JP5507832B2 - Selenodisulfide compound and process for producing the same - Google Patents

Description

  The present invention relates to a selenodisulfide compound and a method for producing the same, and more specifically, the present invention relates to a novel selenodisulfide compound that can be expected to have at least excellent antitumor properties and antimutagenicity (protective action against gene damage), and It relates to a manufacturing method.

Selenium is an essential trace element that is indispensable for life support, and selenium and selenium compounds have been conventionally reported on antitumor properties, antimutagenicity, and preventive action against various diseases.
Rayman MP. “The importance of selenium to human health” Lancet. 2000 Jul15; 356 (9225): 233-41 In Non-Patent Document 1, Rayman is an essential trace element that is fundamentally important for human health. For example, it has been reported that intake of selenium during diet reduces the risk of cancer and other diseases. JP, 61-267514, A Various kinds of selenium compounds have been disclosed or reported so far. For example, Patent Document 1 discloses phenyl selenious acid and esters thereof, selenium oxychloride and various complexes thereof, dialkyl selenites, and the like, and these selenium compounds are said to be active ingredients of antitumor agents. JP 2001-510468 A Patent Document 2 discloses various cyclic organic selenium compounds represented by a certain general formula, and these cyclic organic selenium compounds are used in blood vessels, digestive tracts, respiratory tracts, and the like. It is said to be effective for the treatment of various inflammatory and ischemic conditions.

On the other hand, among various selenium compounds, selenosulfide compounds are particularly important because they are considered to have high physiological activity and safety to living bodies. Regarding the seleno sulfide compound, for example, the following documents are known.
Edgar Page Painter “The Chemistry and Toxicity of Selenium Compound with Special Reference to the Selenium Problem” page 170-213 As Non-Patent Document 2 reported for the first time by Painter, selenium is taken into the living body as selenite and under acidic conditions. Reacts with cysteine to form selenosulfide compounds. Howard E. Ganther “Reduction of the Selenotrisulfide Derivative of Glutathione to a Persulfide Analog by Glutathione Reductase” Biochemistry, Vol. 10, No. 22, 1971 The following thiol compound is reacted with selenious acid under acidic conditions at a molar concentration ratio of 4 to produce a seleno disulfide compound, and the following reaction formula (1) is proposed.

4RSH + H ₂ SeO ₃ → RSSeSR + RSSR + 3H ₂ O (1)
Since then, studies have been conducted on the mechanism of selenosulfide formation by Kice (Kice, 1980), cell-free systems by Braga and Gabel-Jensen, and selenium metabolism models in rats (Braga, 2004, Gabel, 2006). .
T. Nakagawa, Y. Hasegawa, Y. Yamaguchi, H. Tanaka, M. Chikuma, H. Sakurai, M. Nakayama “Isolation, Characterization and Thiol Exchange Reaction of Penicillamine Selenotrisulfides” BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNUCATIONS, vol.135, No 1, 1986, February 26, 1986, page 183-188 More recently, as shown in Non-Patent Document 4, the Nakayama group has isolated a chemically stable selenodipenisilamine (PSSeSP) and is effective in the living body. Use has been studied using mice. This selenodipenicillamine is obtained by reacting 1 mol of selenious acid and 4 mol of penicillamine under acidic conditions, and is obtained by reacting 2 molecules of penicillamine with 1 atom of selenium at its thiol group. Selenodipenicillamine.

By the way, the above-mentioned various conventional selenium compounds are often not sufficiently verified for their physiological activities, and even when verified, it cannot be said that they exhibit sufficiently high effects regarding antitumor properties and antimutagenic properties. There are many.
The present invention provides a novel selenosulfide compound that is not disclosed or suggested in any of the above-mentioned known documents and can be expected to have at least excellent antitumor properties and antimutagenic properties, and an effective production method thereof. Providing is a technical problem to be solved.

  In the course of variously examining the formation reaction of selenodipenicillamine disclosed in Non-Patent Document 4 above, the inventor of the present application sets the reaction conditions, particularly the molar concentration ratio of selenious acid and penicillamine to a specific concentration ratio region. If changed, surprisingly, a polyselenodipenicillamine formed by bonding one molecule of penicillamine to each end of a linear bond of selenium having two or more atoms is formed, and these polyselenodipenicillamines are The present invention was completed by finding that it exhibits excellent physiological activity.

