title: Synthesis and evaluation of analogues of N-phthaloyl-l-tryptophan (RG108) as inhibitors of DNA methyltransferase 1.
abstract: DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.
authors: Laboratoire des BioMolécules, UMR 7203, Université Pierre et Marie Curie-Paris 6, ENS, CNRS, 4, Place Jussieu, 75252 Paris Cedex 05, France.
authors: Saâdia
authors: S
authors: Asgatay
authors: Christine
authors: C
authors: Champion
authors: Gaël
authors: G
authors: Marloie
authors: Thierry
authors: T
authors: Drujon
authors: Catherine
authors: C
authors: Senamaud-Beaufort
authors: Alexandre
authors: A
authors: Ceccaldi
authors: Alexandre
authors: A
authors: Erdmann
authors: Arumugam
authors: A
authors: Rajavelu
authors: Philippe
authors: P
authors: Schambel
authors: Albert
authors: A
authors: Jeltsch
authors: Olivier
authors: O
authors: Lequin
authors: Philippe
authors: P
authors: Karoyan
authors: Paola B
authors: PB
authors: Arimondo
authors: Dominique
authors: D
authors: Guianvarc'h
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D010795:Phthalic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010795:Phthalic Acids; D010797:Phthalimides; C503639:RG108; D014364:Tryptophan; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human