Organic compounds -- part of the class 532-570 series – Organic compounds – Selenium or tellurium containing
Reexamination Certificate
2002-02-20
2004-03-09
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Selenium or tellurium containing
Reexamination Certificate
active
06703524
ABSTRACT:
BACKGROUND OF THE INVENTION
Cancer incidence and mortality have not declined at the same rate as other major causes of death. This suggests that primary prevention, including the use of chemopreventative agents, is a valuable approach to decreasing mortality, as it avoids all the potential shortfalls and difficulties associated with cancer therapy.
Selenium is an essential nonmetallic nutrient in mammals. Its deficiency is associated with increased incidence of leukemia and cancers of bladder, breast, gastrointestinal tract (e.g., colon and rectum), ovary, stomach, lung and prostrate. There is convincing evidence that a dietary supplement of selenium substantially reduces the incidence of a wide variety of cancers in laboratory animals. Higher intake of selenium provides protection by correcting nutritionally deficient status in animals and also increases antitumorigenic activity. El-Bayoumy,
Cancer Res.,
45:3631-3635 (1985); Reedy et al.,
Cancer Res.
47:5901-5904 (1987); Nayini et al.,
Carcinogenesis
10:509-512 (1989); El-Bayoumy et al.,
Cell. Biochem.,
22:92-100 (1995); El-Bayoumy, “The role of selemium in cancer prevention,” in:
Cancer Principles and Practice of Oncology
, DeVita et al., eds., J.B. Lippincot Co., Phildelphia (1991).
Epidemiological studies in humans also suggest a protective role for selenium in human cancers. Human cancer mortality is lower in areas providing an adequate dietary intake of selenium as estimated from the selenium content in grains and forage crops in various regions of the United States, or the dietary selenium intake as calculated from food consumption data in various countries. Schrauzer et al.
Bioinorg. Chem.
7:23-31 (1977).
An excess of selenium is associated with toxicity and a large number of health disorders, such as body weight loss, liver damage, splenomegaly, pancreatic enlargement, anemia, hair loss and abnormal nails. The margin between its protective role and adverse effect is very low and depends on the form of selenium being used. For its protective role, the rate of release of selenium from its compound to the selenium pool should be in the range of its required rate of absorption by the biological system.
The search for the best form of selenium for cancer chemoprevention has led to the investigation of a wide variety of selenium forms. Examples of compounds that have been investigated include inorganic salts like sodium selenite, as well as organoselenium compounds such as selenocysteine (a naturally occurring form of selenium) and a number of structurally designed aliphatic and aromatic selenium-containing compounds such as heptylselenocyanate and pentylselenocyanate. Ip et al.,
Carcinogenesis
16:35-38 (1995).
Although inorganic selenium compounds inhibit carcinogenesis, they are toxic. Organic sources of selenium that have been investigated to date, such as the naturally occurring selenium-containing amino acids selenomethionine and selenocysteine which are ingested via cereals, vegetables, and grains, are somewhat more effective than inorganic selenium in cancer prevention but have comparable toxicity. El-Bayoumy, “The role of selenium in cancer prevention,” in:
Cancer Principles and Practice of Oncology
, DeVita et al., eds., J. B. Lippincot Co., Philadelphia (1991).
Among the organoselenium compounds investigated to date, the benzene-based compound 1,4-phenylenebis(methylene)selenocyanate (also known as p-xyleneselenocyanate, or p-XSC) is reported to exert the most effective chemopreventative effect on chemically induced carcinogenesis in the mammary glands, colon, and lung of laboratory animals. Reddy et al.,
Cancer Res.
52:5635-5640 (1992); Reddy et al.,
J. Natl. Cancer Inst.
89:506-512 (1997); El-Bayoumy et al.,
Cancer Res.
52:2402-2407 (1992); El-Bayoumy et al., Carcinogenesis 14:1111-1113 (1993). Organic compounds having a 5-membered heterocyclic ring substituted with an alkylene isothiocyanate, wherein the heteroatom is sulfur, selenium, or oxygen, have also been described as having cancer chemopreventative activity (U.S. Pat. No. 6,166,003, Lam).
