ABSTRACT

CC-1065 (1) is an extremely potent antitumor antibiotic isolated from Streptomyces zelensis by Upjohn Company.1,2 It is one of the most potent anticancer compounds having a wide spectrum of activities against tumor cells in vitro and in vivo as well as against microbial organisms.3,4 Structurally, the CC-1065 molecule consists of three repeating pyrroloindole subunits, one of which contains the DNA reactive cyclopropylpyrroloindole (CPI) moiety (2), while the other two subunits mediate noncovalent binding interactions with DNA. CC-1065 alkylates the N3 position of adenine with its reactive cyclopropyl group in the minor groove of double helical DNA in a sequence-speciœc manner with a consensus sequence of 5-(T/A)(T/A) A* (where the asterisk indicates the site of alkylation). The preferred site of alkylation by CC-1065 was determined to be the 5-TTA* sequence.4-10

20.1 Introduction ........................................................................................................................ 479 20.2 Drug-DNA Interactions ..................................................................................................... 481 20.3 Modiœcation in the Pharmacophore Unit ........................................................................... 482

20.3.1 CPI Analogs ............................................................................................................ 482 20.3.2 Enantiomers of CPI Analogs ..................................................................................486 20.3.3 CC-1065 Analogs ....................................................................................................486 20.3.4 Further Analogs ...................................................................................................... 489

20.4 Interaction of CC-1065 with Chromatin ............................................................................. 489 20.5 Polyamide Conjugates and Related Sequence Directed Structures .................................... 492 20.6 Bisalkylators (Dimers) ........................................................................................................ 498 20.7 Structural Characterization of Drug DNA Complexes ...................................................... 498 20.8 Cellular and Pharmacological Studies ................................................................................ 501

20.8.1 In Vitro Studies ....................................................................................................... 501 20.8.2 In Vivo Studies ........................................................................................................504