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.