WO2019093699A1 - Selenopsammaplin a and derivative thereof, preparation method therefor, and composition for preventing and treating cancer, containing same as active ingredients - Google Patents

Abstract

The present invention relates to: novel selenopsammaplin A and a derivative thereof, which have anticancer activity; a preparation method therefor; and a pharmaceutical composition containing the same as active ingredients and, more specifically, to: a novel compound selenopsammaplin A and a derivative thereof which exhibit more excellent anticancer activity since a disulfide moiety thereof is substituted with diselenide according to research on the structural activity of psammaplin A, which is known to have an effect of inhibiting the growth of cancer cells; a preparation method therefor; and a composition for preventing or treating cancer, containing the same as active ingredients. According to the present invention, the novel selenopsammaplin A and the derivative thereof exhibit excellent anticancer activity on various human cancer cell lines so as to be expected to be effectively usable in a pharmaceutical composition for cancer prevention and treatment.

Description

Selenosamphyllin A and its derivatives, a method for producing the same, and a composition for preventing and treating cancer comprising the same as an active ingredient

The present invention relates to novel selenosamphilin A having anticancer activity and derivatives thereof, a method for producing the same, and a pharmaceutical composition containing the same as an effective ingredient.

Psammaplin A is a marine natural product having a polymer structure in which a monomer having a bromothyrosine structure is linked to a disulfide structure. The samaflirin A has antimicrobial activity, growth inhibitory action of leukemic cell line P388, DNA topoisomerase inhibitory effect, histone deacetylase inhibitory effect, DNA guarase inhibitory effect, panesyl enzyme transfer inhibitory effect, Inhibitory effect, PPAR-gamma activity effect, and growth inhibitory effect of colon cancer cells.

Recently, Professor Shin Jong - heon of Seoul National University College of Pharmacy has succeeded in isolating samaflirin A from marine animals inhabiting the southern coast of the Korean peninsula and has shown that it inhibits the growth of cancer cells. Based on this research, (1987) reported that the inhibition of the growth of lung cancer cells was more effective than the inhibition of the growth of lung cancer cells (Hong S et al., (2017) Eur. J. Med. Chem. In addition, the structural activity of samaflirin A derivatives against MRSA antimicrobial activity has been studied.

Disclosure of the Invention The present invention was conceived to solve the above-described problems in the prior art. The present invention provides novel selenosamphilin A and derivatives thereof having anticancer activity and treating them, The present invention has been completed on the basis thereof.

Accordingly, an object of the present invention is to provide novel selenosamphilin A having anticancer activity, a derivative thereof, and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a novel method for producing selenosamphilin A having an anticancer activity and derivatives thereof.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a novel selenosamphilin A having anticancer activity, a derivative thereof and a pharmaceutically acceptable salt thereof.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention, the present invention provides selenosamphilin A and its derivatives, isomers thereof, or pharmaceutically acceptable salts thereof, represented by the following formulas (1) or (2)

[Chemical Formula 1]

(2)

In the above formulas (1) and (2)

Wherein X is hydrogen, C _1-5 alkyl,

, 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

When R ₃ and R ₄ are connected to each other through a ring,

(n = 1, 2, 3);

When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl Lt; / RTI >

In an embodiment of the present invention, X is

Or 2-naphthyl;

Wherein R ₁ , R ₂ , and R ₅ are each independently hydrogen;

R ₃ is hydrogen, hydroxy, ethoxy, t-butyl, fluoro, chloro, bromo, nitro, or benzyl;

The R ₄ may be hydrogen, bromo, chloro, or fluoro, but is not limited thereto.

