Liren Huang, James C. Quada and J. William Lown* Pages 543 - 560 ( 18 )
The naturally occurring glycopeptide bleomycin exhibits both antitumor and antibiotic properties. It has an established place in the clinical treatment of certain human malignancies including squamous cell carcinoma and testicular tumors. Structurally it comprises four distinct domains: i) an anchoring group containing a bithiazole moiety that binds to double helical DNA; ii) a chiral peptidic spacer that positions the individual portions of the molecule on the receptor; iii) a sugar moiety bearing a carbamoyl group; and iv) an active moiety bearing ligands capable of coordinating a metal ion, such as iron and which is involved in the redox chemistry ultimately responsible for site specific DNA damage. The observation of serious side effects, principally pulmonary toxicity, has limited the clinical applications of bleomycin and provides the motivation to develop less toxic and more selective versions of the drug. Once the mechanism of action of bleomycin via oxygen mediated and site specific DNA cleavage was elucidated the possibility arose of designing functional models. This article will review progress from the earliest metal-complexing models to the most recent conjugates that fully mimic the action of the natural product and, moreover, are capable of being directed to alternative target sequences.