MXPA00008725A - Monoterpenoid derivatives for treatment of cancer - Google Patents

Abstract

A method of inhibiting or preventing the growth of tumor cells is disclosed. In one embodiment, this method comprises the step of administering a compound selected from the group consisting of citracetal, citral dimethyl acetal, citral diethyl acetal, geranyl benzoate, geranyl tiglate, geranyl anthranilate, farnesyl benzoate, farnesyl anthranilate, farnesyl tiglate, farnesyl acetate and combinations there of to a human tumor patient, wherein the amount is effective to reduce or inhibit tumor growth by at least 50%.

Description

MONOTERPENOID DERIVATIVES FOR FL TREATMENT OF CANCER BACKGROUND OF THE INVENTION Cell proliferation requires the transfer of intermediaries from the mevalonate pathway to a group of proteins, small G proteins and nuclear sheets among others. Agents directed to the inhibition of the transfer process (farnesylation, geranylgeranylation), for example, farnesyl mimetics and perilylic alcohol, have potential value as chemotherapeutic agents. The agents that block the synthesis of the intermediaries of the mevalonate pathway, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzi to A (HMG CoA) -reductase (statins) and the evaluation kinase (sodium phenylacetate) also have therapeutic potential. Statins competitively inhibit the activity of HMG CoA reductase. Various end products of the metabolism of plant evaluation (pure and mixed isoprenoids) suppress the activity of HMG-CoA reductase (Elson, 1995, Elson and Qureshi, 1995, Elson and Yu, 1994).

REF. 122: 753 Endogenous isoprenoids, monoterpene, and sesquiterpene, geraniol, and farnesol alcohols also suppress reductase activity. Geraniol attenuates the translational efficiency of HMG-CoA reductase mRNA and decreases reductase mRNA (Elson, et al., 1998). Farnesol attenuates the translational efficiency of reductase mRNA and points to 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-lives, since they are rapidly converted to the acids, α, β-prenyl-dicarboxylic acids by the cytosolic dehydrogenase and the microsomal onooxygenase activities which sequentially catalyze the formation of the prenyl aldehydes, the acids α-prenoics, α- and β-3-hydroxy-α-prenoic acids and α, α-phenyl-dicarboxylic acids (Christophe and Popjá, 1961; Gonzales-Pacanowska, et al., 1988; Austin, et al.; 1988; Keung, 1991; Girón, et al., 1993). Pentobarbital, an inducer of microsomal P450 monooxygenase activity that catalyzes the formation of α- and β-3-hydroxy-α-prenoic acids, completely 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 the activity of reductase.

DEGRADATION OF ENDOGENOUS ISOPRENOIDS Prenyl diphosphates (Geranil-PP, Farnesil-PP) 4- Microsomal Diphosphatase Prenyl Alcohols (Geraniol, Farnesol) 4- Prenyl Alcohol Dehydrogenase, Cytosolic Prenyl Aldehydes (Geranial, Farnesal) - Prenyl-Aldehyde Dehydrogenase Cytosolic A-Prenoic Acids (Geranoic Acid, Farnesoic Acid) F Monoxygenase, Cytochrome 450 IIB i?,? -3-hydroxylation, oxidation a,? -prenyl-dicarboxylic acids (Hildebrand's acids) geraniol (Shoff, et al., 1991; He, et al., 1997; Burke, et al., 1997 ) and farnesol (Miquel, et al., 1996; He, et al., 1997; Burke, et al., 1997) suppresses the proliferation of cells, a reversed action by the metabolite supplements of the mevalonate pathway ( Shoff, et al., 1991). Peryl alcohol (a cyclic monoterpene) attenuates the translational efficiency of HMG-CoA reductase mRNA (Elson et al., 1998) and suppresses cell proliferation (He, et al., 1997). Farnesylamine (Kothapalli, et al., 1993) and perilylamine (Burke et al., 1997) suppresses cell proliferation with higher potency than the corresponding alcohol, perhaps due to its lower degradation efficiency.

