Analogs of CC-1065 and the duocarmycins

Details Analogs of CC-1065 and the duocarmycins Analogs of CC-1065 and the duocarmycins

1999-09-07

2000-05-09

Stockton, Laura L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548181, 548421, C07D20956, C07D40306, C07D41704, C07D48704

Patent

active

060606088

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

1. 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.
2. Background
(+)-CC-1065 (1) and the duocarmycins represent the initial members of a class of exceptionally potent antitumor antibiotics. Members of this class of antitumor antibiotic derive their biological effects through the reversible, stereoelectronically-controlled sequence selective alkylation of duplex DNA. (H. Sugiyama, et al., Tetrahedron Lett. 1990, 31, 7197; C. H. Lin, et al., J. Am. Chem. Soc. 1992, 114, 10658; H. Sugiyama, et al., Tetrahedron Lett. 1993, 34, 2179; K. Yamamoto, et al., Biochemistry 1993, 32, 1059; A. Asai, et al., J. Am. Chem. Soc. 1994, 116, 4171; and D. L. Boger, et al., Tetrahedron 1991, 47, 2661.) (+)-CC-1065 (1) was first disclosed in 1981 by L. J. Hanka, et al. (J. Am. Chem. Soc. 1981, 103, 7629.) The duocarmycins were first disclosed in 1988 and 1990. (Takahashi, et al. J. Antibiot. 1988, 41, 1915; T. Yasuzawa, et al., Chem. Pharm. Bull. 1988, 36, 3728; M. Ichimura, et al., J. Antibiot. 1988, 41, 1285; M. Ichimura, et al., J. Antibiot. 1990, 43, 1037; M. H. Ichimura, et al., J. Antibiot. 1991, 44, 1045; K. Ohba, et al., J. Antibiot. 1988, 41, 1515; and S. Ishii, J. Antibiot. 1989, 42, 1713.)
Subsequent to their disclosure, extensive efforts have been devoted to establish their duplex DNA alkylation selectivity and its structural origin. (D. L. Boger, Acc. Chem. Res. 1995, 28, 20; D. L. Boger, Proc. Natl. Sci. U.S.A. in press; D. L. Boger, Chemtracts: Org. Chem. 1991, 4, 329; D. L. Boger, In Proceed. R. A. Welch Found. Conf. on Chem. Res., XXXV. Chem. at the Frontiers of Medicine 1991, 35, 137; D. L. Boger, In Advances in Heterocyclic Natural Products Synthesis, Vol. 2, Pearson, W. H. Ed.; JAI Press: Greenwich, Conn., 1992, 1-188; D. L. Boger, Pure Appl. Chem. 1993, 65, 1123; D. L. Boger, Pure Appl. Chem. 1994, 66, 837; R. S. Coleman, In Studies in Nat. Prod. Chem., Vol 3, Rahman, A.-u.-, Ed.; Elsevier: Amsterdam, 1989, 301; and D. L. Boger, In Heterocycles in Bioorganic Chemistry; J. Bergman , H. C. van der Plas, and M. Simonyl, Eds; Royal Society of Chemistry: Cambridge, 1991, 103.) Progress has also been made with respect to characterizing the link between DNA alkylation and the ensuing biological properties. (D. L. Boger, et al., Bioorg. Med. Chem. Lett. 1994, 4, 631.) Extensive efforts have also been devoted to define the fundamental principles underlying the relationships between structure, chemical reactivity, and biological properties. (W. Wierenga, et al., Adv. Enzyme Regul. 1986, 25, 141; M. A. Warpehoski, et al., J. Med. Chem. 1988, 31, 590; D. L. Boger, et al., J. Am. Chem. Soc. 1993, 115, 9025; D. L. Boger, et al., J. Am. Chem. Soc. 1992, 114, 10056; H. Muratake, et al., Tetrahedron Lett. 1994, 35, 2573; Y. Fukuda, et al., Tetrahedron 1994, 50, 2793; Y. Fukuda, et al., Tetrahedron 1994, 50, 2809; Y. Fukuda, et al., Bioorg. Med. Chem. Lett. 1992, 2, 755; Y. Fukuda, et al., Tetrahedron Lett. 1990, 31, 6699; W. Wierenga, J. Am. Chem. Soc. 1981, 103, 5621; P. Magnus, et al., J. Am. Chem. Soc. 1987, 109, 2706; G. A. Kraus, et al., J. Org. Chem. 1985, 50, 283; D. L. Boger, et al., J. Am. Chem. Soc. 1988, 110, 1321, 4796; R. E. Bolton, et al., J. Chem. Soc., Perkin Trans. 1 1988, 2491; R. J. Sundberg, et al., J. Org. Chem. 1988, 53, 5097; R. J. Sundberg, et al., J. Org. Chem. 1991, 56, 3048; V. P. Martin, Helv. Chim. Acta 1989, 72, 1554; M. Toyota, et al., J. Chem. Soc., Perkin Trans. 1 1992, 547; and L. F. Tietze, et al., J. Org. Chem. 1994, 59, 192.) The relationships between structure, chemical reactivity, and biological properties of CI-based analogs have also been characterized. (D. L. Boger, et al., Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1431; D. L. Boger, et al., J. Am. Chem. Soc. 1991, 113, 3980; D. L. Boger, et al., J. Org. Chem. 1989, 54, 1238; D. L. Boger, et al., J. Am. Chem. Soc. 1990, 112, 5230; K. J. Drost, et al., J. Org. Chem. 1989, 54, 5985; J.

REFERENCES:
patent: 5258383 (1993-11-01), Nagamura et al.

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