(First invention)
The configuration of the first invention of the present application for solving the above problem is represented by a general formula of “R _x — (Se) _n —R _y ”, where (Se) _n is a direct number of n selenium atoms. N represents an integer of 2 to 4, R _x and R _y are the same or different organic groups, both having a thiol group (—SH), and the thiol group is the selenium It is a selenodisulfide compound that is bonded to each end of a linear combination of atoms.

(Second invention)
The constitution of the second invention of the present application for solving the above problems is a compound in which the selenodisulfide compound according to the first invention is represented by any one of the following general formulas: In any of these general formulas, “Se _2-4 ” represents a linear bond of 2 to 4 selenium atoms, and a polythiol having a thiol group bonded to each end of the linear bond. It is a seleno disulfide compound which is seleno disulfide.

(In the above “chemical formula 18”, R _{1 to} R ₄ , R ₆ and R ₈ each independently represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and R ₅ and R ₇ each independently represent hydrogen or carbon. An alkyl group or an amide-bonded amino acid of 1 to 3; R ₉ and R ₁₀ each independently represent a hydrogen or amide-bonded amino acid.

(In the above “chemical formula 19”, R ₁ , R ₂ , R ₄ and R ₇ each independently represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and R ₃ represents hydrogen or an alkyl having 1 to 3 carbon atoms. A group or an amide-bonded amino acid, R ₅ represents a hydroxyl group or an amide-bonded amino acid, and R ₆ represents an alkyl group having 1 to 3 carbon atoms or an alkyl carboxylic acid group having 1 to 3 carbon atoms.)

(In the above “chemical formula 20”, R ₁ represents an alkyl group having 1 to 3 carbon atoms or an alkyl carboxylic acid group having 1 to 3 carbon atoms. The two R _{1 s} may be the same or different. R ₂ represents hydrogen or an alkyl group having 1 to 3 carbon atoms, and two R ₂ may be the same or different.)
(Third invention)
The structure of the third invention of the present application for solving the above problem is that the polyseleno disulfide represented by the general formula of “Chemical Formula 18” according to the second invention is any of the following “Chemical Formula 21” to “Chemical Formula 24”. It is a selenodisulfide compound that is represented by

(In the above “Chemical Formula 21” formula, “Se _2-4 ” represents a linear bond of 2 to 4 selenium atoms, and a thiol group is bonded to each end of the linear bond. ing.)

(In the above “Chemical Formula 22”, “Se ₂ ” represents a linear combination of two selenium atoms, and a thiol group is bonded to each end of the linear combination.)

(In the above “Chemical Formula 23”, “Se _2-3 ” represents a linear bond of 2 or 3 selenium atoms, and a thiol group is bonded to each end of the linear bond. doing.)

(In the above “Chemical Formula 24”, “Se _2-3 ” represents a linear bond of two or three selenium atoms, and a thiol group is bonded to each end of the linear bond. doing.)
(Fourth invention)
The constitution of the fourth invention of the present application for solving the above problem is that the polyseleno disulfide represented by the general formula of “Chem. 19” according to the second invention is any one of the following “Chem. 25” to “Chem. 28”. It is a selenodisulfide compound that is represented by

(In the above “Chemical Formula 25”, “Se _2-3 ” represents a linear bond of two or three selenium atoms, and a thiol group is bonded to each end of the linear bond. doing.)

(In the above “Chemical Formula 26”, “Se _2-3 ” represents a linear bond of two or three selenium atoms, and a thiol group is bonded to each end of the linear bond. doing.)

(In the above “Chemical 27” formula, “Se ₂ ” represents a linear combination of two selenium atoms, and a thiol group is bonded to each end of the linear combination.)

(In the above “Chemical Formula 28” formula, “Se ₂ ” represents a linear combination of two selenium atoms, and a thiol group is bonded to each end of the linear combination.)
(Fifth invention)
The structure of the fifth invention of the present application for solving the above problem is that the polyseleno disulfide represented by the general formula of “Chemical Formula 20” according to the second invention is represented by the following “Chemical Formula 29”. Selenodisulfide compound.

