Tocopherol ester compounds

Details Tocopherol ester compounds Tocopherol ester compounds

2003-03-20

2004-04-06

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S407000, C549S410000

Reexamination Certificate

active

06716873

ABSTRACT:

FIELD OF THE INVENTION
This invention pertains to certain novel tocopherol ester derivatives and intermediate compounds utilized in the preparation of the derivatives. More specifically, this invention pertains to &agr;-tocopherol ester compounds that exhibit antiproliferative and growth inhibitory effects on breast cancer cell lines and to substututed dicarboxylic acids and anhydrides.
BACKGROUND OF THE INVENTION
Selenium and &agr;-tocopherol (Vitamin E) are two antioxidants that have attracted great attention due to their cancer chemo-preventive activity showing strong synergism. See, for example, Ip,
J. Nutr.
128, 1845-1854 (1998); Clark, et al.,
J. Am. Med. Assoc.
276, 1957-1963 (1996); El-Bayoumy,
Mutation Research
475, 123-139 (2001); Alaejos, et al.,
Nutrition
16, 376-383 (2000); Burton, et al.,
Arch. Biochem. Biophys.
221, 281-290 (1983), and Burton, et al.,
Acc. Chem. Res.
19,194-201. Thus, the impact of selenium deficiency on cancer risk seemed to be more profound at low serum vitamin E concentrations as reported by Salonen, et al.,
Br. Med. J.
290, 417-420 (1985), Willett, et al.,
Lancet
July 16; 2(8342):130-134 (1983), and Shamberger, et al,
Arch. Environ Health
31, 231-235 (1976).
The reported synergism may be attributed to the redox recycling of the antioxidants [Chaudiere, et al.,
Food Chem. Toxicology
37, 949-962 (1999) and Ip,
Federation Proc.
44, 2573-2578 (1985)] although d-&agr;-tocopherol is suggested to develop an environment of decreased oxidative stress where the anticarcinogenic action of selenium is potentiated through specific molecular mechanisms. Other mechanisms by which selenium compounds spare &agr;-tocopherol in the cells also have been suggested by Li, et al.,
FEBS Letters
508, 489-492 (2001). Previous studies on the cell growth inhibitory effects of vitamin E compounds and derivatives have shown that RRR-&agr;-tocopheryl succinate (VES) has the most potent apoptotic effect in vitro [13. Yu, et al.,
Nutr. Cancer
33, 26-32 (1999)]. As reported by Cheeseman, et al.,
Free Radic Biol Med.
19, 591-598 (1995) and Papas, Tocopherols and Tocotrienols, in A. M. Papas (Ed.) Antioxidant Status, Diet, and Health, pp. CRC Press, Boca Raton, USA, (1998), the succinate derivative of tocopherol is used extensively as a food additive or nutritional supplement because it is more stable than free tocopherol and equally bioavailable in healthy humans. Although the formation of the ester bond blocks the 6-hydroxyl group of the d-&agr;-tocopherol and inhibits the antioxidant activity, VES can be hydrolyzed retaining the active free d-&agr;-tocopherol antioxidant activity.
According to Yu, et al.,
Nutr. Cancer
33, 26-32, this pro-apoptotic effect of VES has not been shared by pure d-&agr;-tocopherol, an effect that can be attributed to the structural modification of the molecule of tocopherol by the succinic esteric bond. This is suggested to enable the esterified form to interact with specific molecules in the biologic process of signal generation and transduction [Yu, et al.,
Nutr. Cancer
27, 267-278 (1997) and Turley, et al.,
Cancer Res.
57, 881-890 (1997)]. It appears from the accumulated evidence [Jiang, et al.,
Bioch. Biophys. Res. Commun.
194, 836-841 (1993); Kaeck, et al.,
Biochem. Pharmacol.
53, 921-926 (1997); Lu, et al.,
Carcinogenesis
17, 1903-1907 (1996); Lu, et al.,
Biochem. Pharmacol.
49, 1531-1535 (1994); Lu, et al.,
Biochem. Pharmacol.
50, 213-219 (1995); and Wilson, et al.,
Biochem. Pharmacol.
43, 1137-1141 (1992)] that the chemical form of selenium is a very important factor in eliciting defined cellular responses in the in vitro system. Aromatic selenium compounds have been preferred to other types of organic selenium compounds due to their higher stability and lower toxicity [Ip,
J. Nutr.
128, 1845-1854 (1998); Ganther, et al.,
Tetrahedron
53, 12299-12310 (1997); and Ganther, et al.,
