The chemistry, mechanism of action and biological properties of CC-1065, a potent antitumor antibiotic.

The structure of CC-1065 (Fig. 1) was determined by X-ray crystallography5,6). Prior to isolation of a suitable crystalline form of CC-1065 for X-ray diffraction data collection, a chemical degradation product (1) obtained by reaction of CC-1065 with ethyl isocyanate in pyridine was crystallized and its structure determined by X-ray crystallography". A closely related compound, PDE I (2), was previously isolated from a fermentation broth8), but is nontoxic in mice at 200 mg/kg. This is in sharp contrast to CC-1065, which is toxic at a dose of 0.1 mg/kg5) Recently the products of alkaline and acidic hydrolysis of CC-1065 have been purified and characterized'). CC-1065 (NSC-298223) is an extremely potent antitumor antibiotic produced by Streptomyces zelensis NRRL 11,183. The microorganism producing this antibiotic was isolated by investigators at The Upjohn Company by screening soil cultures for agents displaying both cytotoxic activity against L1210 cells in culture and in vivo activity against P388 leukemia in mice1~3). The production of CC1065, its in vitro biological activity, microbiological assays and taxonomy have been described1), and more recently improved methods for production and isolation of this compound have also been published3). CC-1065 has also been isolated by scientists in the USSR from Streptomyces canulus4). Fermentation broths of S. zelensis produce only very modest amounts of CC-1065 (approximately 6 9 mg/liter)3) and precautions need to be taken by laboratory workers involved in the isolation and handling of this potent antitumor agent.