(In the above “Chemical 29” formula, “Se ₂ ” represents a linear bond of two selenium atoms, and a thiol group is bonded to each end of the linear bond.)
(Sixth invention)
The structure of the sixth invention of the present application for solving the above-mentioned problems is the following (A) component and (B) in which the molar concentration ratio is adjusted within the range of (A) :( B) = 1: 1 to 1: 8. A kind of polyseleno disulfide in which the thiol group of component (A) is bonded to each end of a linear combination of 2 to 4 selenium atoms by reacting the components under acidic conditions of pH 1 to 4. Or it is a manufacturing method of the selenodisulfide compound which manufactures 2 or more types.
(A) Component: One or two organic compounds having a thiol group (—SH) (B) Component: Selenious acid (H ₂ SeO ₃ ) or a salt thereof (seventh invention)
The constitution of the seventh invention of the present application for solving the above-mentioned problem is that the component (A) according to the sixth invention is penicillamine represented by the following “Chemical 30”, cysteine represented by the following “Chemical 31”, and “Chemical 32” described below. And 2-mercaptopropionic acid, a mercaptosuccinic acid represented by the following “Chemical Formula 33”, and glutathione represented by the following “Chemical Formula 34”.

(Eighth invention)
The configuration of the eighth invention of the present application for solving the above problems is a selenodisulfide compound, which is a monoseleno disulfide corresponding to any of the following (1) to (7).

  (1) Monoselenodisulfide in which one molecule of penicillamine and one molecule of glutathione are bonded to each other at one thiol group with respect to one atom of selenium.

  (2) Monoselenodisulfide in which one molecule of penicillamine and one molecule of 2-mercaptopropionic acid are bonded to each other at one thiol group with respect to one atom of selenium.

  (3) Monoseleno disulfide in which one molecule of cysteine and one molecule of 2-mercaptopropionic acid are bonded to one atom of selenium at their thiol group.

  (4) Monoseleno disulfide in which one molecule of glutathione and one molecule of 2-mercaptopropionic acid are bonded to one atom of selenium at their thiol group.

  (5) Monoseleno disulfide in which one molecule of glutathione and one molecule of mercaptosuccinic acid are bonded at one thiol group to one atom of selenium.

  (6) Monoseleno disulfide in which two molecules of 2-mercaptopropionic acid are bonded to one atom of selenium at their thiol group.

  (7) Monoseleno disulfide in which two molecules of mercaptosuccinic acid are bonded at their thiol group to one atom of selenium.

  (8) A monoseleno disulfide represented by the following formula (35).

  The selenodisulfide compounds according to the first to fifth inventions are novel compounds that have not been reported before, and have a unique chemistry that includes a linear conjugate of 2 to 4 selenium atoms. It is a polyseleno disulfide compound having a structure. Conventionally, a polyseleno disulfide compound having such a structure has not been reported or suggested, and its production method has not been known. Therefore, it is difficult to conceive these polyseleno disulfide compounds by analogy with various known organic selenium compounds.

  As the selenodisulfide compounds according to the first to fifth inventions are proved in the examples described later, or are definitely estimated from the properties of various known organic selenium compounds or known selenodisulfide compounds in common, Also exhibit at least antitumor and antimutagenic properties (protective action against gene damage). Moreover, various physiological activities are extremely excellent, possibly in relation to the unique chemical structure of the polyseleno disulfide compound.

  In addition, the method for producing a selenodisulfide compound according to the sixth invention or the seventh invention comprises an organic thiol compound and selenous acid or a salt thereof in a region of the molar concentration ratio newly found by the present inventor under specific acidic conditions. Can be easily and reliably produced. In practice, the corresponding monoseleno disulfide is often produced together.

  Furthermore, monoseleno disulfides listed in the eighth invention are also novel seleno disulfide compounds that have not been reported so far, and can be expected to have excellent physiological activities such as antitumor properties and antimutagenic properties.

  Next, modes for carrying out the present invention will be described including the best mode.

[Selenodisulfide compounds]
The selenodisulfide compound according to the present invention is represented by the general formula “R _x — (Se) _n —R _y ”, wherein (Se) _n is a linear conjugate of n selenium atoms. N is an integer of 2 to 4, R _x and R _y are the same or different organic groups, both of which have a thiol group (—SH), and the thiol group is a straight chain of the selenium atom A polyseleno disulfide bonded to one end of each of the conjugates. Although it does not limit as an organic compound which has a thiol group, Penicillamine, cysteine, 2-mercaptopropionic acid, mercaptosuccinic acid, and glutathione can be illustrated preferably.