The present invention also relates to a process for preparing a compound represented by the following formula (4) by adding 2,2'-diseleninediyldiethanamine to a compound represented by the following formula (3) And

And a step of synthesizing selenosamphilin A represented by the following formula (1) and a derivative thereof by performing a hydrolysis reaction of the compound represented by the formula (4): Selenosamphafiline A represented by the following formula Lt; RTI ID = 0.0 > of:

(3)

[Chemical Formula 4]

[Chemical Formula 1]

The present invention also relates to a method for producing selenosamphylline A represented by the following formula (2) by adding dithiothreitol to a compound represented by the following formula (1) A process for the preparation of maphilin A and its derivatives is provided:

[Chemical Formula 1]

(2)

In the above formulas (2), (3) and (4), X is as defined in the above formula (1).

The present invention also provides a pharmaceutical composition for preventing or treating cancer, comprising selenosamphilin A and its derivatives represented by the above-mentioned formulas (1) and (2), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

In one embodiment of the present invention, the cancer may be lung cancer or colon cancer.

In another embodiment of the present invention, the selenosamphilin A and derivatives thereof may be selected from the group consisting of the following compounds:

(3-bromo-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Minino) propanamide); (3-chloro-4-hydroxyphenyl) -2- (hydroxyimino (2-ethylhexyl) ) Propane amide); (3-fluoro-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Minino) propanamide); (2E, 2'E) -N, N '- (diesterediylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3-phenylpropanamide); (3- (4-fluorophenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ; (2E, 2'E) -N, N '- (dicentylene diylbis (ethane-2,1-diyl)) bis (3- (4-chlorophenyl) -2- (hydroxyimino) propanamide); (3- (4-bromophenyl) -2- (hydroxyimino) propanamide) (2E, 2'E) -N, N'- (decenylene diylbis ; Bis (3- (3,4-difluorophenyl) -2- (hydroxyimino) propane-2-carboxylic acid (2E, 2'E) Propanamide); (2E, 2'E) -N, N '- (diesterediylbis (ethane-2,1-diyl)) bis (3,4-dichlorophenyl) -2- (hydroxyimino) propanamide; (3- (4-ethoxyphenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ; (4-benzyloxy) phenyl) -2- (hydroxyimino) propanamide (2E, 2'E) -N, N'- (decenylene diylbis ); (2E, 2'E) -N, N '- (dicentylene diylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3- (4-nitrophenyl) propanamide); (3-tert-butylphenyl) -2- (hydroxyimino) propane (2E, 2'E) -N, N'- (dicentylene diylbis amides); (2- (hydroxyimino) -3- (naphthalen-2-yl) propanamide) bis (2E, 2'E) -N, N ' ; (E) -3- (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (3-Chloro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -2- (hydroxyimino) -3-phenyl-N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (4-fluorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (4-chlorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (4-bromophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (3,4-difluorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (3,4-Dichlorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (4-ethoxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (4- (benzyloxy) phenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -2- (hydroxyimino) -3- (4-nitrophenyl) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; (E) -3- (4- (tert-butyl) phenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; And (E) -2- (hydroxyimino) -3- (naphthalen-2-yl) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide.

Further, the present invention provides a method for preventing or treating cancer, comprising the step of administering the pharmaceutical composition to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for the prevention or treatment of cancer.

The present invention provides a novel compound selenosamphilin A and a derivative thereof in which a disulfide moiety is substituted with diselenide according to a structural activity study with respect to semapillin A, which is known to inhibit the growth of cancer cells. The selenosamapillin A And its derivatives exhibit excellent anticancer activity against various human cancer cells and have a superior growth inhibitory effect as compared with existing samaplirin A. The novel compounds are useful as pharmaceutical compositions for cancer prevention and treatment It is expected that it can be used.

Fig. 1 shows the structure of a novel selenosamphilin A of the present invention and derivatives thereof. Fig. 1 (a) shows the structure of selenosamphilin A of the formula (1) and its derivatives, ≪ / RTI > shows the structure of a leucine A derivative.

2 is a view showing a process for producing selenosamphilin A and its derivatives.

FIG. 3 is a diagram showing chemical structures of selenosamphilin A and its derivatives prepared by the method of the present invention.

