title: A DNA methyltransferase modulator inspired by peyssonenyne natural product structures.
abstract: A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5-azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8, but not by the DNMT inhibitor SGI-1027.
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: García-Domínguez
authors.forename: Mélanie
authors.initials: M
authors.lastname: Weiss
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lepore
authors.forename: Rosana
authors.initials: R
authors.lastname: Álvarez
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Ángel R
authors.initials: ÁR
authors.lastname: de Lera
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004789:Enzyme Activation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D019308:Palmitic Acid / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001688:Biological Products; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D019308:Palmitic Acid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse