deregulated and were proposed two decades ago as novel anticancer targets. 12 In fact, experiments suggest that inhibition of DNMTs can lead to demethylation and reactivation of epigenetically silenced tumor suppressor genes. 13 Moreover the emergence of the eld of “behavioral epigenetics” points to the possibility that DNA methylation inhibitors might be of value in treating mental health diseases and psychopathology a Universit´ e du Qu´ ebec ` a Montr´ eal, D´ epartement de chimie, Case Postale 8888, Succursale Centre-Ville, Montr´ eal, Qu´ ebec, H3C 3P8, Canada. E-mail: gagnon. alexandre@uqam.ca; Fax: +1-514-987-4054; Tel: +1-514-987-3000 ext. 6856 b Pharmaqam, D´ epartement de chimie, Case Postale 8888, Succursale Centre-Ville, Montr´ eal, Qu´ ebec, H3C 3P8, Canada. E-mail: gagnon.alexandre@uqam.ca; Fax: +1- 514-987-4054; Tel: +1-514-987-3000 ext. 6856 c USR CNRS-Pierre Fabre no 3388-ETaC Epigenetic Targeting of Cancer, CRDPF 3 avenue Hubert Curien, 31035 Toulouse Cedex 01, France. E-mail: paola.arimondo@ etac.cnrs.fr; Fax: +33 5 34 50 34 92; Tel: +33 5 34 50 64 92 d Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montr´ eal, Qu´ ebec, H3G 1Y6, Canada. E-mail: moshe.szyf@mcgill. ca; Fax: +1-514-398-6690; Tel: +1-514-398-7107 e Centre INRS-Institut Armand-Frappier, 531 Boulevard des Prairies, Laval, Qu´ ebec, H7V 1B7, Canada. E-mail: yves.st-pierre@iaf.inrs.ca; Fax: +1-450-686-5501; Tel: +1- 450-686-5354 Cite this: Med. Chem. Commun., 2013, 4, 1562 Received 24th July 2013 Accepted 20th September 2013 DOI: 10.1039/c3md00214d www.rsc.org/medchemcomm 1562 | Med. Chem. Commun., 2013, 4, 1562–1570 This journal is ª The Royal Society of Chemistry 2013 MedChemComm CONCISE ARTICLE Published on 24 September 2013. Downloaded by McGill University on 22/11/2013 03:44:12. View Article Online View Journal | View Issue