Among the selenodisulfide compounds according to the present invention, particularly preferred are selenodisulfide compounds represented by any one of the general formulas of “Chemical Formula 18” to “Chemical Formula 20” described above. , “Se _2-4 ” represents a linear conjugate of 2 to 4 selenium atoms, and is a polyseleno disulfide in which a thiol group is bonded to each end of the linear conjugate.

  As a particularly preferred example of the selenodisulfide compound represented by the general formula of “Chemical Formula 18”, the polyseleno disulfide represented by any one of “Chemical Formula 21” to “Chemical Formula 24” described above can be exemplified. As a particularly preferred example of the selenodisulfide compound represented by the general formula of “Chemical Formula 19”, the polyseleno disulfide represented by any one of “Chemical Formula 25” to “Chemical Formula 28” described above can be exemplified. As a particularly preferred example of the selenodisulfide compound represented by the general formula of “Chemical Formula 20”, the polyseleno disulfide represented by the above “Chemical Formula 29” can be exemplified.

  Furthermore, as other seleno disulfide compounds, novel monoseleno disulfides listed as (1) to (8) in the eighth invention can be mentioned.

[Method for producing selenodisulfide compound]
In the method for producing a selenodisulfide compound according to the present invention, the molar concentration ratio is in the range of (A) :( B) = 1: 1 to 1: 8, more preferably in the range of 1: 2 to 1: 4. Each of the linear conjugates of 2 to 4 selenium atoms by reacting the adjusted components (A) and (B) below under acidic conditions of pH 1-4, more preferably pH 1-2. One type or two or more types of polyseleno disulfide in which the thiol group of the component (A) is bonded to one end are produced. As the component (B), selenious acid (H ₂ SeO ₃ ) is particularly preferable.
Component (A): one or two organic compounds having a thiol group (-SH) (B) component: a selenite _(H 2 SeO ₃₎ or a salt thereof one or more poly seleno disulfide compound Diseleno disulfide compound in which the thiol group of component (A) is bonded to each end of a linear combination of two selenium atoms; component (A) at each end of a linear combination of three selenium atoms And a triseleno disulfide compound in which a thiol group of the component (A) is bonded to each end of a linear conjugate of four selenium atoms.

  As the component (A), penicillamine, cysteine, 2-mercaptopropionic acid, mercaptosuccinic acid, glutathione and the like are particularly preferable.

In the case where two types of thiol compounds A1 and A2 are used as the component (A), the following polyseleno disulfide of (a) is mainly produced, and the following polyselenos of (b) and (c) are combined. Disulfide is also produced.
(A) a polyseleno disulfide in which A1 and A2 are thiol-bonded to each end of a linear combination of 2 to 4 selenium atoms,
(B) Polyselenodisulfide in which one molecule of A1 is thiol-bonded to both ends of a linear combination of 2 to 4 selenium atoms.
(C) Polyseleno disulfide in which one molecule of A2 is thiol bonded to both ends of a linear combination of 2 to 4 selenium atoms.

  Furthermore, in the method for producing a selenodisulfide compound according to the present invention, in fact, monoselenodisulfide corresponding to the above-mentioned various polyselenodisulfides is often produced together. Generally, in the reaction system, the larger the molar concentration ratio of the component (B) (selenous acid) to the component (A) (organic compound having a thiol group), the greater the amount of polyselenodisulfide compound produced. To do.

  In the method for producing a selenodisulfide compound according to the present invention, the reaction conditions for the component (A) and the component (B) are not limited as long as they are under the acidic conditions described above. The means for maintaining such acidic conditions is not limited, but for example, an appropriate amount of hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, etc. can be administered to the reaction system.

  Various reaction conditions at the time of the reaction between the component (A) and the component (B) may be appropriately set and are not particularly limited. However, as the reaction solvent, the thiol compound and selenious acid or a salt thereof are almost uniform. It is sufficient that the solvent dissolves and does not react with these, preferably water, alcohol such as dimethyl sulfoxide, methanol, or a mixed solvent thereof. The reaction temperature is desirably between -20 ° C and 50 ° C.

The generation of the selenodisulfide compound according to the present invention can be easily confirmed by observing the abundance ratio of the natural isotope of selenium of the hydrogenated molecular ion peak [M + H] ⁺ obtained from LC-MS analysis. it can.

