Synthetic and DNA cross-linking studies of bioxalomycinα₂
Date
1999
Authors
Herberich, Bradley James, author
Williams, Robert M., advisor
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Abstract
The preparation of a [3 + 2] cycloaddition precursor towards the total synthesis of bioxalomycin α2 is presented. The route contains four key steps. These include a Staudinger reaction that sets the required syn stereochemistry at C-13a and C-13b, a stereoselective Pictet-Spengler reaction, an intramolecular transamidation to open a β-lactam ring, and a regioselective reduction of a diketopiperazine. The cycloaddition product afforded by this route though not amenable to the total synthesis of bioxalomycin α2, may be an entry into analogs of bioxalomycin α2. Evidence for interstrand DNA cross-linking induced by bioxalomycin α2 is outlined. The sequence specificity for the cross-link formation and the alkylated residue of DNA is identified. The requirement of reductive activation of cyanocycline A for DNA cross-linking is presented. The synthesis of quinocarcin analogs, which contain the epi stereochemistry at C-11a, was completed. The analogs were designed to alkylate DNA without any undesired indiscriminate DNA strand scission. When evaluated the analogs demonstrated no evidence of DNA strand scission nor DNA alkylation. From these efforts a new quinocarcin analog, which may have the capacity to alkylate DNA, has been proposed.
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Subject
Antineoplastic antibiotics
Organic compounds -- Synthesis