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Dna-binding polyamide drug conjugates

Dna-binding polyamide drug conjugates description/claims

This patent application is a divisional of copending U.S. patent application Ser. No. 10/506,085, filed Oct. 1, 2004, which is a U.S. National Phase of International Patent Application No. PCT/US03/06006, filed Feb. 27, 2003, which claims the benefit of U.S. Provisional Patent Application No. 60/361,050, filed Feb. 27, 2002, and U.S. Provisional Patent Application No. 60/370,168, filed Apr. 5, 2002, the disclosures of the '085, '006, '050 and '168 applications are incorporated by reference.

The present invention relates to conjugates comprising one or more DNA intercalator(s) and/or one or more DNA alkylator(s) linked to one or more polyamide DNA minor groove binder(s). The conjugates of the present invention and compositions thereof are useful in the treatment of cancer in a mammal.

Specificity is one of the goals of modern drug design. It is known that DNA is a target of most antitumor drugs, since many antitumor drugs are effective by inhibiting nucleic acid (DNA or RNA) or protein synthesis. There are many potent antitumor compounds with a wide spectrum of activities against many tumor cell lines, both in vitro and in vivo, but because these compounds are so toxic, normal cells and tissue can be adversely affected as well. Many researchers have proposed ideas of increasing selectivity, while maintaining a high degree of toxicity.

Polyamides that contain polypyrrole carboxamide and/or polyimidazole carboxamide subunits are known to bind specifically to the minor groove of DNA (see, for example, Dervan, Bioorganic and Medicinal Chemistry, 9: 2215-2235 (2001); Soto et al., Nucleic Acids Research, 29(17): 3638-3645 (2001); and Reddy et al., Current Medicinal Chemistry, 8: 475-508 (2001)). Such polyamides can be designed so that they bind to DNA in a sequence-specific manner. These polyamide minor groove binders can inhibit or suppress gene functions. The polyamide minor groove binders bis-lexitropsins (Reddy et al., Current Medicinal Chemistry, 8: 475-508 (2001)), for example, have shown enhanced cytotoxic activity against KB human nasopharyngeal carcinoma. It also has been shown that double-stranded hairpin polyamides can permeate cellular and nuclear membranes of eukaryotes and, when targeted to promoter regions, can inhibit specific gene expression (Gottesfeld et al., Nature, 387: 202-205 (1997); and Dickinson et al., Proc. Natl. Acad. Sci. U.S.A., 95: 12890-12895 (1998)). In addition to the double-stranded hairpin polyamides, the single-stranded analogues have been proven to carry out inhibition of gene expression in Drosophila (Maeshima et al., The EMBO Journal, 20: 3218-3228 (2001)).

Researchers have linked toxic compounds to polyamide sequences, such as netropsin, distamycin and lexitropsin (see, for example, Chang et al., J. Am. Chem. Soc., 122: 4856-4864 (2000); Gupta et al., Anti-Cancer Drug Design, 11(8): 581-596 (1996); Jia et al., Heterocyclic Commun., 4(6): 557-560 (1998); Jia et al., Chem. Commun., (2): 119-120 (1999); Jia et al., Synlett, (5): 603-606 (2000); and Wang et al., Gene, 149(1): 63-67 (1994)). While these conjugates may show some antitumor activity, the conjugates, themselves, have the wrong geometric and/or electronic parameters that hinder the fit in the minor groove. A poor fit can result in a lower efficacy or selectivity as well as higher side effects due to nonspecific binding to untargeted genomic elements or DNA sequences.

Thus, there still exists a need for therapeutic conjugates that have improved antitumor selectivity and DNA sequence-specific binding properties. Ideally, these conjugates would elicit fewer side effects and less damage to healthy cells and tissue. Effective therapeutic conjugates can be designed rationally, because an understanding of the geometry of the conjugates enables a better fit of the drug into the shape of the minor groove pocket, thereby increasing the sequence-specificity. The present invention provides such therapeutic conjugates. The conjugates of the present invention bind in the minor groove of DNA in a sequence-specific manner and effectively deliver a toxic moiety.

The present invention provides a conjugate of formula:

V—(Y)a-Z-T  (I) or

T-X—B—(Y)a-Z-T′  (II),

in which V is a DNA intercalator, X is a DNA alkylator, B is a heteroaromatic residue that is attached to the N-terminus of the alkylator subunit (X), Y is a linker, T and T′ are the same or different and each is a terminal subunit, Z is a polyamide group that binds to the minor groove of DNA, and a is 0 or 1, provided that when V is naphthalimide, then Z is not lexitropsin, and further provided that when V is doxorubicin, then Z is not netropsin or distamycin. In addition, the present invention provides a conjugate of formula:

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