Acyclic isoprenoid ether derivatives as chemotherapeutics

Details Acyclic isoprenoid ether derivatives as chemotherapeutics Acyclic isoprenoid ether derivatives as chemotherapeutics

2001-07-16

2003-05-20

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S544000, C514S529000, C514S546000, C514S722000, C514S670000, C514S717000, C514S718000, C549S398000, C549S401000, C549S404000

Reexamination Certificate

active

06566397

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
BACKGROUND OF THE INVENTION
Farnesol activates a microsomal cysteine protease with high specificity for HMG CoA reductase (Correll, C. C., et al.,
J. Biol. Chem.
269:17390-17393, 1994; Meigs, T. E., et al.,
J. Biol. Chem.
271:7916-7922, 1996). As a consequence, the cellular pool of mevalonic acid becomes limiting for cell proliferation. Neoplastic cells have much greater sensitivity than normal cells to farnesol-mediated actions (Adany, I., et al.
Cancer Lett.
79:175-179, 1994; Yazlovitskaya E. M. and Melnykovych, G.,
Cancer Lett.
88:179-183, 1995).
Diet studies show that farnesol (90 mmol/kg diet) suppressed the growth of pancreatic tumors implanted in Syrian Golden hamsters (Burke, et al.,
Lipids
32:151-156, 1997). The elevation of farnesol is short-lived as cytosolic prenyl alcohol dehydrogenase and microsomal oxidase activities convert farnesol to &agr;-, &ohgr;-prenyl dioic acids which are excreted (Christophe, J. and Popjak, G.,
J. Lipid Res.
2:244-257, 1961; Gonzalez-Pacanowska, D. G., et al.,
J. Biol. Chem.
263:1301-1306, 1988). He, et al. (He, L., et al.,
J. Nutr.
127:668-674, 1997) reported findings that &ggr;-tocotrienol, a farnesol mimetic, suppressed the growth of implanted melanomas with nearly 100×greater efficacy than farnesol (<1 mmol/kg diet). When coupled with the tocol ring the farnesyl moiety is not converted to the prenyl acids and thus is not excreted.
BRIEF SUMMARY OF THE INVENTION
In one embodiment, the present invention is a method of suppressing the growth of tumor cells in a patient, comprising treating the patient with an effective amount of an isoprenoid ether-linked compound, wherein the isoprenoid ether-linked compound comprises a first acyclic isoprenoid molecule linked via an ether linkage to a second molecule, wherein the second molecule can suppress tumor formation. Preferably, the second molecule comprises a cyclic isoprenoid or hydroxyphenol acetate.
In another embodiment the second molecule is selected from the group consisting of flavonols, isoflavonols and polyphenols and substituted hydroquinones.
In another embodiment, the present invention is a chemotherapeutic compound comprising an acyclic isoprenoid alcohol linked via an ether linkage to a cyclic isoprenoid alcohol or 4-hydroxyphenyl acetate and a pharmaceutical carrier.
In another embodiment, the present invention is a chemotherapeutic compound comprising M364 and a pharmaceutical carrier.
It is a feature of the present invention that a chemotherapeutic compound is provided.
It is an object of the present invention to treat tumor patients by ingestion of an acyclic isoprenoid ether linked compound.
Other objects, features and advantages of the present invention will become apparent to one of skill in the art after review of the specification, claims and drawings.


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Bryant et al., “Physiological genetics of melanotic tumors inDrosphila melanogaster. VI. Tumorigenic effects of juvenile hormonelike substances” Genetics, 62(2), pp. 321-336, 1969.*
J.H. Marriott, et al., Synthesis of the Farnesyl Ether 2,3,5-trifluoro-6-hydroxy-4-(E,E)-3,7-11-trimethyldodoca-2,6,10 . . . J. Chem. Soc., Perkin Trans 1:4265-4278 2000.
H. Mo and C. Elson, “Apoptosis and Cell-Cycle Arrest in Human and Murine Tumor Cells are Initiated by Isoprenoids,” Am. Soc. Nut. Sci., pp. 804-813, 1999.
H. Mo, et al., “Farnesyl Anthranilate Suppresses the Growth, In Vitro and In Vivo, of Murine B16 Melanomas,” Cancer Letters 157:145-153, 2000.
J.H. Marriott, et al., “Synthesis of the Farnesyl Ether 2,3,5-trifluoro-6-hydroxy-4-[(E,E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy] nitrobenzene, and Related Compounds Containing a Substituted Hydroxytrifluorophenyl Residue: Novel Inhibitors of Protein Farnesyltransferase, Geranylgeranyltransferase I and Squalene Synthase,” J. Chem. Soc. 1:4265-4278, 2000.
H. Mo, et al., “Blends of Farnesol and Genistein Synergistically Suppress B16 Melanoma Cell Proliferation,” FASEB J. 15:A281, 2001 (abstract).

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