Synthesis of dysidiolide and uses thereof

Details Synthesis of dysidiolide and uses thereof Synthesis of dysidiolide and uses thereof

2000-08-01

2002-11-19

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...

C549S315000, C549S430000, C568S446000

Reexamination Certificate

active

06482851

ABSTRACT:

Throughout this application, various references are referred to by Arabic numerals within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
A variety of structurally fascinating and biologically active natural products can be obtained from marine sources. The isolation, structural formulation, and biological evaluation of natural products from the aquatic biomass constitutes a frontier of growing importance in chemistry. In some instances, where the structures are especially novel or the biological profiles of action hold particular promise, a program in total synthesis may be appropriate. Such a situation pertained in the case of the dysidiolide (1), a sesterterpene isolated from the marine sponge
Dysidea etheria
de Laubenfels. From a biogenetic point of view, dysidiolide corresponds to a novel cyclization mode of an acyclic C
25
isoprenoid precursor. Moreover, the difficulty available dysidiolide is a potent inhibitor of the human cdc25A protein phosphatase. (2,3) Since this enzyme complex (cdc25A, B and C) is involved in dephosphorylation at the G
2
/M transition of the cell cycle, it has been proposed that inhibitors could produce specific cell cycle arrest. Early results have shown that dysidiolide inhibits growth of lung carcinoma and murine leukemia cell lines. (1)
The total synthesis problem was approached from the perspective of testing a dioxolenium (Gassman) typed of activated dienophile. (4,5) A Diels Alder reaction of the type 2+4 was performed, wherein the presumed mechanistically active intermediate would undergo cycloaddition in the regio-sense indicated, and with tight diastereoface governance based on differing demands of R
1
and R
2
. Most interesting was the matter of endo/exo selectivity. It would be necessary for the dioxolenium function to direct endo in the Diels Alder step. (4,5a,6) The realization of this line of thinking is described below in the context of a total synthesis.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of dysidiolide of the formula:
comprising the steps of:
(a) adding lithium dimethylcuprate to a dioxolane;
(b) trapping the compound formed in step (a) under suitable conditions to form an olefin;
(c) converting the ester function to a protected two carbon alcohol residue to form a dienophile;
(d) converting a ketone, derived by alkylating with an alkyl iodide, to a vinyl triflate;
(e) performing a Stille cross coupling on the vinyl triflate of (d) under suitable conditions to form a diene;
(f) performing a Diels Alder reaction on the dienophile of step (c) and the diene of step
(e) under suitable conditions to form a compound having the structure:
(g) cleaving the acetal function of the compound in (f) under suitable conditions to form a compound having the structure:
(h) performing a Wolff Kishner reduction and desilylating the compound in step (g) to form an alcohol having the structure:
(i) oxidizing the alcohol formed in step (h) under suitable conditions to form an aldehyde;
(j) treating the aldehyde in step (i) with 3-lithiofuran and photo-oxidizing under suitable conditions to form a racemic mixture of dysidiolide.
The present invention further provides a product produced by the process.
Further, the present invention provides a pharmaceutical composition comprising a racemic mixture of dysidiolide.
Further, the invention provides a method for inhibiting growth of cancerous cells comprising contacting an amount of a racemic mixture of dysidiolide effective to inhibit the growth of said cells. Wherein the amount comprises a quantity of the compound to inhibit, reduce, or cause remission of the cells.
The present invention additionally provides a method for treating cancer in a subject which comprises administering to the subject a therapeutically effective amount of racemic mixture of dysidiolide. Where the cancer is of the breast, colon, lung, liver, brain or ovary and the therapeutically effective amount comprises an amount of the compound to inhibit, reduce, or cause remission of the cancer. Further, the therapeutically effective amount is an amount from about to 50 to about 5000 mm
3
/day, 50 to about 500 mm
3
/day, 60 to about 275 mm
3
/day, 0.5 to 50 mg/kg body weight or about 5 to 10 mg/kg body weight. The administration comprises epidural, intraperitoneal, intramuscular, subcutaneous or intravenous injection; infusion; or topical, nasal, oral, anal, ocular or otic delivery.
This invention further provides a compound having the structure:
Additionally this invention provides a compound having the structure:
Finally, the present invention provides a compound having the structure:


REFERENCES:
Baratte, B.; Meijer, L.; Galaktionov, K.; Beach, D.Anticancer Res.1992, 12, 873. (Exhibit 1).
Gassman, P.G.; Chavan, S.P.J. Org. Chem.1988, 53, 2392. (Exhibit 2).
Gassman, P.G.; Chavan, S.P.Tetrahedron Lett.1988, 29, 3407. (Exhibit 3).
Gassman, P.G.; Chavan, S.P.J. Chem. Soc., Chem. Commun.1989, 837. (Exhibit 4).
Gassman, P.G.; Singleton, D.A.; Wilwerding, J.J.; Chavan, S.P.J. Am. Chem. Soc.1987, 109, 2182. (Exhibit 5).
Gunasekera, S.P.; McCarthy, P.J.; Kelly-Borges, M.; Lobkovsky, E.; Clardy,J. J. Am. Chem. Soc.1996, 118, 8759. (Exhibit 6).
Hashimoto, Y.; Nagashima, T.; Hasegawa, M.; Saigo, K.Chem. Lett.1992, 1353. (Exhibit 7).
Hashimoto, Y.; Saigo, K.; Machida, S.; Hasegawa, M.Tetrahedron Lett.1990, 39, 5625. (Exhibit 8).
Millar, J.B.A.; Russell, P.Cell1992, 68, 407. (Exhibit 9).
Sammakia, T.; Berliner, M.A.J. Org. Chem.1994, 59, 6890. (Exhibit 10).
Sipf. P.; Xu, W.Tetrahedron1995, 51, 4551 (Exhibit 11).
Yoon, T.; Danishefsky, S.J.; de gala, S.Angew, Chem. Int. Ed. Engl.1994, 33, 85. (Exhibit 12).
PCT International Search Report of PCT/US99/02347 (Exhibit 13).

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