BRIEF DESCRIPTION OF THE INVENTION The present invention is a method for inhibiting the development 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 diethylacetal, geranyl benzoate, geranyl tiglato, geranyl anthranilate and combinations thereof to a patient with tumor. The amount is effective to inhibit or prevent the proliferation or development of tumor cells. Preferably, the inhibition is at least 50% of the control development. More preferably, the inhibition is 80%. More preferably, the inhibition is 100%. In yet another embodiment of the present invention, a sesquiterpenoid structure of 15 carbon atoms has replaced the monoterpenoid structure of 10 carbon atoms in the compounds described above. Therefore, farnesyl derivatives, such as farnesyl tiglato and farnesyl anthranilate, are very active and suitable compounds for the present invention. In still another embodiment, the present invention is a pharmaceutical composition effective to inhibit or prevent the development of tumor cells, comprising a compound selected from the group consisting of citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate, geranyl tiglato , 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 tiglato, geranyl anthranilate and combinations thereof. In yet another embodiment, the present invention is a pharmaceutical composition, as described above, but substituting the carbon-containing compound, preferably farnesyl anthranilate, farnesyl benzoate, farnesyl tiglato or farnesyl acetate. In a more preferred embodiment, the pharmaceutical preparation allows the total dose of the compound of 1 to 2 grams per day per human patient of 68 kg (150 pounds). In a preferred embodiment, the dose is between 1 and 4 grams per day for a human patient of 68 kg (150 pounds). An objective of the present invention is to provide an effective chemotherapeutic. Preferably, this chemotherapeutic has a potency relative to that of the perilylic alcohol of at least 5 times, preferably 6 times. The potency is indicated by the IC50 value, the concentration of a compound required to suppress cell development by 50%. A lower IC50 indicates higher power. Therefore, a higher proportion indicates greater power. An advantage of the present invention is to provide a chemotherapeutic agent with attributes similar to perilylic alcohol but effective at approximately 20% of the dose of perilylic alcohol, necessary to inhibit or prevent the development of tumor cells.

DESCRIPTION OF THE DIFFERENT VIEWS OF THE DRAWINGS Figure 1 illustrates the structures of the geraniol and farnesyl derivatives, the IC5o values, and the potencies relative to those of the perilylic alcohol. Figures 2-6 are graphs of the growth response of B16 murine melanoma cells (FIO) to geranyl tiglato (Figure 2), citracetal (Figure 3), geranyl anthranilate, geranyl benzoate, diethylacetal citral, and citral dimethylacetal (Figure 4), geraniol (Figure 5) and farnesyl tiglato (Figure 6).

DETAILED DESCRIPTION OF THE INVENTION A. In General The present invention is a method for inhibiting or preventing the development of tumor cells, comprising the step of exposing the tumor cells to an amount of a compound selected from the group consisting of citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate , geranyl tiglato. and geranyl anthranilate and combinations thereof, effective to inhibit or prevent the development of tumor cells. Preferably, the compound is either geranyl tiglato or geranyl anthranilate or combinations thereof. In yet another embodiment of the present invention, a sesquiterpenoid structure of 15 carbon atoms has replaced the monoterpenoid structure of 10 carbon atoms in the compounds described above. Therefore, farnesyl anthranilate, farnesyl benzoate and farnesyl tiglato and combinations thereof are also suitable. It is considered that one may wish to combine the compounds of 10 carbon atoms and 15 carbon atoms. Most preferably, the compound is administered orally to a tumor patient. It is considered that the compound is more preferably encapsulated or combined with a food product. Alternatively, the composition could be in a tablet or liquid format. In a second preferred embodiment, the compound is administered as an ointment or balm. The preparation administered typically comprises a pharmaceutically acceptable carrier and a composition selected from the group consisting of citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate, geranyl tiglato, geranyl anthranilate and combinations thereof. The amount of the preparation is effective to decrease or inhibit the development of the tumor cells by at least 50% and preferably 80%. More preferably, the development of the tumor cells is 100% inhibited. Preferably, the doses for the compounds of the present invention are from 1 to 4 grams per day per 150 pound (68 kg) human patient. More preferably, the dose is 1-2 grams per day per human patient of 68 kg (150 pounds). All the farnesol and geranyl derivative compounds of the present invention are GRAS or FEMA and have toxicities indicating that a chemotherapeutic amount could be well tolerated. For example, geranyl tiglato has an oral LD05 of 5 g / kg as measured in rats.

