Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-02-27
2004-01-13
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S034000, C536S006400, C536S006500
Reexamination Certificate
active
06677309
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds useful in the treatment of cancer. Particularly, this invention relates to anti-cancer drugs comprising an amino alcohol functionality, e.g. anthracyclines. More particularly, this invention relates to anthracycline aldehyde conjugates formed by reaction of an anthracycline with an aldehyde, e.g. formaldehyde.
BACKGROUND OF THE INVENTION
Doxorubicin (adriamycin) continues to be one of the most important anti-cancer drugs available. It is a broad spectrum drug particularly useful in the treatment of Hodgkin's disease, non-Hodgkin lymphomas, acute leukemias, sarcomas, and solid tumors of the breast, lung, and ovary (young, R. C. et al. (1981) New Engl. J. Med. 305:139-153). The closely related drug daunorubicin (daunomycin) is used primarily for the treatment of acute leukemia. A major problem associated with doxorubicin and daunorubicin chemotherapy is multi-drug resistance. Multi-drug resistance is characterized by resistance to several drugs developed by tumor cells upon treatment with one drug. Mechanisms proposed for tumor cell multi-drug resistance include overexpression of cell membrane proteins which enhance efflux of the drug, and overexpression of glutathione transferase which transforms xenobiotics to glutathione conjugates for excretion (Volm, M. (1991) Br. J. Cancer 64:700-704; Giai, M. et al. (1991) Eur. J. Gynaecol. Oncol. 12:359-73; Black, S. M. and Wolf (1991) Pharmac. Ther. 51:139-154; Serafino, A. et al. (1998) Anticancer Res. in press). Glutathione itself is also thought to be involved in resistance in a variety of tumors (Blair, S. L. (1997) Cancer Res. 57:152-155). Resistance to anthracycline anti-cancer antibiotics has been shown to involve a lower concentration of drug-produced reactive oxygen species, presumably resulting from overexpression of enzymes which destroy superoxide and hydrogen peroxide (Sinha, B. K. and Mimnaugh, E. G. (1990) Free Radicals Biol. Med.8:567-581.
In spite of intensive investigation of the mode of action of doxorubicin and daunorubicin, the events leading to cell death and differential cytotoxicity are not totally understood. This has hindered the development of new analogs which are both more effective and which overcome multi-drug resistance. Both drugs are excellent DNA intercalators, and have been shown to concentrate in the cell nucleus (Chaires, J. B. et al. (1996) Biochemistry 35:2047-2053; Egorin, M. J. et al. (1974) Cancer Res. 34:2243-2245; Coley, H. M. et al. (1993) Br. J. Cancer 67:1316-1323). Crystallographic data have established specific sequences as the sites of drug intercalation (Wang, A. H.-J. et al. (1987) Biochemistry 26:1152-1163; Frederick, C. A. et al. (1990) Biochemistry 29:2538-2549). The drugs are redox active through the quinone functionality and are substrates for one-electron redox enzymes such as xanthine oxidase, cytochrome P450 reductase, and mitochondrial NADH dehydrogenase (Pan, S. et al. (1981) Mol. Pharmacol. 19:184-186; Schreiber, J. et al. (1987) J. Am. Chem. Soc. 109:348-351; Schreiber, J. et al. (1987) J. Am. Chem. Soc. 109:348-351; Kappus, H. (1986) Biochem. Pharmacol. 35:1-6). Furthermore, reduction in the presence of molecular oxygen results in catalytic production of superoxide and hydrogen peroxide (Lown, W. J. et al. (1982) Biochem. Pharmacol. 31:575-581; Doroshow, J. H. (1983) Cancer Res.43:4543-4551; Sinha, B. K. (1989) Chem. Biol. Interact. 69:293-317). In an anaerobic environment, reduction leads to glycosidic cleavage to produce a quinone methide transient, long thought to be an alkylating agent for DNA (Kleyer, D. and Koch, T. H. (1984) J. Am. Chem. Soc. 106:2380-2387; Abdella, B. R. J. and Fisher, J. A. (1985) Envir. Health Perspect. 64:3-18; Gaudiano, G. et al. (1994) J. Am. Chem. Soc. 116:6537-6544; Moore, H. W. and Czerniak, R. (1981), Med. Res. Rev. 1:249-280). Currently, the most popular explanation for cytotoxicity is induction of topoisomerase-mediated DNA strand breaks through intercalation, with modulation through a signaling cascade involving a cell membrane receptor for doxorubicin (Liu, L. F. (1989) 58:351-375; Tritton, T. R. (1991) Pharmac. Ther. 49:293-301).