The present invention provides novel selenosamphilin A and derivatives thereof having anticancer activity, isomers thereof, pharmaceutically acceptable salts thereof, and compositions for preventing or treating cancer comprising the same as an active ingredient. In addition, the compounds according to the present invention inhibit the growth of cancer cells and have a prophylactic or therapeutic effect against cancer, and thus they can be usefully used for the prevention or treatment of cancer.

Hereinafter, the present invention will be described in detail.

The present invention provides selenosamphilin A represented by the following general formula (1) or (2), a derivative thereof, an isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

(2)

In the above formulas (1) and (2)

Wherein X is hydrogen, C _1-5 alkyl,

, 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

When R ₃ and R ₄ are connected to each other through a ring,

(n = 1, 2, 3);

When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl Lt; / RTI >

More preferably, X is

Or 2-naphthyl; Wherein R ₁ , R ₂ , and R ₅ are each independently hydrogen; R ₃ is hydrogen, hydroxy, ethoxy, t-butyl, fluoro, chloro, bromo, nitro, or benzyl; R ₄ may be hydrogen, bromo, chloro, or fluoro.

The following describes the definitions of the various substituents for preparing the compounds according to the invention.

The term " C _1-5 alkyl " used in the present invention means a _monovalent alkyl group having 1 to 5 carbon atoms, and " C _1-3 alkyl " means a _monovalent alkyl group having 1 to 3 carbon atoms. The term includes functional groups such as methyl, ethyl, n - propyl, i - propyl, n - butyl, i - butyl, tert - butyl, n - hexyl and the like.

The alkyls described in the present invention, as well as the substituents comprising other alkyl moieties, include both straight chain and branched forms.

The term " C _1-3 alkoxy " as used in the present invention means an -OR group, wherein R means " C ₁ -C ₃ alkyl ". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, and the like.

Substituents comprising alkyl, alkoxy and other alkyl moieties described in this invention include both straight chain and branched forms.

Preferred embodiments of the selenosamphilin A and derivatives thereof represented by the formula (1) or (2) according to the present invention are as follows:

(3-bromo-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Bis (3- (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) propane amide) ((2E, 2'E) -N, N '- (diselanediylbis propanamide), SSM-1);

(3-chloro-4-hydroxyphenyl) -2- (hydroxyimino (2-ethylhexyl) ) Propane amide) ((2E, 2'E) -N, N'- (diselanediylbis (ethane-2,1-diyl)) bis 3- (3-chloro-4-hydroxyphenyl) -2- ), SSM-2);

(3-fluoro-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Bis (3- (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) propane amide) ((2E, 2'E) -N, N'- (diselanediylbis propanamide), SSM-3);

(2E, 2'E) -N, N '- (dicelene diyl bis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3- phenylpropanamide) E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (2- (hydroxyimino) -3-phenylpropanamide), SSM-4);

(3- (4-fluorophenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ((2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (3- (4-fluorophenyl) -2- (hydroxyimino) propanamide), SSM-5);

(4-chlorophenyl) -2- (hydroxyimino) propanamide) (2E, 2'E) -N, N '- (dicentylene diylbis (2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (3- (4-chlorophenyl) -2- (hydroxyimino) propanamide), SSM-6);

(3- (4-bromophenyl) -2- (hydroxyimino) propanamide) (2E, 2'E) -N, N'- (decenylene diylbis ((2E, 2'E) -N, N '- (diselanediylbis (ethane-2,1-diyl) bis (3- (4-bromophenyl) -2- (hydroxyimino) propanamide) SSM-7);

Bis (3- (3,4-difluorophenyl) -2- (hydroxyimino) propane-2-carboxylic acid (2E, 2'E) Propane amide) (bis (3- (3,4-difluorophenyl) -2- (hydroxyimino) propanamide), SSM -8);

(3,4-dichlorophenyl) -2- (hydroxyimino) propanamide) (((2E, 2'E) -N, N'- (decenylene diyl bis 2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (3- (3,4-dichlorophenyl) -2- (hydroxyimino) propanamide), SSM-9);

