Acyclic monoterpenoid derivatives

Details Acyclic monoterpenoid derivatives Acyclic monoterpenoid derivatives

1999-03-05

2001-10-16

Tate, Christopher (Department: 1651)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S532000, C514S534000, C514S546000, C514S716000, C514S717000, C514S718000, C514S722000

Reexamination Certificate

active

06303654

ABSTRACT:

BACKGROUND OF THE INVENTION
Cell proliferation requires the transfer of mevalonate pathway intermediates to a group of proteins, small G-proteins and the nuclear lamins among others. Agents targeted to the inhibition of the transfer process (farnesylation, geranylgeranylation), e.g., farnesyl mimetics and perillyl alcohol, have potential value as chemotherapeutic agents. Agents that block the synthesis of the mevalonate pathway intermediates, e.g., inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (statins) and mevalonate kinase (sodium phenylacetate) also have therapeutic potential. The statins competitively inhibit HMG CoA reductase activity. Diverse end products of plant mevalonate metabolism (pure and mixed isoprenoids) suppress HMG CoA reductase activity (Elson, 1995; Elson and Qureshi, 1995; Elson and Yu, 1994).
The endogenous isoprenoids, the monoterpene and sesquiterpene alcohols geraniol and farnesol, also suppress reductase activity. Geraniol attenuates the HMG CoA reductase mRNA translational efficiency and decreases reductase mRNA (Elson, et al., 1998). Farnesol attenuates reductase mRNA translational efficiency and signals the proteolytic degradation of HMG CoA reductase (Correll, et al., 1994). These isoprenoids accumulate in mammalian cells only in the presence of excess mevalonate. These prenyl alcohols have relatively short biological half-lifes as they are rapidly converted to &agr;,&ohgr;-prenyl dicarboxylic acids by cytosolic dehydrogenase and microsomal monooxygenase activities which sequentially catalyze the formation of prenyl aldehydes, &agr;-prenoic acids, &ohgr;- and &ohgr;-3-hydroxy-&agr;-prenoic acids and &agr;,&ohgr;-prenyl dicarboxylic acids (Christophe and Popják, 1961; Gonzales-Pacanowska, et al., 1988; Austin, et al., 1988; Keung, 1991; Giron, et al., 1993).
Pentobarbital, an inducer of the microsomal P450 monooxygenase activity that catalyzes the formation of &ohgr;- and &ohgr;-3 hydroxy-&agr;-prenoic acids, totally reverses the isoprenoid-mediated suppression of HMG CoA reductase activity (Yu, et al., 1994). These inducible activities decrease the half-life of the endogenous isoprenoids (geraniol and farnesol) that down-regulate reductase activity.
Degradation of Endogenous Isoprenoids
Prenyl diphosphates (Geranyl-PP, Farnesyl-PP)
↓ Microsomal diphosphatase
Prenyl alcohols (Geraniol, Farnesol)
↓ Cytosolic Prenyl Alcohol Dehydrogenase
Prenyl aldehydes (Geranial, Farnesal)
↓ Cytosolic Prenyl Aldehyde Dehydrogenase
&agr;-Prenoic acids (Geranoic acid, Farnesoic acid)
| Monooxygenase, cytochrome P450 IIB
↓ &ohgr;,&ohgr;-3-hydroxylation, oxidation
&agr;,&ohgr;-Prenyl dicarboxylic acids (Hildebrandts Acids)
Geraniol (Shoff, et al., 1991; He, et al., 1997; Burke, et al., 1997) and farnesol (Miquel, et al., 1996; He, e t al., 1997; Burke, et al., 1997) suppress the proliferation of cells, an action reversed by supplements of mevalonate pathway metabolites (Shoff, et al., 1991). Perillyl alcohol (a cyclic monoterpene) attenuates the HMG CoA reductase mRNA translational efficiency (Elson, et al., 1998) and suppresses cell proliferation (He, et al., 1997). Farnesyl amine (Kothapalli, et al., 1993) and perillyl amine (Burke et al., 1997) suppress cell proliferation with greater potency than the corresponding alcohol, perhaps because of their less efficient degradation.
BRIEF SUMMARY OF THE INVENTION
The present invention is a method of inhibiting the growth of tumor cells. In one embodiment, this method comprises the step of administering an effective amount of a compound selected from the group consisting of citracetal, citral dimethyl acetal, citral diethyl acetal, geranyl benzoate, geranyl tiglate, geranyl anthranilate and combinations thereof to a tumor patient. The amount is effective to inhibit or prevent tumor cell proliferation or growth. Preferably, the inhibition is at least 50% of control growth. More preferably, the inhibition is 80%. Most preferably, the inhibition is 100%.
In another embodiment of the present invention, a 15-carbon sesquiterpenoid structure has replaced the 10-carbon monoterpenoid structure in the compounds described above. Therefore, farnesyl derivatives, such as farnesyl tiglate and farnesyl anthranilate, are very active compounds and suitable for the present invention.
In another embodiment, the present invention is a pharmaceutical composition effective to inhibit or prevent the growth of tumor cells comprising a compound selected from the group consisting of citracetal, citral dimethyl acetal, citral diethyl acetal, geranyl benzoate, geranyl tiglate, geranyl anthranilate and combinations thereof and a pharmaceutically acceptable carrier. In a preferred embodiment of the present invention, the compound is selected from the group consisting of geranyl tiglate, geranyl anthranilate and combinations thereof.
In another embodiment, the present invention is a pharmaceutical composition, as described above, but substituting the 15-C compound, preferably farnesyl anthranilate, farnesyl benzoate, farnesyl tiglate or farnesyl acetate.
In a most preferred embodiment, the pharmaceutical preparation allows for the total dose of compound of 1-2 g per day per 150 lb. human. In a preferred embodiment, the dose is between 1 and 4 g per day per 150 lb. human.
It is an object of the present invention to provide an effective chemotherapeutic. Preferably, this chemotherapeutic has a relative potency to that of perillyl alcohol of at least 5 times, preferably 6 times. Potency is indicated by the IC
50
value, the concentration of a compound required to express cell growth by 50%. A lower IC
50
indicates higher potency. Therefore, a higher ratio indicates higher potency.
It is an advantage of the present invention to provide a chemotherapeutic of similar attributes to perillyl alcohol but effective at approximately 20% of the dosage of perillyl alcohol necessary to inhibit or prevent tumor cell growth.


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patent: WO 95/13059 (1995-05-01), None
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C.E. Elson and A.A. Qureshi, “Coupling the Cholesterol- and Tumor-suppressive Actions of Palm Oil to the Impact of Its Minor Constituents on 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity,”Prostaglandins Leukotrienes and Essential Fatty Acids,52:205-208 (1995).
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