  After the reaction, the selenodisulfide compound according to the present invention can be isolated pure by purifying the selenodisulfide compound according to the present invention and other disulfide compounds produced in various proportions by an appropriate separation means. Separation means include HPLC using a reverse phase silica gel column, column chromatography using normal phase silica gel, or chromatography using a resin (for example, Amberlite XAD-2 or OASIS HLB). In some cases, a recrystallization method is also effective. It is.

  Examples of the present invention will be described below together with comparative examples. The technical scope of the present invention is not limited by these examples and comparative examples.

[Example 1-1: Synthesis, isolation and purification of polyselenodipenicillamine]
To 0.4 mL of water, 0.2 mL of 500 mM D-penicillamine aqueous solution, 0.4 mL of 1 M aqueous selenious acid solution, and 0.05 mL of 0.1 N hydrochloric acid aqueous solution were added, and the mixture was allowed to stand at room temperature for 1 hour. Next, after centrifugation at 3,000 rpm for 5 minutes, the supernatant was subjected to high performance liquid chromatography-linked electrospray ion trap mass spectrometry (high performance liquid chromatography: Agilent 1100 Series; Mobile phase: 15% linear concentration gradient from aqueous solution containing 0.05% formic acid to methanol; flow rate: 0.8 mL / min; mass spectrometry: LCQ DECAXP IonTrap mass spectrometer manufactured by ThermoFisher Scientific; detection : Selected ion amount or total ion amount), and measuring the mass spectrum of the peak eluted at 6.36 minutes, 7.83 minutes and 9.44 minutes, diselenodipenicillamine which is polyselenodipenicillamine. ( PSe2P ), triselenodipenicillamine ( PSe3P ) and tetraselenodipeni Production of silamine ( PSe4P ) was confirmed.

The hydrogenated molecular ion peak [M + H] ⁺ of these polyselenodipenicillamines shows a characteristic natural isotope ratio depending on the number of selenium atoms contained (see FIGS. 1 to 4). In these isolation and purification, the supernatant is separated by high performance liquid chromatography (high performance liquid chromatography: DC Series, Shimadzu Corporation; column: develosyl C18, 3 microns, No. 10 mm, length 200 mm, Nomura Chemical Co., Ltd.) Mobile phase : A linear concentration gradient from 0.05% formic acid-containing aqueous solution to methanol for 60 minutes; flow rate: 4.5 mL / min; detection: UV 300 nm), collecting peaks eluted from 40 minutes to 60 minutes, and concentrating under reduced pressure. Pure diselenodipenicillamine, triselenodipenicillamine, and tetraselenodipenicillamine can be obtained, respectively.

[Example 1-2: Synthesis, isolation and purification of other polyselenodipenicillamine]
(A) As a component (thiol compound), one type selected from L-cysteine, 2-mercaptopropionic acid, mercaptosuccinic acid and glutathione instead of or together with D-penicillamine used in Example 1-1 Or 2 types were used. Then, the total dose of these components (A) was adjusted to the same concentration as D-penicillamine in Example 1-1, and the same process as in Example 1-1 was performed. Various monoseleno disulfides or polyseleno disulfides listed were obtained.

In Table 1 above, what is described as “known substance” in the column of “compound” is a selenodisulfide compound that has been found to be known as long as the inventors have investigated, and other compounds are referred to as “compound”. The corresponding chemical formula number such as “Chemical Formula 21” is shown in the column of

  In Table 1, the abbreviations of the respective compounds are shown in the “abbreviation” column. In this notation, “P” is D-penicillamine, “C” is L-cysteine, “MP” is 2-mercaptopropionic acid, “MC” is mercaptosuccinic acid, “G” is glutathione, “ “Se” represents selenium. For example, the notation “PSeP” in the column of “abbreviation” indicates that the compound is a monoseleno disulfide compound in which two molecules of D-penicillamine are bonded to one atom of selenium at the thiol group. . In addition, for example, the expression “PSe3G” in the “abbreviation” column indicates that one molecule of D-penicillamine and glutathione is present at each end of a linear bond of selenium having three atoms of the compound, and the thiol group. It shows that it is the polyseleno disulfide compound couple | bonded in.

