Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides containing saccharide radicals – e.g. – bleomycins – etc.
Reexamination Certificate
1999-12-03
2001-12-11
Gitomer, Ralph (Department: 1623)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides containing saccharide radicals, e.g., bleomycins, etc.
C514S008100, C536S024310, C435S006120
Reexamination Certificate
active
06329497
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to analogs of sandramycin, to the synthesis of analogs of sandramycin, and to their use as anti-cancer and anti-HIV agents. More particularly, the invention relates to analogs of sandramycin having deep-seated structural changes in the chromophore including the deletion of key functional groups or core structural elements, to the synthesis of these compounds the penultimate introduction of substitution chromophores on a key intermediate, and to the use of these compounds against various leukemia, melanoma, carinoma, and adenocarcinomas. Furthermore, some of the analogs possess the ability to inhibit HIV-1 reverse transcriptase.
BACKGROUND
Sandramycin (1) is a natural product having potent antitumor antibiotic activity. Sandramycin has been structurally characterized through spectroscopic and chemical degradation studies. Sandramycin constitutes one of the newest members of a growing class of cyclic decadepsipeptides including luzopeptins A-C and E
2
, quinaldopeptin and guinoxapeptins A and B which possess potent antitumor, antiviral, and antimicrobial activity (
FIG. 1
; Matson, et al.
J. Antibiot
. 1989, 42, 1763; Matson et al.
J. Antibiot
. 1993, 46, 162; Ohkuma et al.
J. Antibiot
. 1980, 33, 1087; Tomita et al.
J. Antibiot
. 1980, 33, 1098
; J. Antibiot
. 1981, 34, 148; Konishi et al.
J. Am. Chem. Soc
. 1981, 103, 1241; Arnold et al.
J. Am. Chem. Soc
. 1981, 103, 1243; Toda et al.
J. Antibiot
. 1990, 43, 796). Characteristic of this class of agents, sandramycin possesses a two-fold axis of symmetry and two heteroaromatic chromophores that results in sequence-selective DNA bis-intercalation spanning two base-pairs preferentially at 5′-AT sites. In this respect, the agents are functionally related to the quinoxaline antitumor antibiotics including echinomycin and triostin A which also bind to DNA by bis-intercalation but with a substantially different sequence selectivity (5′-CG versus 5′-AT).
The cytotoxic activity of luzopeptin A and sandramycin has been shown to be 100-300 times greater than echinomycin and smoothly declines in the series with luzopeptin A>B>C. A reverse order of antiviral activity was observed with luzopeptin C>B>A in inhibiting human immunodeficiency virus (HIV) replication in vitro. Notably, this is observed at noncytotoxic concentration for luzopeptin C through inhibition of HIV reverse transcriptase (Take et al.
J. Antibiot
. 1989, 42, 107; Inouye et al.
J. Antibiot
. 1987, 40, 100). The recent disclosure of the quinoxapeptins as potent inhibitors of HIV-1 and HIV-2 reverse transcriptase that are equally active against two resistant single mutants and a double mutant of HIV-1 reverse transcriptase has increased the interest in this class of agents especially since they were found not to inhibit human DNA polymerase &agr;, &bgr;, &ggr;, and &dgr; at comparable concentrations (Lingham et al.
J. Antibiot
. 1996, 49, 253).
What is needed are analogs of sandramycin having enhanced cytotoxic activities against various tumor cell lines and sandramycin analogs having inhibitatory activity against reverse transcriptase. Furthermore, what is needed are active analogs of sandramycin which can be synthesized from economically accessable sources.
BRIEF SUMMARY OF THE INVENTION
The invention is directed to sandramycin analogs which possesses unique and specific properties against various leukemia, melanoma, carinoma, and adenocarcinoma cells. The invention is also directed to analogs having inhibitory activity with respect to HIV-1 reverse transcriptase. The synthesis of a series of these analogs is carried out by the penultimate introduction of substitution chromophores on a key intermediate (23). Each analog contains a deep-seated structural change in the chromophore including the deletion of key functional groups or core structural elements which reveals each functional groups role in the high affinity bis-intercalation binding of sandramycin.
One aspect of the invention is directed to Sandramycin analogs following structure:
In the above structure, R
1
is a radical represented by any of the following structures:
R
2
is a radical selected from hydrogen, —OH, —OBenzyl, and —Omethyl. R
3
is a radical selected from hydrogen, —OMethyl, and Methyl. R
4
is a radical selected from hydrogen and —Cl.
R
5
is a radical selected from hydrogen, —OH, and O-Benzyl.
R
6
is a radical selected from hydrogen, —OH, and O-Benzyl.
R
7
is a radical selected from hydrogen, —OH, and O-Benzyl.
Preferred sandramycin analogs are represented by the following structures:
Another aspect of the invention is directed to a topical formulation comprising a sandramycin analog admixed with a pharmaceutically acceptable carrier for treating melanoma. Preferred sandramycin analog are indicated above. A preferred topical formulation for treating melanoma employs a sandramycin analog is represented by the following structure:
Another aspect of the invention is directed to a method for treating melanoma. The method employs the step of applying the above topical formulation to the melanoma.
REFERENCES:
patent: 4582639 (1986-04-01), Matson et al.
Denny, et al., “Potential Antitumor Agents. 44. Synthesis and Antitumor Activity of New Classes of Diacridines: Importance of Linker Chain Rigidity for DNA Binding Kinetics and Biological Activity”,J. Med. Chem. 28: 1568-1574 (1985).
Rance, et al., “UK-63,052 Complex, New Quinomycin Antibiotics fromStreptomyces BraegensisSubsp. Japonicus; Taxonomy, Fermentation, Isolation, Characterisation and Antimicrobial Activity”,J. Antibiotics 42: 206-217 (1989).
Matson, et al., “Sandramycin, A Novel Antitumor Antibiotic Produced by aNocardiodesSp. Product Isolation, Characterization and Biological Properties”,J. Antibiotics 42: 1763-1767 (1989).
Fox, “Footprinting Studies of the Interaction of Quinomycin Antibiotic UK63052 with DNA: Comparison with Echinomycin”,J. Antibiot. 43: 1307-1315 (1990).
Matson, et al., “Sandramycin, a Novel Antitumor Antibiotic Produced by ANocardiodessp. II. Structure Determination”,J. Antibiot. 46: 162-166 (1993).
Boger, et al., “(-)-Sandramycin: Total Synthesis and Preliminary DNA Binding Properties”,J. Am. Chem. Soc. 115: 11624-11625 (1993).
Boger, et al., “A Modified Friedlander Condensation for the Synthesis of 3-Hydroxyquinoline-2-carboxylates”,J. Org. Chem. 60: 7369-7371 (1995).
Boger, et al., “(-)-Sandramycin: Total Synthesis and Characterization of DNA Binding Properties”,J. Am. Chem. Soc. 118: 1629-1644 (1996).
Lingham, et al., “Quinoxapeptins: Novel Chromodepsipeptide Inhibitors of HIV-1 and HIV-2 Reverse Transcriptase I. The Producing Organism and Biological Activity”,J. Antibiot. 49: 253-259 (1996).
Boger, et al., “An Exceptionally Potent Analog of Sandramycin”,Bioorg. Med. Chem. Lett. 7: 919-922 (1997).
Gitomer Ralph
Khare Devesh
Lewis Donald G.
The Scripps Research Institute
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