title: Synthesis and biochemical evaluation of δ(2)-isoxazoline derivatives as DNA methyltransferase 1 inhibitors.
abstract: A series of Δ(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno, Fisciano, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuck
authors.forename: Monica
authors.initials: M
authors.lastname: Viviano
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.forename: Fabian
authors.initials: F
authors.lastname: López-Vallejo
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D012436:S-Adenosylmethionine / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C569675:5-(N,N-dimethylaminomethyl)-3-(4-nitrophenyl)-4,5-dihydroisoxazole; D000970:Antineoplastic Agents; D007555:Isoxazoles; D011994:Recombinant Proteins; D012436:S-Adenosylmethionine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human