SUMMARY
The invention provides novel organoselenium compounds for use in cancer chemoprevention. In one embodiment, the compound of the invention is a 5-membered heterocyclic ring substituted with an alkylene selenocyanate at least at the 2-position on the ring, as shown in formula I:
wherein:
R
1
is H, (alkylene)-SeCN, or a blocking group;
R
2
is H, (alkylene)-SeCN, or a blocking group;
R
3
is H, (alkylene)-SeCN, or a blocking group; and
R
4
is (alkylene)-SeCN; and
Z is S, Se or O.
Also provided by the invention are cysteine-containing conjugates of the organoselenium compound shown in formula I, wherein the cyanate group (—CN) at one or more of R
1
, R
2
, R
3
and R
4
is replaced with a cysteine or a cysteine-containing peptide such as the tripeptide glutathione (&ggr;-glutamylcysteinylglycine). Preferably, the sulfur atom of the cysteine residue is covalently linked to the selenium atom of the at least one (alkylene)-SeCN moiety. A preferred conjugate is the compound of formula I wherein the cyanate group (—CN) of at least one (alkylene)-SeCN moiety is replaced with a cysteine, an N-acetyl cysteine, a cysteinylglycine, or the tripeptide glutathione.
Preferably, in compounds wherein R
1
=R
4
=methylene-SeCN, at least one of R
2
and R
3
is not H. However, in pharmaceutical and food additive compositions and in methods of use of the cancer chemopreventive compounds of the invention, the compound can include formula I wherein R
1
=R
4
=methylene-SeCN and R
2
=R
3
=H.
In another embodiment, the compound of the invention is a 5-membered heterocyclic ring substituted with an alkylene isoselenocyanate at least at position 2 on the ring, as shown in formula II:
wherein:
R
1
is H, (alkylene)-NCSe, or a blocking group;
R
2
is H, (alkylene)-NCSe, or a blocking group;
R
3
is H, (alkylene)-NCSe, or a blocking group;
R
4
is (alkylene)-NCSe; and
Z is S, Se or O.
Also provided by the invention are cysteine-containing conjugates of the organoselenium compound shown in formula II, wherein the isoselenocyanate group (—NCSe) at one or more of R
1
, R
2
, R
3
and R
4
is replaced with a cysteine-containing moiety having the general formula —N(H)C(Se)R
5
wherein R
5
is cysteine, a derivative thereof, or a peptide containing cysteine. For example, one or more of R
1
, R
2
, R
3
and R
4
is replaced with —N(H)C(Se)cysteine or —N(H)C(Se)glutathione where R
5
is cysteine or glutathione, respectively. Preferably, the sulfur atom of the cysteine residue is covalently linked to the carbon atom of the at least one (alkylene)-NCSe moiety. A preferred conjugate is the compound of formula II wherein the isoselenocyanate group (—NCSe) of at least one (alkylene)-NCSe moiety is replaced with —N(H)C(Se)cysteine, —N(H)C(Se)—N-acetylcysteine, —N(H)C(Se)cysteinylglycine, or —N(H)C(Se)glutathione.
In yet another embodiment, the compound of the invention is a xyleneisoselenocyanate compound as shown in formula III:
wherein:
R
1
is H, (alkylene)-NCSe, or a blocking group; and
R
2
is (alkylene)-NCSe.
The disubstituted form of the compound of formula III, 1,4-phenylenebis(alkylene)selenocyanate, (also known as p-xyleneisoselenocyanate, or p-XISC) is especially preferred.
Also provided by the invention are cysteine-containing conjugates of the organoselenium compound shown in formula III, wherein the isoselenocyanate group (—NCSe) at one or both of R
1
and R
2
is replaced with a cysteine-containing moiety having the general formula —N(H)C(Se)R
3
wherein R
3
is cysteine, a derivative thereof, or a peptide containing cysteine. For example, one or both of R
1
and R
2
is replaced with —N(H)C(Se)cysteine or —N(H)C(Se)glutathione where R
3
is cysteine or glutathione, respectively. Preferably, the sulfur atom of the cysteine residue is covalently linked to the carbon atom of the at least one (alkylene)-NCSe moiety. A preferred conjugate is the compound of formula III wherein the isoselenocyanate group (—NCSe) of at least one (alk
Ahmed Nayaz
Lam Luke K. T.
LKT Laboratories, Inc.
Mueting Raasch & Gebhardt, P.A.
Owens Amelia
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