Metal Activation of Organic Drugs

Bleomycin (BLM) was first isolated as a copper complex from a culture of Streptomyces verticillus. Since then numerous analogs have been prepared by modifying the conditions of fermentation. Bleomycins (114, bleomycin A2) are used clinically in combination cancer chemotherapy for the treatment of head and neck cancer, certain lymphomas, and testicular cancer (555). 

The cytotoxicity of BLM is believed to result from its ability to bind iron, activate oxygen, and form an activated BLM (Fe-114) (556) which cleaves DNA and possibly RNA (557). The ability of the Fe(II)-BLM complex to bind to oxygen and produce oxygenated BLM species such as 02-Fe(III)-BLM or 02-Fe(II)-BLM may be due to the presence of delocalized 77-electrons around the iron and the strong iron-pyrimidine 77-back-bonding (558, 559). Oxygenated BLM accepts an additional electron to form activated low-spin ferric-peroxide-BLM (Oi -Fe(III)-BLM) (558, 559). The structural features of Fe-BLM responsible for DNA (or RNA) degradation remain unclear (560). Bleo- 

The antiulcer drug famotidine 115 exerts its activity by blocking the histamine H2 receptor in a similar manner to cimetidine. Famoti- 

Quinobenzoxazine compounds such as 116 are a class of potential antineoplastic agents that are catalytic inhibitors of topoisomerase II. 

Metal ions such as Cu(II) (566) and Mn(II) (567) react specifically with the hormone vasopressin and vasopressin-like peptides, and this 

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