Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-07
2001-08-28
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S017400, C043S004000
Reexamination Certificate
active
06281196
ABSTRACT:
This application is a 371 of PCT/US99/12935, filed on Jun. 9, 1999.
1. Field of the Invention
This invention relates generally to the field of chemotherapy and more particularly, to the discovery and structural elucidation of new cell growth inhibitor denominated “agelagalastatin” which was located in Western Pacific marine sponge Agelas sp.
This research was funded in part by the Outstanding Investigator Grant CA 44344-01A1-1922 and PHS Grant CA-16049-09-09-12, both awarded by the Division of Cancer Treatment, National Cancer Institute, DHHS. Accordingly, the United States government may have certain rights to this invention.
2. Background Art
Ancient marine invertebrate species of the
Phyla Bryozoa
, Molluska, and Porifera have been well established in the oceans for over one billion years. Such organisms have undergone trillions of biosynthetic reactions of their evolutionary chemistry to reach their present level of cellular organization, regulation and defense.
More particularly, marine sponges have changed minimally in their physical appearance over the last 500 million years. This suggests a very effective chemical resistance to evolution in response to changing environmental conditions over that period of time. Recognition of the potential for utilizing this biologically potent marine animal for medicinal purposes was recorded in Egypt about 2,700 B.C. and by 200 B.C. certain sea hare extracts were being used in Greece for their curative effect. This consideration along with the observation that marine animals, e.g., invertebrates and sharks, rarely develop cancer led to the systematic investigation of marine animal and plant anticancer compounds.
By 1968, ample evidence had been obtained, based on the U.S. National Cancer Institute's (NCI) key experimental cancer study systems, that certain marine organisms could provide new and antineoplastic and/or cytotoxic agents useful in chemotherapy and might also lead to compounds which would be effective in the control and/or eradication of viral diseases.
Further, these marine organisms were believed to possess potentially useful drug candidates of unprecedented structure which had eluded discovery by other methods of medicinal chemistry. Fortunately, these expectations have been realized, e.g. the discovery of the bryostatins, dolastatins and cephalostatins, and others, many of which are now in preclinical development or human clinical studies.
Those researchers who are presently involved in medicinal chemistry know well the time lag between the isolation of a new compound and its introduction to the market. Often this procedure takes several years and may take decades. As a result, industry, in association with the U.S. Government, has developed a system of testing criteria which serves two purposes. One is to eliminate those substances which are shown through testing to be economically counterproductive to pursue. The second, more important purpose serves to identify those compounds which demonstrate a high likelihood of success and therefore warrant the further study and qualification, and attendant expense, necessary to meet the stringent regulatory requirements which control the ultimate market place.
The current cost to develop the necessary data required for lawful marketing of a new drug compound approaches ten million dollars per compound. Economics dictate that such a huge investment be made only when there is a reasonable likelihood that it can be recovered. Absent such a likelihood, there will be no investment and, without investment, the research requisite for the discovery of these potentially life saving compounds will cease. Current research in the control of cancer in the United States is coordinated by the National Cancer Institute (NCI). To determine whether a substance has anti-cancer properties, the NCI has established a systematic protocol. This protocol, which involves the testing of a substance against a standard cell line panel containing 60 human tumor cell lines, has been verified and is accepted in scientific circles. The protocol, and the established statistical means for analyzing the results obtained by the standardized testing are fully described in the literature. See: Boyd, Dr. Michael R.,
Principles & Practice of Oncology
, PPO Updates, Volume 3, Number 10, October 1989, for a general overview of the testing protocol; Monks, Anne et al., “Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines”, 83
J. Nat. Cancer Inst
., No. 11, 757 (1991); and Paull, K. D., “Display and Analysis of Patterns of Differential Activity of Drugs Against Human Tumor Cell Lines; Development of Mean Graph and COMPARE Algorithm”, 81
Journal of the National Cancer Institute Reports
, No. 14, 1088, (1989), for a description of the methods of statistical analysis. Each of these references are incorporated herein by this reference thereto.
Numerous substances have been discovered which demonstrate significant antineoplastic or tumor inhibiting characteristics. As stated above, many of these compounds have been extracted, albeit with great difficulty, from marine animals such as the sponge and sea hare. Once isolation and testing of these compounds has been accomplished, a practical question remains, namely, how to produce commercially significant quantities of the desired substance.
The work with substances extracted from living creatures has other problems not incurred with those substances sourced from botanicals. For example, quinine, which is available in practical quantities from the bark of the cinchona plant, differs materially from the compounds which are extracts of marine creatures possessing antineoplastic qualities. The collection and processing of these later compounds from their natural sources ranges from grossly impractical to the utterly impossible. Ignoring the ecological impact, the population of these creatures and the cost of collection and extraction make the process unworkable. Artificial synthesis of the active compounds is the only possible solution.
The isolation and identification of substances from living marine creatures requires that the structure of these antineoplastic compounds be elucidated. For only after the structure has been determined, can a means of synthesis be developed. This is often a long and arduous procedure because of the idiosyncratic complexity of these naturally occurring, evolutionary modified compounds. In addition, research is necessary to determine whether any portion of the naturally occurring compound is irrelevant to the desired properties, so that focus can be had on the simplest structure having the perceived properties.
DISCLOSURE OF INVENTION
In accordance with the overall program, a human cancer cell line bioassay-directed investigation of the Western Pacific marine sponge Agelas sp. led to isolation of a trace (7.42×10
−6
% yield) cancer cell growth inhibitor (lung NCI-H460 GI
50
0.77 &mgr;g/ml to ovary OVCAR-3 GI
50
2.8 &mgr;g/ml) designated agelagalastatin (6). Agelagalastatin is the first example of a natural product containing a digalactofuranosyl unit.
The marine porifera genus Agelas (class Demospongae, order Agelasida, family Agelasidae) has previously been shown to be a rich source of new marine alkaloids (see D'Ambrosio et al.,
Helv. Chim. Acta,
1996, 79, 727.; Caffieri et al. (I),
Tetrahedron Lett.,
1995, 36. 7893.; Jimenez et al.,
Tetrahedron Lett.,
1995, 35, 1375.) such as the cytotoxic (L1210 leukemia cell line) agelastatin A (1) (see: D'Ambrosio et al.,
Helv. Chim. Acta,
1996, 79, 727.) and a series of glycosphingolipids (Natori et el.,
Tetrahedron,
1994, 50, 2771.; Caffieri et al. (II),
Liebigs Ann. Chem.,
1994, 1187.; Costantino et al. (I),
Liebigs Ann. Chem.,
1994, 1181.; Costantino et al. (II),
Tetrahedron,
1996, 52, 1573.; Caffieri et al. (III),
Liebigs Ann. Chem.,
1995, 1477.; Costantino et al. (III),
Liebigs Ann. Chem.,
1995, 1471; Morita et al.,
J. Med. Chem.,
1995, 38, 2176; Cafieri et al. (IV),
Gazz. Chim. Ita.,
1996, 126, 7
Pettit George R.
Xu Jun-ping
Arizona Board of Regents
Jones Dwayne C.
Mybeck Richard R.
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