Bioorg. Med. Chem.
9,1459-1466 (2000). Specific molecular mechanisms of their preventive action remain to be elucidated.
BRIEF SUMMARY OF THE INVENTION
We have discovered that certain derivatives of &agr;-tocopherol exhibit cell growth inhibitory properties such as antiproliferative and growth inhibitory effect on breast cancer cell lines. Thus, the present invention provides &agr;-tocopherol ester compounds having formula (I):
wherein X is a chain of 2 or 3 carbon atoms, e.g., ethylene and trimethylene, joining the 2 carbonyl groups to which they are bonded; and R
1
is a group having the formula —Y—R
4
wherein Y is a selenium, tellurium or sulfur atom and R
4
is an alkyl cycloalkyl or aryl radical. Certain of the compounds of formula (I) have shown significant antiproliferative and growth inhibitory effect on breast cancer cell lines.
Another embodiment of the present invention is a process for the preparation of compounds of formula (I) by the steps comprising:
(1) contacting a compound having the formula Z—Y—R
4
with a dicarboxylic acid anhydride having the formula:
 in the presence of an alkanol having the formula R
3
—OH to obtain an ester having the formula:
(2) separating the ester of formula (III) produced in step (1) from the alkanol solvent;
(3) contacting the ester of formula (III) with aqueous inorganic acid to convert the ester to the corresponding dicarboxylic acid;
(4) contacting the dicarboxylic acid formed in step (3) with acetic anhydride to convert the dicarboxylic acid to an anhydride having the formula:
 and
(5) contacting the anhydride of formula (IV) with RRR-&agr;-tocopherol to obtain an &agr;-tocopherol ester having formula (I);
wherein X and R
1
are defined above; R
3
is alkyl of 1 to 3 carbon atoms and Z is an alkali metal.
The compounds having the formula (V) are especially preferred:
wherein R
1
and R
2
each is hydrogen or phenylselenyl, i.e., phenyl-Se-, provided that R
1
≠R
2
, i.e., one of R
1
and R
2
is phenylselanyl and the other is hydrogen. The compounds of formula (V) exhibit antiproliferative and growth inhibitory effects on breast cancer cell lines superior to the effect of &agr;-tocopheryl succinate and its equimolar combination with 2-phenylselanyl-succinic acid.
DETAILED DESCRIPTION
The compounds of our invention may be prepared by means of known procedures using available materials. For example, the compounds may be prepared by contacting RRR-&agr;-tocopherol with an anhydride having formula (IV) in the presence of an acidic catalyst and a hydrocarbon solvent. For example, phenylselenosuccinic anhydride may be contacted with &agr;-tocopherol in the presence of zinc chloride and toluene. The compounds of formula (I) typically comprise a mixture of compounds, e.g., phenylselanyl-succinic acid RRR-&agr;-tocopherol having the structure
typically comprises a mixture of the 2-phenylselanyl compound [Compound (I)—R
1
=H, R
2
=phenylselanyl] and the 4-phenylselanyl compound [Compound (I)—R
1
=phenylselanyl, R
2
=H]. The anhydride having formula (IV) may be obtained by contacting the corresponding dicarboxylic acid with acetic anhydride at elevated temperatures. The dicarboxylic acid is obtained by the hydrolysis of an ester of formula (III) at elevated temperature using a mineral acid such as hydrochloric acid. Ester (III) X can be prepared by first contacting a compound having the formula R
4
—Y—R
4
, e.g., diphenyldiselenide, with an alkali metal borohydride, e.g., sodium borohydride in the presence of an alkanol solvent, e.g., methanol, and then adding bromosuccinic anhydride to the alkanol soluton of the Z—Y—R
4
intermediate. Anhydride (II) can be obtained by heating bromosuccinic acid with acetic anhydride.
The groups represented by R
4
may be unsubstituted or substituted alkyl, cycloalkyl or aryl containing up to about 20 carbon atoms. The alkyl radicals preferably are alkyl of 1 to about 6 carbon atoms. Examples of the aryl groups include phenyl and phenyl substituted with one or two substituents selected from alkyl, alkoxy, nitro, halogen and the like

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