B Comparative values of IC 50 The IC501 values (μmol / L) for the suppression of the proliferation of B16 melanoma cells by limonene (450), perilylic alcohol (250), geraniol (150) and farnesol (50) show that acyclic monoterpene, geraniol, and acyclic sesquiterpene, farnesol, have higher potency than monocyclic monoterpenes. However, geraniol and farnesol suffer from subsequent oxidation before excretion via the kidney. The tumor suppressor activity of a number of geraniol derivatives that may have a longer half-life has been monitored. We report the findings that citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate, geranyl tiglato and geranyl anthranilate have in vitro tumor suppressor activities 5 times higher than perilylic alcohol. These derivatives may have the advantage of being effective at lower doses than perilylic alcohol and having a longer half-life than geranium., the geranial and farnesol. The agents suppress the in vitro development of highly metastatic murine B16 melanoma. This line of tumor cells is more resistant than human tumor cell lines to the suppression of isoprenoid-mediated development. Where it was tested, the results of the in vitro tests are in parallel to the in vivo responses. These agents are approved for use in food and / or cosmetics.

FEMA TSCA Citracetal X Citral Dimethylacetal 2305 X Citral Diethylacetal 2304 X Geranyl Benzoate 2511 X Geranyl Tiglate X Geranyl Antilarylate X TSCA: Registered under the Toxic Substances Control Act for use in cosmetics, food and food additives. foods.

C. Ex emplos 1. Background It was found that the activity of HMG CoA reductase is suppressed by tocotrienols but not by tocopherols (Qureshi, et al., 1986) which led to evaluate the suppressive potency of reductase, of geraniol (Fitch, et al. ., 1989). Geraniol can be considered as a structural analog of the side chain of the tocotrienols. It was subsequently reported that lemongrass oil (a GRAS substance consisting essentially of geraniol and citral), administered to 22 hypercholesterolemic subjects (140 mg / day) effected a decrease in serum cholesterol that approached significance (P < 0.06). Subsequent analyzes found that one subgroup of subjects (n = 14) did not respond to the treatments, while the second (n = 8) experienced a 11% (P <0.025) decrease in serum cholesterol. The cholesterol values for these responding subjects returned to the pre-study levels after the completion of the study (Elson, et al., 1989). Following the evidence presented that the intermediate diverted from the mevalonate pathway (cholesterogenic) plays an essential role in cell division (reviewed in Shoff, et al., 1991) the it of geraniol and mevinolin, an inhibitor, was tested. of competitive reductase, on the proliferation of murine P388 leukemia and melanoma B16 cells. Finding similar in vitro responses Shoff, et al. (1991) gave a diet of food containing 0.1% geraniol (10 g, 65 mmol / kg of diet) for 14 days before and after the intraperitoneal implantation of P388 leukemic cells. The mean survival time was increased by 50% (24 to 36 days) and 20% of the mice remained tumor-free through 50 days. Yu, et al. (1995) gave food geraniol (3.5 g, 23 mmol / kg diet) to buffalo rats for 14 days before and after hepatoma implantation Morris 777. At 27 days the mean volume of the hepatomas in the experimental rats was 16% (P <0.001) than the controls. Yu, et al. gave geraniol food (1 g, 6.5 mmol / kg of diet and 10 g, 65 mmol / kg of diet) to mice for 14 days before and after the implantation of B16 melanoma tumor cells. At 21 days after implantation, the weight of the excised tumors from the mice that received the geraniols was 70% (P <0.02) and 56% (P <0.02) than the control. In these studies, geraniol had no negative effect on weight gain. Burke et al. (1997) coed the its of perilylic alcohol (40 g, 263 mmol / kg of diet), geraniol (20 g, 130 mmol / kg of diet) and farnesol (20 g, 90 mmol / kg of diet) on the development of implanted pancreatic tumors. Hamsters were acclimated to the diets for a week before the tumor was implanted. At 25 days after implantation, the average diameter of the tumors in the Hamster groups that received perilylic alcohol, geraniol and farnesol were 55% (NS), 15% (P <0.025), and 23% (P < 0.05) respectively than the control group. Burke et al. They gave food then geraniol and farnesol in the diets to the hamsters after a pancreatic tumor. At 20 days, the average diameter of the tumors in the hamsters that received the experimental diets was 25% (P <0.05) than that recorded for the controls. In these studies, geraniol had no negative effects on the change in weight. 2. Compound Selection The present investigation of the catalogs of chemical products (Aldrich) and Flavors and Fragrances (Bedoukian Research, Aldrich) for the structural analogs of geraniol that can be resistant to degradation, led us to test a number of geraniol derivatives (and citral). Several had little it on the proliferation of melanoma cells (Table 1).

