Reductive and nucleophilic activation products of dynemicin A with methyl thioglycolate. A rational mechanism for DNA cleavage of the thiol-activated dynemicin A.
The reaction products of methyl thioglycolate with dynemicin A, dynemicin H and dynemicin S, were isolated by HPLC purification and identified spectroscopically. The major product, dynemicin H (C30H23NO9), was determined to be a C-8 hydrogen analogue of dynemicins L and N in which the enediyne core is aromatized. The minor product, dynemicin S (C33H27No11S), is an adduct of methyl thioglycolate at the C-8 position. By using NADPH instead of methyl thioglycolate, the reaction with dynemicin A also gives the same major product (dynemicin H). The nucleotide-specific cleavage of dynemicin A induced by addition of methyl thioglycolate is remarkably similar to that induced by addition of NADPH, whereas dynemicins H and S show no DNA cleavage activities. The formation of dynemicins H and S provides a rationale for the reductive and nucleophilic activations of dynemicin A.
Sugiura
Y
Y
Institute for Chemical Research, Kyoto University, Japan.
Arakawa
T
T
Uesugi
M
M
Shiraki
T
T
Ohkuma
H
H
Konishi
M
M
D000475:Alkenes; D000880:Anthraquinones / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D004587:Electrophoresis, Agar Gel; D053281:Enediynes; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013864:Thioglycolates / Q000737:chemistry*
D000475:Alkenes; D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D013438:Sulfhydryl Compounds; D013864:Thioglycolates; C068022:dynemicin H; C068024:dynemicin S; D004247:DNA; C061229:dynemicin A; C037474:methyl thioglycolate