The column “n” in Table 1 represents the number of selenium atoms contained in one molecule of the compound. Also, in the columns of “R1” to “R10” in Table 1, the types of substituents such as “R1” and “R2” in the chemical formulas of the corresponding numbers are specifically shown. Further, in the column “Retention time”, as described in Example 1-1, an ODS column (develosyl C18, 3 microns, inner diameter 4.6 mm, length 50 mm, manufactured by Nomura Chemical Co., Ltd.) was used, and the mobile phase (liquid A) : Time when the compound elutes when 0.05% formic acid-containing aqueous solution, B solution: methanol) is flowed from 100% A solution to 100% B solution with a linear concentration gradient over 15 minutes at a flow rate of 0.8 mL / min ( Minutes). Detection was performed using a mass spectrometer for selected ions or total ions. “Proton-added molecular ion [M + H] ⁺ at ⁸⁰ Se” in Table 1 is one of the peaks observed in the mass spectrum.

[Example 2: Measurement of inhibitory effect on oxidative DNA damage]
A DNA damage system consisting of calf thymus DNA (100 μM), NADH (40 μM), CuCl ₂ (20 μM), catechol (40 μM), and phosphate buffer (4 mM, pH 7.8) has a final concentration of 2 to 16 μM. Monoselenodipenicillamine (Comparative Example) or Diselenodipenicillamine (Example) was added to the sample, kept at 37 ° C. for 1 hour, agarose gel electrophoresis (1% agarose, 1 × TAE buffer, pH 8.1), and then full length DNA. The amount was quantified with a fluorescence bioimage analyzer (FMBIO · II Multi-view manufactured by Hitachi, Ltd.).

  As a control, the amount of full-length DNA was similarly quantified under the condition of DNA damage caused by copper (II) and catechol, and in the non-damaged condition where no monoselenodipenisilamine or diselenodipenicillamine was added.

  And the inhibitory effect with respect to the oxidative DNA damage by said copper * catechol was computed from following formula (2). In the formula (2), (A) is a measured value of the total DNA amount when monoselenodipenicillamine or diselenodipenicillamine of each concentration is added to the above-described DNA damage system, and (B) is under non-damaged conditions. It is the measured value of the amount of full length DNA.

[(A) / (B)] × 100 (%) (2)
As a result, as shown in FIG. 6, monoselenodipenicillamine has a concentration of 13.5 μM, and diselenodipenicillamine has a concentration of 7.0 μM as shown in FIG. %, And a significant difference between the two was confirmed.

  The present invention provides a novel selenosulfide compound exhibiting excellent antitumor properties and antimutagenicity (protective action against gene damage).

2 is a total cation chromatograph showing the analysis result of the reaction solution of D-penicillamine and selenious acid by high performance liquid chromatography coupled electrospray ion trap mass spectrometry in Example 1. FIG.

Mass spectrum of diselenosipenicillamine (PSSe ₂ SP) showing the analysis result of the reaction solution of D-penicillamine and selenious acid by high performance liquid chromatography coupled electrospray ion trap mass spectrometry in Example 1 (proton-added molecule) Ion).

Mass spectrum of triselenosipenicillamine (PSSe ₃ SP) showing the analysis result of the reaction solution of D-penicillamine and selenious acid by high performance liquid chromatography coupled electrospray ion trap mass spectrometry in Example 1 (proton-added molecule) Ion).

Mass spectrum (proton-added molecule) of tetraselenosipenicillamine (PSSe ₄ SP) showing the analysis result of the reaction solution of D-penicillamine and selenious acid by high performance liquid chromatography coupled electrospray ion trap mass spectrometry in Example 1 Ion).

It is a graph which shows the inhibitory effect with respect to the oxidative DNA damage by copper and catechol by the diselenodipenicilamine in Example 2 (vertical axis: inhibition rate with respect to oxidative DNA damage by copper and catechol (%); horizontal axis: diseleno Dipenicillamine concentration (microM)).

It is a graph which shows the inhibitory effect with respect to the oxidative DNA damage by copper and catechol by the selenodipenicillamine in Example 2 (vertical axis: inhibition rate with respect to the oxidative DNA damage by copper and catechol (%); horizontal axis: selenodipenicillamine. Concentration (micro M)).

