MCBI analogs of CC-1065 and the duocarmycins

Details MCBI analogs of CC-1065 and the duocarmycins MCBI analogs of CC-1065 and the duocarmycins

1998-09-04

1999-11-16

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514411, 548425, 548427, C07D40314, A61K 3140

Patent

active

059859083

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

The invention relates to antitumor antibiotics. More particularly, the invention relates to analogs of CC-1065 and the duocarmycins having antitumor antibiotic activity.


BACKGROUND

(+)-CC-1065 (1) and the duocarmycins represent the initial members of a class of exceptionally potent antitumor antibiotics that derive their biological effects through the reversible, stereoelectronically-controlled sequences alkylation of DNA (Boger et al. J. Org. Chem. 1990, 55, 4499; Boger et al. J. Am. Chem. Soc. 1990, 112, 8961; Boger et al. J. Am. Chem. Soc. 1991, 113, 6645; Boger et al. J. Am. Chem. Soc. 1993, 115, 9872; Boger et al. Bioorg. Med. Chem. Lett. 1992, 2, 759). Subsequent to their initial disclosure, extensive efforts have been devoted to establish their DNA alkylation selectivity and its structural origin. Efforts have also been devoted to establish the link between DNA alkylation and the ensuing biological properties, i.e., to define the fundamental principles underlying the relationships between structure, chemical reactivity, and biological properties (FIG. 1; 1-3).
CBI (1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one) has been identified as an alkylation subunit which corresponds to the alkylation subunit of CC-1065 and the duocarmycins. (Boger et al. J. Am. Chem. Soc. 1989, 111, 6461; Boger D. L.; Ishizaki et al. J. Org. Chem. 1990, 55, 5823). Agents which include the CBI-based analogs have proven especially useful as DNA alkylating agents. This was significant since preceding studies had attributed such unique characteristics to the naturally occurring alkylation subunits that they left the perception that even small structural perturbations, let alone deep-seated structural changes, would have detrimental effects on the properties. (Hurley et al. Science 1984, 226, 843; Reynolds et al. Biochemistry 1985, 24, 6228; Hurley et al. Biochemistry 1988, 27, 3886; Hurley et al. J. Am. Chem. Soc. 1990, 112, 4633; Warpehoski et al. Biochemistry 1992, 31, 2502.) Not only has this proven inaccurate, but the natural enantiomers of the CBI-based analogs of (+)-CC-1065 have proven chemically more stable (4.times.), biological more potent and considerably more synthetically accessible than the corresponding agents incorporating the natural CPI alkylation subunit of CC-1065. (Boger et al. J. Org. Chem. 1990, 55, 5823; Boger et al. J. Org. Chem. 1992, 57, 2873; Boger et al. J. Org. Chem. 1995, 60, 1271.) Moreover, selected agents within the series of CBI analogs not only exhibited potent cytotoxic activity but also potent and efficacious in vivo antitumor activity. (Boger et al. Bioorg. Med. Chem. Lett. 1991, 1, 115).
The natural enantiomers of the CBI-based analogs have been shown to alkylate DNA with an unaltered sequence selectivity at an enhanced rate and with a greater efficiency than the corresponding CPI analog. (Boger et al. Bioorg. Med. Chem. Lett. 1991, 1, 115; Boger et al. J. Am. Chem. Soc. 1991, 113, 2779; Boger et al. J. Am. Chem. Soc. 1992, 114, 5487.) This indicates that the simplified CBI alkylation subunit offers important advantages over the natural alkylation subunit of CC-1065. In recent studies, models of the DNA alkylation reactions of CC-1065 and the duocarmycins have been developed. (Boger et al. J. Org. Chem. 1990, 55, 4499; Boger et al. J. Am. Chem. Soc. 1990, 112, 8961; Boger et al. J. Am. Chem. Soc. 1991, 113, 6645; Boger et al. J. Am. Chem. Soc. 1993, 115, 9872; Boger et al. Bioorg. Med. Chem. Lett. 1992, 2, 759; Boger et al. J. Am. Chem. Soc. 1994, 116, 1635. ) These models accomodate the reversed and offset AT-rich adenine N.sub.3 DNA alkylation selectivity of the enantiomeric agents and their structural analogs. The diastereomeric adducts derived from the unnatural enantiomers have been found to suffer a significant destabilizing steric interaction between the CPI C7 center (CH.sub.3) or the CBI C8 center with the base adjacent to the alkylated adenine which is not present with the natural enantiomer adducts. Consistent with this observation, the distinguishing

REFERENCES:
Boger, J Org Chem 61(5) 1710, May 1996.

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