Oxygen Isotope Effect on Activated Bleomycin Stability

摘要

The bleomycins comprise a family of antitumor antibiotics that act by damaging DNA~4 through formation of an activated complex of bleomycin, Fe(Ⅲ), and oxygen. When activated bleomycin initiates DNA degradation, H4′ is removed from deoxyribose and C4′ is exposed to attack by endogenous O_2. How this occurs is unclear because activated bleomycin has not been adequately characterized. Activated bleomycin can form from bleomycin, Fe(Ⅱ), and O_2 (eq 1) as well as through routes involving Fe(Ⅲ) and peroxides or superoxide. In each case, a dioxygen species is involved. An O—O cleavage must occur in the course of activated bleomycin formation or decay, since activated bleomycin spontaneously yields the stable compound Fe~Ⅲ—bleomycin and water without releasing significant quantities of peroxide or superoxide. It has been hypothesized that the Fe(Ⅲ)-complexed oxygen in activated bleomycin is a peroxide (activated bleomycin is at the redox level of a ferric peroxide, and mass spectroscopy indicates that it contains both added oxygen atoms). However, the absence of evidence for O—O linkage or information about the immediate products of activated bleomycin decay prevents assignment of a particular oxygen structure to the complex. Depending on this oxygen structure, activated bleomycin may be envisaged to react by breaking either an O—O or an Fe-O bond. These alternative events can be distinguished, since the distinct bond strengths of the hypothetical reactants and products (Table 1) lead to predictions of very different oxygen isotope effects on activated bleomycin decay (Table 2 and below).