(3- (4-ethoxyphenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ((2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (3- (4-ethoxyphenyl) -2- (hydroxyimino) propanamide) SSM-10);

(4-benzyloxy) phenyl) -2- (hydroxyimino) propanamide (2E, 2'E) -N, N'- (decenylene diylbis Bis (3- (4- (benzyloxy) phenyl) -2- (hydroxyimino) propanamide), SSM- (2E, 2'E) -N, N'- (diselenediylbis 11);

(2- (hydroxyimino) -3- (4-nitrophenyl) propanamide) (2E, 2'E) -N, N'- (dicentylene diylbis (2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (2- (hydroxyimino) -3- (4-nitrophenyl) propanamide) SSM-12);

(3-tert-butylphenyl) -2- (hydroxyimino) propane (2E, 2'E) -N, N'- (dicentylene diylbis 2- (hydroxyimino) propanamide), (2E, 2'E) -N, N '- (diselanediylbis (ethane-2,1- SSM-13);

(2- (hydroxyimino) -3- (naphthalen-2-yl) propanamide) bis (2E, 2'E) -N, N ' (2E, 2'E) -N, N '- (diselanediylbis (ethane-2,1-diyl) bis (2- (hydroxyimino) -3- (naphthalen- 2- yl) propanamide) ; (E) -3 (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) - (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide, SSM-15); (E) -3- (3-chloro-4-hydroxyphenyl) -2- (hydroxyimino) 3-chloro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide, SSM-16); (E) -3 (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) - (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide, SSM-17); (E) -2- (hydroxyimino) -3-phenyl-N- (2 - ((phenylthio) cyanyl) ethyl) propanamide (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-18); (E) -3- (4-fluorophenyl) -2-hydroxyphenyl) -2- (hydroxyimino) ) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-19); ((E) -3- (4-chlorophenyl) ethyl) propaneamide was obtained in the same manner as in Example 1, except that (E) -3- (4-chlorophenyl) -2- (hydroxyimino) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-20); (E) -3- (4-bromophenyl) -2- (hydroxyimino) -N- (2- (phenylthio) ) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-21); ((E) -3- ((E) -3- (3,4-difluorophenyl) -2- (hydroxyimino) 3,4-difluorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-22); ((E) -3- (3, 4-dichlorophenyl) -2- (hydroxyimino) 4-dichlorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-23); (E) -3- (4-ethoxyphenyl) ethyl) propanamide was obtained in the same manner as in Example 1, except that (E) -3- (4-ethoxyphenyl) -2- (hydroxyimino) ) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-24); ((E) -3- (4-tert-butoxycarbonylamino) phenyl) -2- - (benzyloxy) phenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-25); (E) -2- (hydroxyimino) -3 (4-nitrophenyl) -N- (2- (phenylthio) - (4-nitrophenyl) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-26); ((E) -3- ((E) -3- (4- (tert-butyl) phenyl) -2- (hydroxyimino) 4- (tert-butyl) phenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-27); Ethyl) propanamide (E) -2- (hydroxyimino) -3- (naphthalen-2-yl) -N- 3- (naphthalen-2-yl) -N- (2 - ((phenylthio) selanyl) ethyl) propanamide, SSM-28).

SSM-1, SSM-2, SSM-3, SSM-4, SSM-10 and SSM-12 may be more preferably used as selenosamphilin A and derivatives thereof represented by Formula 1 according to the present invention.

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salt formed by a pharmaceutically acceptable free acid is useful.

As used herein, the term " salt " is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Butyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-carboxylate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the above compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile . It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

In addition, the base may be used to make a pharmaceutically acceptable metal salt. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the compounds of the present invention include not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates and solvates which can be prepared by conventional methods.

