Antitumor Antibiotics: Bleomycin, Enediynes, and Mitomycin Ute Galm, ² Martin H. Hager, ² Steven G. Van Lanen, ² Jianhua Ju, ² Jon S. Thorson,* ,² and Ben Shen* ,²,‡ Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53705 Received July 19, 2004 Contents 1. Introduction 739 2. Bleomycin 739 2.1. Discovery and Biological Activities 739 2.2. Clinical Resistance 740 2.2.1. Bleomycin Hydrolase 741 2.2.2. Enhanced DNA Repair 742 2.2.3. Bleomycin Binding Protein 742 2.2.4. Other Mechanisms 743 2.3. Resistance by the Producing Organisms 743 2.3.1. Bleomycin N-Acetyltranferase (BlmB) 743 2.3.2. Bleomycin Binding Protein (BlmA) 743 2.3.3. Transport Proteins 744 3. EnediynessNine-Membered Enediyne Core Subfamily 744 3.1. Discovery and Biological Activities 745 3.2. Resistance by the Producing Organisms 746 3.2.1. Apo-Protein 746 3.2.2. DNA Repair 747 3.2.3. Transport 747 4. EnediynessTen-Membered Enediyne Core Subfamily 748 4.1. Discovery and Biological Activities 748 4.2. Clinical Resistance 750 4.3. Resistance by the Producing Organisms 751 5. Mitomycin 752 5.1. Discovery and Biological Activities 752 5.2. Clinical Resistance 754 5.3. Resistance by the Producing Organisms 754 6. Perspective 754 7. Abbreviations 755 8. Acknowledgment 755 9. References 755 1. Introduction Natural-product-derived cytotoxics remain a main- stay in current chemotherapy. 1 This review focuses on the current level of understanding and emerging trends relevant to the DNA-damaging metabolite families of the bleomycins, 9- and 10-membered enediynes, and mitomycins. Within the context of their clinical utilities and shortcomings, a comparison of resistance mechanisms within producing organ- isms to those predominant among tumor cells reveals remarkable potential for continued development of these essential anticancer agents. 2. Bleomycin 2.1. Discovery and Biological Activities The bleomycins (BLMs), such as bleomycinic acid (1), BLM A2 (2), or BLM B2 (3), are a family of glycopeptide-derived antibiotics originally isolated from several Streptomyces species. 2,3 Several struc- ture variations of the naturally occurring BLMs have been identified from fermentation broths, primarily differing at the C-terminus of the glycopeptide. The BLM structure was revised in 1978 4 and confirmed by total synthesis in 1982. 5,6 Structurally and bio- synthetically related to the BLMs are the phleomy- cins (PLMs), such as PLM 12 (4) or PLM D1 (5), 7-10 and tallysomycins (TLMs), such as TLM S 2 B(6) and TLM S 10 B(7) 11,12 (Figure 1). BLMs are thought to exert their biological effects through a sequence-selective, metal-dependent oxi- dative cleavage of DNA and RNA in the presence of oxygen. 13-16 The BLMs can be dissected into four functional domains: (i) the pyrimidoblamic acid (PBA) subunit along with the adjacent -hydroxyl histidine constitutes the metal-binding domain that provides the coordination sites required for Fe(II) complexation and molecular oxygen activation re- sponsible for DNA cleavage; (ii) the bithiazole and C-terminal amine provide the majority of the BLM- DNA affinity and may contribute to polynucleotide recognition and the DNA cleavage selectivity; (iii) the (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid (AHM) subunit not only provides the connectivity between the metal-binding and DNA-binding sites but also plays an important role in the efficiency of DNA cleavage by BLMs; (iv) the sugar moiety is likely to participate in cell recognition by BLMs and possibly in cellular uptake and metal-ion coordina- tion. Consequently, there have been continuing at- tempts to develop new BLM congeners to define the fundamental functional roles of the individual do- mains and search for anticancer drugs with better clinical efficacy and lower toxicity. However, the structural complexity of BLMs has limited most of the modifications at either the C-terminal amine or the N-terminal -aminoalaninamide moiety by either directed biosynthesis or semisynthesis. Total chemi- * To whom correspondence should be addressed. J.S.T.: phone, 608-262-3829; fax, 608-262-5345; e-mail, jsthorson@ pharmacy.wisc.edu. B.S.: phone, (608) 263-2673; fax, (608) 262- 5345.; e-mail, bshen@pharmacy.wisc.edu. † Division of Pharmaceutical Sciences. ‡ Department of Chemistry. 739 Chem. Rev. 2005, 105, 739-758 10.1021/cr030117g CCC: $53.50 © 2005 American Chemical Society Published on Web 01/21/2005