title: Total synthesis of the proposed structures of the DNA methyl transferase inhibitors peyssonenynes, and structural revision of peyssonenyne B.
abstract: The purported structures of the peyssonenynes A and B isolated from Peyssonnelia caulifera, and considered to be geometric isomers at the acetoxyenediyne moiety, have been synthesized. The E and Z geometries of the synthetic compounds were secured by the magnitude of the (3)J(H9-C7) values measured using the EXSIDE band-variant of the gradient HSQC pulse sequence and by the chemical shifts of C(6). Comparison of the NMR data of the synthetic and natural products revealed that only those of the Z isomers matched, which correspond to peyssonenyne A. Using HPLC analysis it was found that peyssonenyne B must correspond to the sn-2 positional isomer of the Z sn-1/3 counterpart. The four synthetic sn-1/3 diastereomers are roughly equipotent as DNMT1 inhibitors when evaluated on a radioactive methyl transfer enzymatic assay after immunoprecipitation from K562 human leukemia cells with anti-DNMT1 antibody.
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: García-Domínguez
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lepore
authors.forename: Cathie
authors.initials: C
authors.lastname: Erb
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Rosana
authors.initials: R
authors.lastname: Álvarez
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
mesh_terms: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D053281:Enediynes / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005231:Fatty Acids, Unsaturated / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D053281:Enediynes; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C488239:peyssonenyne B; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human