Table 1. Derivatives with low power Geranylacetone Geranyl acetate Geranyl butyrate Geranyl caprylate Geranyl formium Geranyl isobutyrate Geranyl isovalerate Geranyl propionate Peryl alcohol However, six derivatives of 10 carbon atoms having potency were identified according to the present selection test, several times greater (Figures 2-4) than geraniol (Figure 5, Table 1) and the same as that of farnesol. Active compounds have also been identified in which a sesquiterpenoid structure of 15 carbon atoms replaces the monoterpenoid structure of 10 carbon atoms (Figure 6, Table 1).

Materials and methods ICsp determinations: B16 murine melanoma cells (FIO), a line of tumor cells with high metastatic potential (Tsuka oto, et al., 1991) were grown in a monolayer culture (35 x 10 mm flasks) in 3 L of RMPI 1640 medium (Sigma) supplemented with 10% neonatal calf serum (GIBCOBRL, Grand Island, NY) and 80 mg / L gentamicin (Sigma, St. Louis, MO). The cultures, seeded with 1-1.5 x 10 5 cells, were incubated for 24 hours at 37 ° C in a humidified atmosphere of 5% C02. The isoprenoids, dissolved in absolute ethanol, were added at 24 hours (time 0); all cultures contained 5 ml of ethane.l / L (85 mmol / L). The cultures were incubated for an additional 48 hours. The medium was removed and the monolayers were washed twice with Hanks Balanced Saline Solution (Sigma) and then incubated with a solution of trypsin-EDTA (Sigma) at 37 ° C for 2 minutes. Trypsin was inactivated by suspending the cells in medium containing 10% fetal bovine serum (Sigma). The cells were concentrated at 250 x g and resuspended in Hanks Balanced Salt Solution. Viable cells, the cells that excluded 0.4% trypan blue (GIBCOBRL), were counted with a hemocytometer; Cell counts at 24 hours were deducted from the final cellular accounts to provide an estimate of the net increase in cell numbers. The concentration of an isoprenoid required to inhibit the net increase in cell counts at 48 hours by 50% (IC50) is determined from the graphs of the data (Mo, et al., 1998). Figure 1 describes the structures of various isoprenoids, selected derivatives, the IC 50 value and the potency of each isoprenoid relative to that of perilylic alcohol (250 μmol / L) and the source. The IC50 value is the concentration of isoprenoid required to suppress the net increase in the population of B16 melanoma cells by 50%. Figures 2-6 are graphs of the development response of murine melanoma cells B16 (FIO) to geranyl tiglato (Figure 2), citracetal (Figure 3), geranyl anthranilate, geranyl benzoate, citral diethylacetal, and citral dimethylacetal (Figure 4), geraniol (Figure 5) and farnesyl tiglato (Figure 6). Figure 2 is a graph showing the geranyl tiglato-mediated suppression of the development of murine melanoma B16 cells and leukemic cells HL-60. Figure 6 is a graph of suppression mediated by farnesyl tiglato and mediated by citronella of 48-hour development (net increase in cell number) of murine B16 melanoma cells and estimates of IC5o- values. Experiments on human cells were performed in the same way as on B16 laurin cells, except that the development of the cells was checked periodically in the suspension culture. Acute human promyelocytic leukemia cells HL-60 (CCL-240, ATCC) were grown in suspension culture (25 cm2 flasks) in 8 ml of RPMI 1640 'medium with 20% FBS and 2% penicillin / streptomycin. . The cultures, seeded with 1.25 x 108 cells / liter, were incubated with the test agents for 24 hours at 37 ° C in a humidified atmosphere of 5% C02. The HL-60 cells were concentrated at 250 x g and resuspended in HBSS. Viable cells, the cells that excluded 0.4% trypan blue, were counted with a hemocytometer; Cell counts at time 0 (seeding) were deducted from the final cellular accounts to provide an estimate of the net increase in cell numbers.

