Cytotoxic pyridoacridine alkaloids

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C544S014000, C435S119000

Reexamination Certificate

active

06350743

ABSTRACT:

BACKGROUND OF THE INVENTION
Marine organisms, especially soft cerals, sponges and tunicates, provide many secondary metabolites and exhibit a varying degree of biological activity (Reference 13: Faulkner, D. J.
Nat.Prod.Reports.,
1997, 14, 259-302 and references cited therein). An important family of these metabolites is the alkaloid family; in 1983 it was reported the structure of a marine alkaloid, amphimedine (Reference 14: Schmitz, F. J. et al.
J.Am.Chem.Soc.
1983, 105, 4835-4836), which was the first of a new class of marine-derived alkaloids that collectively have come to be known as the “pyridoacridines”. Since then, over 40 additional examples have been published (Reference 1: Molinski, T. F.
Chem.Rev.
1993, 93, 1825-1838). The pyridoacridines are highly colored marine derived alkaloids majority based on the 11H-pyrido[4,3,2-mn]acridine skeleton, as shown below:
A family of remarkable cytotoxic marine pyridoacridine alkaloids is the Shermilamine family (Reference 6: Scheuer, P. J. et al.
J.Org.Chem.
1988, 53, 4619-4620. Reference 5: Scheuer, P. J. et al.
J.Org.Chem.
1989, 54, 4231-4232. Reference 3: Kashman, Y. et al.
J.Org.Chem.
1989, 54, 5335-5337. Reference 12: Barrows, L. R.; Ireland, C. M. et al,
J.Med.Chem.
1994, 37, 3819-3827), which structure is showed below:
Shermilamines were all isolated from tunicates, A and B from
Trididemnum sp.
and C from
Cystodytes sp.
SUMMARY OF THE INVENTION
The present invention provides new pyridoacridines having the following formula (I):
wherein R is independently selected from the group consisting of hydrogen or bromine.
More particularly, the present invention relates to Shermilamine D (R═H in formula (I)), extracted and isolated from the tunicate
Cystodytes violatinctus.
Shermilamine D exhibits antitumor activity. In particular, Shermilamine D exhibits antitumor activity against cell lines derived from human solid tumors, such as human lung carcinoma, human colon carcinoma and human melanoma, and, the like, it is active against other tumor cell lines, like leukemia and lymphoma.
The present invention also provides a method of testing a mammal affected by a malignant tumor sensitive to a compound with the formula (I), which comprises administering a therapeutically effective amount of the compound with the formula (I), or a pharmaceutical composition thereof.
The present invention further provides pharmaceutical compositions which contain as active ingredient a compound with the formula (I), as well as process for its preparation.
A further aspect of the invention is a method for preparing the compound Shermilamine D (R═H in the formula (I)), which comprises extraction and isolation from the tunicate
Cystodytes violatinctus.


REFERENCES:
patent: 5432172 (1995-07-01), Spector et al.
patent: WO 00/20411 (2000-04-01), None
Gunawardana et. al., “New Cytotoxic Acridine Alkaloids From Two Deep Water Marine Sponges Of The Family”,Tetrahedron Letters,vol. 30, No. 33, pp. 4359-4362, 1989.
Ciufolini et. al., “A Unified Strategy for The Synthesis of Sulfer-Containing Pyridoacridine Alkaloids: Agents of Marine Origin”,J. Amer. Chem. Soc1995, 117, 12460-12469.
Carroll et. al., A Second Shermilamine Alkaloid From a Tunicate Trdidemnum sp.J. Org. Chem.1989, 54, 4231-4232.
Schmitz et. al., “Cytotoxic Aromatic Alkaloids from the Ascidian Amphicarpa meridiana and Leptoclinides sp.: Meridine and 11-Hydroxyascididemin”,J. Org. Chem.1991, 56, 804-808.
Carroll et. al., “Kuanoniamines A, B, C, and D: Pentacyclic Alkaloids from a Tunicate and Its Prosobranch Mollusk Predator Chelynotus semperi”,J. Org. Chem.1990, 55, 4426-4431.
Gunawardana et. al., “Pyridoacridine Alkaloids from Deep-Water Marine Sponges of the Family Pachastrellidae: Structure Revision of Dercitin and Related Compounds and Correlation with the Kuanoniamines”,J. Org. Chem.1992, 57, 1523-1526.

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