Claims (6)

Is represented by the general formula of _{"-S- R x (Se) n -S-} R y ', _{(Se) n} in the general formula is a straight conjugates of n selenium atom, n represents is an integer of 2 to 4, _R x -S- and _R y -S- are penicillamine, cysteine, 2-mercaptopropionic acid, mercaptosuccinic acid or glutathione derived _groups, R x -S- and _{R y} - S- the seleno disulfide compound, wherein may be the same or different groups. However, diselenodipenicillamine, triselenodipenicillamine and tetraselenodipenicillamine are excluded. A seleno disulfide compound represented by any one of formulas of the "formula 1" - "of 3" follows, both in these formulas is "Se _2-4" 2-4 selenium atom features and to Rousset Reno disulfide compound that the linear conjugate is shown to Po Li seleno disulfide. However, diselenodipenicillamine, triselenodipenicillamine and tetraselenodipenicillamine are excluded.
(In the above “Chemical Formula 1” formula, R _{1 to} R ₄ , R ₆ and R ₈ each independently represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and R ₅ and R ₇ each independently represent hydrogen or carbon. An alkyl group or an amide-bonded amino acid of 1 to 3; R ₉ and R ₁₀ each independently represent a hydroxyl group or an amide-bonded amino acid.
(In the above “chemical formula 2”, R ₁ , R ₂ , R ₄ and R ₇ each independently represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and R ₃ represents hydrogen or an alkyl having 1 to 3 carbon atoms. A group or an amide-bonded amino acid, R ₅ represents a hydroxyl group or an amide-bonded amino acid, and R ₆ represents an alkyl group having 1 to 3 carbon atoms or an alkyl carboxylic acid group having 1 to 3 carbon atoms.)
(In the above “chemical formula 3”, R ₁ represents an alkyl group having 1 to 3 carbon atoms or an alkyl carboxylic acid group having 1 to 3 carbon atoms. The two R _{1 s} may be the same or different. R ₂ represents hydrogen or an alkyl group having 1 to 3 carbon atoms, and two R ₂ may be the same or different.) The seleno according to claim 2, wherein the polyseleno disulfide represented by the general formula of "Chemical Formula 1" is represented by any of the following "Chemical Formula 4" to " Chemical Formula 6 ". Disulfide compounds.
(In "Formula 4" formula of the "Se _2" is shown to a linear coupling of the two selenium atoms.)
(In "Formula 5" formula of the "Se _2-3" is shown to a linear coupling of two or three selenium atoms.)
(In "Formula 6" formula of the "Se _2-3" is shown to a linear coupling of two or three selenium atoms.) 3. The seleno according to claim 2, wherein the polyseleno disulfide represented by the general formula of “Chemical Formula 2” is represented by any of the following “ Chemical Formula 7 ” to “ Chemical Formula 10 ”: Disulfide compounds.
(In "Formula 7" formula of the "Se _2-3" represents a linear coupling of two or three selenium atoms.)
(In "Formula 8" type described above, "Se _2-3" represents a linear coupling of two or three selenium atoms.)
(In "Formula 9" formula of the "Se _2" represents a linear coupling of the two selenium atoms.)
(In "Formula 10" formula of the "Se _2" is shown to a linear coupling of the two selenium atoms.) 3. The selenodisulfide compound according to claim 2, wherein the polyseleno disulfide represented by the general formula of “Chemical Formula 3” is represented by the following “ Chemical Formula 11 ”.
(In "Formula 11" formula of the "Se _2" is shown to a linear coupling of the two selenium atoms.) By reacting the following component (A) and component (B), whose molar concentration ratio is adjusted within the range of (A) :( B) = 1: 1 to 1: 8, under acidic conditions of pH 1-4, A method for producing a seleno disulfide compound, comprising producing one or more of the seleno disulfide compounds according to claim 1 . However, the production method of diselenodipenicillamine, triselenodipenicillamine and tetraselenodipenicillamine is excluded.
Component (A): penicillamine represented by “ Chemical Formula 12 ” below, cysteine represented by “ Chemical Formula 13 ” below, 2-mercaptopropionic acid represented by “ Chemical Formula 14 ” below, mercaptosuccinic acid represented by “ Chemical Formula 15 ” below , Or 1 type of organic compound (B) component selected from glutathione shown in “ 16 ”: Selenious acid (H ₂ SeO ₃ ) or a salt thereof