Isoprenoids: Citracetal, citral diethylacetal, citral dimethylacetal, geranyl anthranilate, geranyl benzoate, geranyl tiglato were donations from Bedoukian Research, Inc., Danbury, CT and are described in more detail below. The citral (geranial), farnesol, geraniol, d-limonene, perilylic alcohol, and perilaldehyde were purchased from Aldrich Chemical, Milwaukee, WI. The IC 50 values determined during these tests for geraniol (~ 150 μmol / L) and perilylic alcohol (~ 250 μml / L) fall within 10% of the reported values (He, et al., 1997).

Acrylic monoterpenoid alcohols Geraniol; 3, 7-dimethyl-2,6-octadien-l-ol CAS Name: 2,6-octadien-l-ol, 3, 7-dimethyl-, (E) - CAS No .: 106-24-1 FEMA: 2507 Very high quality, odor of roses used in perfumes and fruit flavors Molecular weight: 154.26 Molecular formula: C? OH? 80 Nerol 3, 7 -dimethyl-2, 6-octadien-l -ol CAS Name: 2, 6-octadien-l-ol, 3, 7-dimethyl-, (Z) - CAS-No .: 106-25-2 FEMA : 2770 Citrus-lemon flavor used in various floral fragrances, blackberry flavors Molecular weight: 154.25 Molecular formula: C? 0H? 80 Citronellol: 3, 7-dimethyl-6-octen-l-ol Linalool 3, 7-dimethyl-l-6-octadien-3-ol Acrylic monoterpenoid aldehydes Geranial: 3, 7-dimethyl-2, 6-octadien-1-al Neral: 3, 7-dimethyl-2, 6-octadien-1-al Citral: a mixture of geometric isomers Derivatives Citracetal CAS Name: 1, 3-dioxolane, 2- (2,6-dimethyl-l, 5-heptadienyl) - CAS No .: 66408-78-4 FEMA: Clean, lemony, floral odor Molecular weight: 196. 28 Molecular formula: C? 2H2o02 Citral diethylacetal CAS Name: 2, 6-octadiene, 1, l-diethoxy-3, 7-dimethyl- CAS No .: 7492-66-2 FEMA: 2395 Fine, fresh, citrus odor, used in citrus perfumes and flavors Molecular weight: 226.36 Molecular formula: C? 4H2602 Citral Dimethylacetal CAS Name: 2, 6-octadiene, 1, l-dimethoxy-3,7-dimethyl- CAS No .: 7549-37-3 FEMA: 2304 Floral lemon scent, very pleasant, used in perfumes and flavors of citric Molecular weight: 198.31 Molecular formula: C? 2H2202 Geranyl anthranilate CAS name: 2,6-octadien-l-ol, 3, 7-dimethyl-, 2-aminobenzoate, (E) -No. CAS: 67874-69-5 FEMA: Smell of honeysuckle, strong, used in perfumes (honeysuckle, gardenia). Molecular weight: 273.38 Molecular formula: Ci7H23N02 Geranyl Benzoate CAS Name: 2, 6-octadien-l-ol, 3, 7-dimethyl-, benzoate, (E) - CAS-No .: 94-48-4 FEMA: 2511 Amber Odor, roses, long duration, used in perfumes and fruit flavors Molecular weight: 258.36 Molecular formula: C? 7H2202 Geranyl Tiglato CAS Name: 2-butenoic acid, 2-methyl-, 3,7-dimethyl-2,6-octadienyl ester, (E, E) - CAS No .: 7785-33-3 FEMA: Smelling something fruity, similar to geranium, used in fragrances of geranium, roses and lavender. Molecular weight: 236 36 Molecular formula: Ci5H2402 Acyclic sesquiterpenoid alcohols Farnesyl anthranilate: 2,6,10-didecatrien-l-ol, 3,7, 11-trimeti1-2-aminobenzoate (E, E) Farnesyl benzoate: 2,6,10-dodecatrien-l-ol, 3,7, 11-trimethyl-benzoate (E, E) Farnesyl tiglato: 2, 6, 10-dodecatrien-l-ol, ester 3, 7, 11-trimethyl-octadienyl (E, E) Farnesyl acetate: 2, 6, 10-dodecatrien-l-ol, 3, 7, 11-trimethyl-octadienyl ester (E, E) REFERENCES Austin, C.A., Shephard, E.A., Pike, S.F., Rabin, B.R. and Phillips, J.R. (1988) "The effect of terpenoid compounds on cytochrome P-450 levéis in rat liver," Biochem. Pharmacol, 37: 2223-2229.