According to another aspect of the present invention, there is provided a process for preparing a compound represented by the following formula (3), comprising the steps of: synthesizing a compound represented by the following formula (4) by adding 2,2'-diseleninediyldiethanamine to a compound represented by the following formula And

And a step of synthesizing selenosamphilin A represented by the following formula (1) and a derivative thereof by performing a hydrolysis reaction of the compound represented by the formula (4): Selenosamphafiline A represented by the following formula ≪ / RTI > can be provided:

(3)

[Chemical Formula 4]

According to another aspect of the present invention, the present invention provides a method for producing selenosamphilin A, which comprises the step of synthesizing selenosamphilin A represented by the following formula (2) and a derivative thereof by adding dithiothreitol to a compound represented by the following formula A method for producing selenosamphilin A represented by the formula (2) and a derivative thereof can be provided:

[Chemical Formula 1]

(2)

In the above formulas (2), (3) and (4), X is as defined in the above formula (1).

The compound of formula (3) may be prepared by a method including the following steps, but is not limited to the following method:

Condensing compound S with compound 2 in a benzene solvent in the presence of piperidine and acetic acid catalyst to synthesize compound 3;

Synthesizing Compound 4 by adding tributyltin hydride (n-Bu ₃ SnH) to the compound 3 in a toluene solvent;

Synthesizing Compound 5 by adding butyl nitrite (n-BuONO) to the compound 4 in the presence of an ethanolic ethoxide base;

Adding dihydropyran (DHP) to compound 5 under para-toluenesulfonic acid catalyst to obtain compound 6, followed by hydrolysis to synthesize compound 7; And

Condensing the compound 7 with N-hydroxysuccinimide to synthesize Compound 8 (Formula 3).

[Reaction Scheme 1]

In the above Reaction Scheme 1, X is as defined in Formula 1 above.

The compound of the formula (1) and the formula (2) is prepared by the reaction according to the reaction scheme 1. The substituted aryl aldehyde type substrate (compound S) is reacted with piperidine and acetic acid catalyst Beta-unsaturated ethyl acetoacetate (Compound 3) by condensation reaction with ethyl acetoacetate (Compound 2) in an existing benzene solvent.

Then, Compound 3 is reacted with tributyltin hydride (n-Bu ₃ SnH) in a toluene solvent to synthesize ethyl acetoacetate (Compound 4) substituted at the alpha position. Then, butyl nitrite (n-BuONO) is added to Compound 4 in the presence of an ethanolic ethoxide base to synthesize an oxime (Compound 5). Compound 5 was reacted with dihydropyran (DHP) in the presence of p-toluenesulfonic acid (p-TsOH) catalyst to obtain compound 6, which was then hydrolyzed with an aqueous solution of potassium hydroxide (1N-KOH) Respectively. Then, Compound 7 is condensed with N-hydroxysuccinimide in 1,4-dioxane to synthesize Compound 8 (compound of Formula 3). Compound 9 (the compound of Formula 4) is reacted with 2,2'-diselenediiodiethanamine in the presence of a base of triethylamine (TEA) to the synthesized Compound 8 (compound of Formula 3) And the hydrolysis reaction was carried out using hydrochloric acid (1M-HCl) ether (Et ₂ O) solution as an acid catalyst to synthesize selenosamaphylline A derivative (compound 1, compound of formula 1), and phenyldisulfide, After dissolving orotretol in a phosphoric acid buffer solution and a dimethylsulfoxide solvent, the reaction solution is diluted with ethyl acetate and separated by column chromatography to synthesize a selenosamaphylline A derivative (compound 10, compound of formula 2).

In one embodiment of the present invention, selenosamphilin A and derivatives thereof represented by Formula 1 or Formula 2 were prepared, and the structure was analyzed and confirmed by NMR or Mass spectroscopy (see Examples 1 to 28). The forms of substituents X of the compounds prepared according to Examples 1 to 28 are shown in Table 1 below.

In another aspect of the present invention, the present invention provides a method for preventing or ameliorating cancer comprising selenosamphilin A and its derivatives represented by Formulas (1) and (2), its isomer or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutical composition for therapeutic use.

As used herein, the term " prophylactic " means any act that inhibits cancer or delays the onset of cancer by administration of the pharmaceutical composition according to the present invention.

