Cyclopropylindole Alkylating Agents

This name, although incorrect from the point of view of chemical nomenclature, is usually employed to design a number of antitumor compounds that contain a cyclopropane ring fused to an indole system. The first member of this class was the natural product CC-1065, an extremely potent cytotoxic agent isolated in trace quantities from the culture of S. zelensis in 1978, whose unique structure was confirmed by single-crystal X-ray diffraction in 1981. In spite of its very high in vitro antitumor activity, CC-1065 cannot be used in humans because it caused deaths in experimental animals due to its delayed hepatotoxicity.77 In the search for compounds with better antitumor selectivity and DNA sequence specificity, many CC-1065 analogues have been synthesized in an attempt to avoid the undesired side effects while retaining its potency against tumor cells. Among them, the duocarmycins,78,79 adozelesin, and halomethyl analogues such as bizele-

sin,80 U-80224, and KW-218982 may be mentioned. Among these compounds, the water-soluble prodrug KW-2189, which is activated by carboxyl esterases, is the most advanced one, having undergone Phase II clinical trials in patients with advanced malignant melanoma.83 Hybrid compounds containing the cyclopropy-lindole fragment or its precursors and minor groove binding distamycin portions have also been prepared.84

Wzory Haftow




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