Recent reports from several laboratories have rekindled interest in the concept of drug alkylation of DNA via a redox pathway as an important cytotoxic event. Phillips and co-workers reported in a series of papers that in vitro reductive activation of doxorubicin and daunorubicin in the presence of DNA led to transcription blockages (Cullinane, C. R. (1994) Biochemistry 33:4632-8; Cullinane, C. (1994) Nucl. Acids Res. 22:2296-2303; van Rosmalen, A. (1995) Nucl. Acids Res. 23:42-50; Cutts, S. M. and Phillips, D. R. (1995) Nucl. Acids Res. 23:2450-6; Cutts, S. M. (1996)3J. Biol. Chem. 271:5422-9). These transcription blockages were attributed to the alkylation and crosslinking of DNA by reductively activated drug, possibly involving a quinone methide transient. The site of alkylation and crosslinking was proposed to be the 2-amino substituents of 2′-deoxyguanosines at the location. 5′-GpC-3′ in DNA. At about the same time, Skladanowski and Konopa established crosslinking of DNA by doxorubicin in HeLa S3 cells using a mild DNA denaturation-renaturation assay (Skladanowski, A. and Konopa, J. (1994) Biochem. Pharmacol. 47:2279-2287; Skladanowski, A. and Konopa, J. (1994) Biochem. Pharmacol. 47:2269-2278). They concluded that DNA crosslinks, although unstable to isolation, induced tumor cell apoptosis (Skladanowski, A. and Konopa, J. (1993) Biochem. Pharmacol. 46:375-382). We have recently demonstrated that the reported DNA alkylation and crosslinking does not involve the intermediacy of the quinone methide. The primary purpose of reductive activation of doxorubicin and daunorubicin is the production of superoxide and hydrogen peroxide (Taatjes, D. J. et al. (1996) J. Med. Chem. 39:4135-4138; Taatjes, D. J. et al. (1997) J. Med. Chem. 40, 1276-1286). These two reduced dioxygen species oxidize constituents in the medium to formaldehyde via Fenton chemistry (Taatjes, D. J. et al. (1997) Chem. Res. Toxicol. 10, 953-961). The resulting formaldehyde couples the 3′-amino group of intercalated doxorubicin or daunorubicin to the 2-amino group of deoxyguanosine via Schiff base chemistry. Thus, what Phillips and co-workers call a DNA “crosslink” by drug at 5′-GpC-3′, we describe as a “virtual crosslink” involving one covalent bond from formaldehyde and one intercalative-hydrogen bonding interaction with the opposing strand (Cullinane, C. R. (1994) Biochemistry 33:4632-8). This virtual crosslink is shown in Formula I for the DNA sequence 5′-CpGpC-3′ (Taatjes, D. J. et al. (1997) J. Med. Chem. 40, 1276-1286).
There is a long-felt need in the art for improved anti-cancer drugs, particularly those with greater efficacy against resistant cancers. This invention provides such drugs.
SUMMARY OF THE INVENTION
This invention provides dimeric drug aldehyde conjugate compounds which are anti-cancer drugs, and pharmaceutically acceptable salts thereof, of Formula II:
Formula B illustrates Formula A when Z
1
is N(1) and Z
2
is N(2). (The use of the numerals 1 and 2 inside parentheses is to distinguish one nitrogen atom from the other.) Z
1
, Z
2
, are the same or different heteroatoms, selected from the group consisting of N, S, P, Si, Se, and Ge. More preferably, Z
1
, Z
2
, are the same or different heteroatoms selected from the group consisting of N or S. Z
1
′ and Z
2
′, are the same or different heteroatoms selected from the group consisting of N, O, S, P, Si, Se, and Ge. Preferably, Z
1
′ and Z
2
′ are the same or different heteroatoms selected from the group consisting of N, S and O. Most preferably Z
1
is N of an amino group and Z
1
′ is an N of an amino group or O of an alcohol group, and Z
2
is N of an amino group and Z
2
′ is an N of an amino group or O of an alcohol group. If Z
1
′ is N, then preferably it is N of an amino group which is substituted with a non-hydrog
Fenick David J.
Koch Tad H.
Taatjes Dylan J.
Greenlee Winner & Sullivan PC
Owens, Jr. Howard V.
Richter Johann
University Technology Corporation
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