Cribrostatins 3-5

Details Cribrostatins 3-5 Cribrostatins 3-5

2001-02-16

2002-08-20

Shah, Mukund (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C546S147000

Reexamination Certificate

active

06437128

ABSTRACT:

The present invention relates generally to the isolation and structural elucidation of new compounds herein denominated Cribrostatin 3, Cribrostatin 4 and Cribrostatin 5, which are obtained from Cnbrochalina sp., (Niphatidae faily, Haplosclerida order, Demospongiae class) found off of remote islands in the Republic of Maldives.
BACKGROUND OF THE INVENTION
In early research devoted to the first systematic investigation of marine animals as new sources of potential anticancer drugs, the phylum Porifera rapidly became of increasing importance. Subsequent detection of antineoplastic activity in some of these sponge species led to the isolation of such cell growth inhibitory compounds, as macrocyclic lactones, pyrroles, peptides and proteins. Meanwhile the isolation of heterocyclic marine sponge constituents such as pyrroles, imidazoles, oxazoles, indoles, pyndines, quinolizidines, pteridines, acridines, other nitrogen systems and quinones has been rapidly accelerating. So far ten isoquinolinequinones have been isolated from blue species of the sponge genera Reniera and Xestospongia. In 1986, an exploratory survey of marine Porifera off remote islands in the Republic of the Maldives was conducted which located a deep blue colored specimen of Cribrochaina sp. (Haplosclerida order) that afforded an orange ethanol extract. The encrusting sponge was found in areas of strong (and dangerous) currents to −45 m in the South side of East reef passages and yielded an ethanol extract that provided 40% life extension (at mg/kg) against the U.S. National Cancer Institute's in vio murine P388 lymphocytic leukemia (PS system). Bioassay directed isolation using the in vitro PS leukemia led to the discovery of new cytostatic isoquinoline-quinones designated cribrostatin 1 and cribrostatin 2, described and claimed in U.S. Pat. No. 5,514,689.
Continued investigation of cancer cell growth inhibitory constituents of the blue marine sponge Cribrochalina sp. has led to the further discovery of cribrostatins 3 (4a), 4 (5), and 5 (4b) in 10
−5
to 10
−7
percent yields. The structure of cribrostatin 3 (4a) was determined by results of high field (500 MH)
1
H- and
13
C-nmr and high resolution mass spectral interpretations. The same general approach to the structures of cribrostatins 4 (5) and 5 (4b) was completed by x-ray crystal structure determinations. Cribrostatins 3,4 and 5 provided significant cancer cell line inhibitory activities. In addition, the newly isolated cribrostatins 3,4 and 5 also display antibacterial and/or antifungal activities.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to the isolation and structural elucidation of three new isoquinolinequinones herein denominated cribrostatin 3, cribrostatin 4 and cribrostatin 5, which are obtained from Cribrochalina sp. (Haplosclerida order) found off of remote islands in the Republic of the Maldives. All three isolates demonstrated cytostatic properties using ED
50
and NCI human cell lines tests. The general structural formulas are shown below:
Accordingly, the primary object of the present invention is the isolation and elucidation of new antineoplastic and antibacterial and/or antifuingal agents denominated herein as “Cribrostatin 3”, “Cribrostatin 4” and “Cribrostatin 5”.
A further object of the present invention is to isolate and identify new natural substances which can be utilized in the treatment and management of those neoplastic diseases which are characterized by an uncontrolled cell growth and have an established correlation to the NCI protocol for P388 murine lymphocytic leukemia and human cancer cell lines.
Another object of the present invention is to elucidate unequivocally the structure of a newly discovered isoquinolinequinone denominated “cribrostatin 3” so as to provide a readily discernible target for further synthetic endeavors.
Another object of the present invention is to elucidate unequivocally the structure of a newly discovered isoquinolinequinone denominated “cribrostatin 4” so as to provide a readily discernible target for further synthetic endeavors.
Still another object of the present invention is to elucidate unequivocally the structure of a newly discovered isoquinolinequinone denominated “cribrostatin 5” so as to provide a readily discernible target for further synthetic endeavors.
These and still further objects as shall hereinafter appear are readily fulfilled by the present invention in a remarkably unexpected manner as will be readily discerned from the following detailed description of an exemplary embodiment thereof


REFERENCES:
patent: 4372947 (1983-02-01), Arai et al.
Balasubramanian, B.N. et al, “Recent Developments in Cancer Cytoxics” in “Annual Reports in Medicinal Chemistry, vol. 33”, Academic Press, San Diego, 1998, pp. 151-159.*
Draetta, G. and Pagano, M. in “Annual Reports in Medicinal Chemistry, vol. 31”, 1996, Academic Press, San Diego, p241-246.*
Salmon, S.E. et al “Principles of Cancer Therapy” in “Cecil Textbook of Medicine, 20th Edition”, W.B. Saunders, Philadelphia, 1996, pp. 1036-1049.

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