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It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Use of a compound selected from the group consisting of citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate, geranyl tiglato and geranyl anthranilate, farnesyl benzoate, farnesyl anthranilate, farnesyl tiglato, farnesyl acetate and combinations of the same for the manufacture of a drug to inhibit or prevent the development of tumor cells.

2. The use according to claim 1, characterized in that the compound is geranyl tiglato, geranyl anthranilate or combinations thereof.

3. The use according to claim 2, characterized in that the compound is geranyl anthranilate.

4. The use according to claim 2, characterized in that the compound is geranyl tiglato.

5. Use of a compound selected from the group consisting of citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate, geranyl tiglato and geranyl anthranilate, farnesyl benzoate, farnesyl anthranilate, farnesyl tiglato, farnesyl acetate and combinations of the same for the manufacture of a medicament for inhibiting or preventing the development of tumor cells, wherein the amount administered is effective to reduce or inhibit the development of the tumor by at least 50%.

6. The use according to claim 5, characterized in that the compound is geranyl tiglato, geranyl anthranilate or combinations thereof.

7. The use according to claim 6, characterized in that the compound is geranyl anthranilate.

8. The use according to claim 1, characterized in that the compound is geranyl tiglato.

9. The use according to claim 8, characterized in that the compound is citracetal.

10. The use according to claim 5, characterized in that the compound is citral dimethyl acetal.

11. The use according to claim 5, characterized in that the compound is citral diethylacetal.

12. The use according to claim 5, characterized in that the compound is geranyl benzoate.

13. The use according to claim 5, characterized in that the compound is farnesyl benzoate.

14. The use according to claim 5, characterized in that the compound is farnesyl anthranilate.

15. The use according to claim 5, characterized in that the compound is farnesyl acetate.

16. The use according to claim 5, characterized in that the compound is farnesyl tiglato.

17. The use according to claim 5, characterized in that the inhibition is at least 50% of the control development.

18. The use according to claim 17, characterized in that the inhibition is at least 80%.

19. The use according to claim 18, characterized in that the inhibition is 100%.

20. A pharmaceutical composition, characterized in that it comprises a compound selected from the group consisting of citracetal, citral dimethylacetal, citral diethylacetal, geranyl benzoate, geranyl tiglato, geranyl anthranilate, farnesyl benzoate, farnesyl anthranilate, farnesyl tiglato, acetate of farnesyl and combinations thereof in a pharmaceutically acceptable carrier.