Synthesis and Biological Evaluation of Novel Analogues and Prodrugs of the Cytotoxic Antibiotic CC-1065 for Selective Cancer Therapy

Abstract

This paper describes novel seco-analogues 25−27 of the cytotoxic antibiotic CC-1065 (1) and their prodrugs 5, 6a, and 6b, for antibody-directed enzyme prodrug therapy (ADEPT). The partially hydrogenated seco-CCI-analogue 7 and the corresponding methyl-CCI analogues 8a and 8b were synthesized by alkylation of 9 with 15 and 16, respectively, followed by radical cyclization and deprotection. Treatment of 7, 8a, and 8b with the galactose trichloroacetimidate 21 and the bisindolyl-carboxylic acid 20 in the presence of EDC followed by solvolysis gave the desired prodrugs 5, 6a, and 6b, respectively. Compounds 25−27 were prepared by treatment of 7, 8a, and 8b with 20 after deprotection. In vitro tests showed a strong cytotoxicity for 25 and a fairly low toxicities for 26 and 27. However, the selectivity of the prodrugs 5, 6a, and 6b was not sufficient for ADEPT. Interestingly, 8a and 8b did not undergo Winstein cyclization to produce the spirocyclopropylcyclohexadienone moiety. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)