Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-28
2002-12-17
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S460000, C514S529000, C549S292000, C560S183000
Reexamination Certificate
active
06495594
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to organic compounds and compositions which have useful therapeutic properties. More particularly, the invention concerns novel discodermolide compounds having immunomodulatory and antitumor activities, pharmaceutical compositions comprising such compounds, and methods of their use for therapeutic purposes. Another aspect of the present invention pertains to the identification of regions of the discodermolide molecule which are responsible for certain aspects of the bioactivity of discodermolide.
BACKGROUND OF THE INVENTION
Of great importance to man is the control of pathological cellular proliferation such as that which occurs in the case of cancer. Considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and antitumor chemical compositions are needed.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, the diterpene commonly known as Taxol, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978
] Cancer Treat. Rep.
62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [1979
] Nature (London)
22:665-667). Taxol is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995
] N. Engl. J Med.
332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine sponges have also proven to be a source of biologically active chemical molecules. A number of publications disclose organic compounds derived from marine sponges including Scheuer, P. J. (ed.)
Marine Natural Products, Chemical and Biological Perspectives
, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985)
J. Am. Chem. Soc.
107:4796-4798; Minale, L. et al. (1976)
Fortschr. Chem. org. Naturst.
33:1-72; Faulkner, D. J. (1998)
Natural Products Reports
15:113-158; Gunasekera, S. P., M. Gunasekera, R. E. Longley and G. K. Schulte (1990) “Discodermolide: A new bioactive polyhydroxy lactone from the marine sponge
Discodermia dissoluta” J. Org. Chem.,
55:4912-4915 [correction (1991)
J. Org. Chem.
56:1346]; Hung, Deborah T., Jenne B. Nerenberg, Stuart Schreiber (1994) “Distinct binding and cellular properties of synthetic (+)- and (−) discodermolides”
Chemistry and Biology
1:67-71; Hung, Deborah T., Jie Cheng, Stuart Schreiber (1996) (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks Taxol binding and results in mitotic arrest”
Chemistry and Biology
3:287-293; Nerenberg, Jennie B., Deborah T. Hung, Patricia K. Somers, Stuart L. Schreiber (1993) “Total synthesis of immunosuppressive agent (−)-discodermolide”
J. Amer. Chem. Soc.
115:12621 -12622; Smith III, Amos B., Yuping Qiu, David R. Jones, Karoru Kobayashi (1995) “Total synthesis of (−) discodernolide”
J. Amer. Chem. Soc.
117:12011-12012; Harried, Scott H., Ge Yang, Marcus A. Strawn, David C. Myles (1997) “Total synthesis of (−)-discodermolide: an application of a chelation-controlled alkylation reaction”
J. Org. Chem.
62:6098-6099; Balachandran, R., ter Haar, E., Welsh, M. J., Grant, S. G., and Day, B. W. (1998) “The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells-preliminary comparisons to paclitaxel.”
Anticancer Drugs
9: 67-76 and references cited therein. U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp. (International Patent Application No. WO 9824429; Kowalski, R. J., P. Giannakakou, S. P. Gunasekera et al. (1997)
Mol. Pharmacol
52:613-622; ter Haar, E., R. J. Kowalski, E. Hamel et al. (1996)
Biochemistry
35:243-250; Stafford, J. A. and M. M. Mehrotra (1995)
Chemtract: Org. Chem.
8:41-47; and U.S. Pat. No. 5,789,605.
BRIEF SUMMARY OF THE INVENTION
A principal object of the subject invention is the provision of novel compositions of biologically active discodermolide analogs which can advantageously be used for immunomodulation and/or treating cancer. The compounds of the subject invention have utility for use in the treatment of cancer, and as tubulin polymerizers and as microtubule stabilization agents.
In a specific embodiment, the novel compositions and methods of the subject invention can be used in the treatment of an animal hosting cancer cells including, for example, inhibiting the growth of tumor cells in a mammalian host. More particularly, the subject compounds can be used for inhibiting in a human the growth of tumor cells, including cells of breast, colon, CNS, ovarian, renal, prostate, liver, pancreatic, uterine, or lung tumors, as well as human leukemia or melanoma cells. The mechanisms for achieving anticancer activity exhibited by the subject compounds would lead a person of ordinary skill in the art to recognize the applicability of the subject compounds, compositions, and methods to additional types of cancer as described herein.
The subject invention provides new analogs of discodermolide which, advantageously, possess useful biological activity against tumors and other forms of cancer. Another aspect of the present invention pertains to the identification of regions of the discodermolide molecule which are responsible for certain aspects of the bioactivity of discodermolide.
In specific embodiments, the subject invention provides four new analogs of discodermolide isolated from nature and nine new analogs of discodermolide produced through organic synthesis. The compounds of the subject invention have not been isolated previously from a natural source nor have they been previously synthesized. These compounds indicate the effects on biological activity caused by 1) modification of functionality located at the lactone end of the molecule; 2) reduction of selected double bonds present in the molecule and 3) the contribution of the carbamate functionality towards the biological activity.
Included in these embodiments are analogs which can be prepared through modifications to five regions ofthe discodermolide molecule, those being 1) the C-1 through C-7 lactone and connector region, 2) the C-8 through C-15 first hairpin, 3) the C-16 through C-20 second hairpin, 4) the C-21 through C-24 diene and 5) the carbamate at C-19. The activity of the compounds vary according to the region(s) modified. The structure activity data promotes the C-8 through C-15 and C-16 through C-20 hairpin regions as critical to the activity of the discodermolide molecule by providing an optimal spatial relationship between the C-11 hydroxyl and the C-17 hydroxyl functionalities found in natural and synthetic analogs which are essential for induction of tubulin polymerization and stabilizing of the microtubule network, thus causing a block in the cell cycle at the G
2
/M checkpoint. In addition, the C-1 though C-7 lactone and connector region provide a hydrogen bond acceptor such as a carbonyl group and the C-21 through C-24 diene region serve to provide a hydrophobic group; both functionalities being positioned in the same spatial relationship to the C-11 and C-17 hydroxyl groups as is found in discodermolide and active analogs.
In accordance with the subject invention, methods for inhibiting cancer cells in a host include contacting tumor cells with an effective amount of the new pharmaceutical compositions of the invention. The cancer cells inhibited by the invention are
Gunasekera Sarath P.
Isbrucker Richard A.
Longley Ross E.
Paul Gopal K.
Pomponi Shirley A.
Harbor Branch Oceanographic Institution Inc.
Owens Amelia
Saliwanchik Lloyd & Saliwanchik
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