As used herein, the term " treatment " refers to any action that improves or alters the symptoms of cancer by the administration of the pharmaceutical composition according to the present invention.

&Quot; Cancer " which is a preventive and therapeutic disease caused by the composition of the present invention is classified into diseases in which normal tissue cells proliferate unlimitedly for some reason and continue rapid development regardless of the life phenomenon of the living body or the surrounding tissue state. The cancer in the invention may preferably be lung cancer, or colon cancer, but is not limited to this kind.

In one embodiment of the present invention, the anticancer activity against various human cancer cells was evaluated using selenosamphilin A and its derivatives synthesized according to the production method of the present invention (see Example 15), and the compound SSM -1, SSM-2, SSM-3, SSM-4, SSM-10 and SSM-12 showed 20 to 60 times more potent anticancer activity than samapillin A compound, (Etoposide), which is an effective inhibitor of cancer cell growth.

Accordingly, the selenosamphilin A and its derivatives, its isomers or pharmaceutically acceptable salts thereof represented by the above-mentioned formulas (1) and (2) according to the present invention are useful as pharmaceuticals for preventing, improving or treating cancer, May be useful as a composition.

The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

In another aspect of the present invention, the present invention provides a method of treating cancer comprising administering the pharmaceutical composition to a subject. In the present invention, the term " individual " refers to a subject in need of treatment for a disease, and more specifically refers to a human or non-human primate, a mouse, a mammal such as a dog, a cat, a horse and a cow.

As confirmed in Example 15 of the present invention, the novel compound selenosamphilin A and its derivatives synthesized in the present invention exhibited excellent growth inhibitory activity against human lung cancer and colon cancer cells, And is expected to be useful as a pharmaceutical composition.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

In Examples 1 to 14, selenosamphilin A and derivatives thereof as shown in Fig. 1A are prepared, and the preparation of compounds in Examples 1 to 14 is carried out according to Reaction Scheme 1 (Fig. 2) described above . The synthesis examples of SSM-1 are shown below.

First, 1.424 g of 3-bromo-4-hydroxybenzaldehyde (compound S) was dissolved in ethyl acetoacetate (compound 2) under a pressure of 27.6 mL of a benzene solvent in which 108.1 μL of piperidine and 398.7 μL of acetic acid catalyst (AcOH) 2.0 g and a condensation reaction were conducted for 3.5 hours to synthesize 2.587 g of alpha, beta -unsaturated ethylacetoacetate (Compound 3). 2.568 g of the compound 3 was reacted with 4.364 mL of tributyltin hydride (n-Bu ₃ SnH) in 40 mL of toluene solvent for 1 hour to synthesize 2.241 g of ethyl acetoacetate (Compound 4) substituted at the alpha position Respectively. To 42.233 g of the synthesized compound, 1.109 g of the ethanolic ethoxide base and 911.3 μL of butyl nitrite (n-BuONO) were added to 23 mL of an ethanol solvent and reacted for 18 hours to synthesize 1.482 g of oxime (Compound 5). 1.475 g of the compound 5 was reacted with 92.9 mg of p-toluenesulfonic acid (p-TsOH) catalyst and 24 mL of dichloromethane (CH ₂ Cl ₂ ) solvent in 1.782 mL of dihydropyran (DHP) for 40 minutes to obtain 1.372 g ≪ / RTI > 1.363 g of the synthesized Compound 6 was hydrolyzed in 10.6 mL of an aqueous solution of potassium hydroxide (1N-KOH) in an ethanol solvent for 3.5 hours to synthesize Compound 1 (7,167 g). Then 1.618 g of the compound 7 was dissolved in 32 mL of a 1,4-dioxane solvent to obtain 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ) Was condensed with 987.6 mg of N-hydroxysuccinimide for 21.5 hours to synthesize Compound 8 (1.804 g). To 1.800 g of the compound 8 synthesized above was added 1.103 mL of triethylamine (TEA) base, 15 mL of 1,4-dioxane, and 15 mL of a 2,2'-diseleninediyldiethanamine (2,2'- '-diselanediyldiethanamine) was allowed to react for 2 hours to synthesize 1.338 g of Compound 9, and 1.267 g of Compound 9 was reacted with 14.3 mL of methanol solvent under p-toluenesulfonic acid (p-TsOH) 897.8 mg of nosamphilin A (SSM-1) was synthesized. In the following Examples 2 to 14, compounds were synthesized in the same manner as described above.

