Design and synthesis of bleomycin and related analogs: DNA binding and cleavage agents
Abstract
The bleomycins are a family of glycopeptides isolated from culture of streptomyces as copper chelates. These naturally occuring compounds clearly have the ability to recognize and noncovalently bind to specific sequences in DNA and then to perform chemistry on a specific deoxynucleoside residue that can ultimately lead to strand scission and antitumor activity. Blenoxane, a naturally occuring mixture containing 60-70% bleomycin A$\sb2$, 20-30% bleomycin B$\sb2$ and other minor bleomycins continues to be used in the clinical treatment of several types of cancer, notably Hodgkins disease, squamous cell carcinoma, lymphomas, and tumor of the testis. Despite the intense interest in the clinical use of bleomycins over the last 25 years, the structural features contributing to their selective interaction with DNA and the delineation of their geometry of binding remain unresolved. We anticipate addressing these important questions of molecular recognition, functional reactivity and antitumor activity, through the preparation of naturally occuring bleomycin A$\sb2$ and an extensive series of analogs. In efforts that initiate a detailed examination of the functional role of the individual bleomycin subunits and substituents, we describe herein the synthesis and preliminary evaluation of deglycobleomycin A$\sb2,$ deglycobleomycin A$\sb1,$ desacetamido deglycobleomycin A$\sb2,$ GABA, Gly deglycobleomycin A$\sb2$, GABA, Gly desacetamido deglycobleomycin A$\sb2,$ desimidazole deglycobleomycin A2, P-3A and epi P-3A. Also detailed is a simple method for the puiification and isolation of natural bleomycin A$\sb2$ and deglyco bleomycin A$\sb2$ which were used as comparative standards.
Degree
Ph.D.
Advisors
Boger, Purdue University.
Subject Area
Organic chemistry|Biochemistry
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