Molecular aspects of the interaction of (+)-CC-1065 with DNA

Abstract

(+)-CC-1065 (Figure 4.1) was discovered in 1974 by scientists at The Upjohn Company in a fermentation screening program sponsored by the National Cancer Institute (Hanka et al. 1978). An X-ray structure of the drug was published in 1981 (Chidester et al., 1981) and the first detailed account of its interaction with DNA was published in 1982 (Li et al. 1982). (+)-CC-1065 is produced in fermentation broths of Streptomyces zelensis (Hanka et al. 1978), and although the biosynthetic precursors have been identified (Hurley and Rokem, 1983), the low antibiotic titre has hampered subsequent studies on its biosynthesis. At the time of isolation, (+)-CC-1065 was the most potent, small-molecular-weight compound known and showed cytotoxic potency and efficacy against a wide variety of tumours in vitro (Martin et al., 1981; Li et al., 1982). Unfortunately, the subsequent discovery of an unusual delayed lethality in mice at sub-therapeutic doses precluded (+)-CC-1065 from further development as a clinical agent (McGovren et al.1984). Subsequently, an aggressive and highly successful synthetic programme at The Upjohn Company has provided a series of three new compounds that appear to be more suitable for clinical development. These agents, Adozelesin, U-77779 and U-80244 (Figure 4.1), have been shown to have improved antitumour efficacy over (+)-CC-1065 and do not show delayed lethality (Warpehoski et al., 1988; Li et al. 1991).