In addition, in Examples 15 to 28, selenosamaphyllin A monomer derivatives as shown in Fig. 1B were prepared. In Examples 15 to 28, the preparation of the compounds was carried out according to Reaction Scheme 1 (Fig. 2) will be. Once the pH was adjusted to 8.3 with phosphoric acid buffer (2 mL) and dimethylsulfoxide (6 mL), the synthesized selenosamphafiline A (1,133 mg), phenyl disulfide (44.2 mg) and dithiothreitol (3.2 mg) After dissolving in a solvent, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL x 10), and distilled under reduced pressure. The residue was separated by column chromatography to give a mixture of selenosamphafilin A monomer (SSM- mg).

Nuclear magnetic resonance spectra (1H and 13C NMR) were recorded using a DMSO-d ⁶ , CD ₃ OD, CDCl ₃ solution in an 800-MHz Bruker Avance III HD spectrometer with a 5-mm triple resonance inverse (TCI) CryoProbe spectrometer And the chemical shift is expressed in parts per million (ppm). The resonance pattern is represented by s (singlet), d (doublet), t (triplet), q (quartet), quint Is used. The coupling constant (J) is expressed in hertz (Hz).

Bis (3- (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) propanamide) (SSM-1)

According to the method of Scheme 1 above, SSM-1 was obtained using 3-bromo-4-hydroxybenzaldehyde as a starting material. (Total yield: 23%).

^{1 H-NMR (800MHz, DMSO} -d 6): δ = 11.84 (s, 2H), 10.02 (s, 2H), 8.10 (t, J = 5.88 Hz, 2H), 7.29 (s, 2H), 7.01 ( (d, J = 8.28, 1.16 Hz, 2H), 6.83 (d, J = 8.32 Hz, 2H), 3.45

Example 2 Synthesis of (2E, 2'E) -N, N'- (diselanediylbis (ethane-2,1-diyl)) bis (3- (3-chloro-4-hydroxyphenyl) -2- (hydroxyimino) propanamide) (SSM-2)

According to the method of Scheme 1 above, SSM-2 was obtained using 3-chloro-4-hydroxybenzaldehyde as a starting material. (Total yield: 26%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.06 (dd, J 1 = 36.35Hz, J 2 = 8.04Hz, 8H), 3.85 (s, 4H), 3.47 (t, J = 6.57Hz, 4H ), 2.76 (t, J = 6.78 Hz, 4H), 2.23 (s, 6H) ppm

Example 3 Synthesis of (2E, 2'E) -N, N '- (diselanediylbis (ethane-2,1-diyl)) bis (3- (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) propanamide) (SSM-3)

SSM-3 was obtained by using 3-fluoro-4-hydroxybenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 24%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.25 ~ 7.15 (m, 8H), 3.86 (s, 4H), 3.47 (t, J = 6.6Hz, 4H), 2.76 (t, J = 6.96Hz , 4H), 1.25 (s, 18H) ppm

EXAMPLE 4 Preparation of (2E, 2'E) -N, N '- (diselanediylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3-phenylpropanamide) (SSM-

SSM-4 was obtained using benzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 24%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 7.24 (d, J = 7.68 Hz, 4H), 7.19 (t, J = 7.68 Hz, 4H), 7.12 (t, J = 7.36 Hz, 2H), 4.90 (s, 4H), 3.53 (t, J = 6.92 Hz, 4H), 2.99

Example 5 Synthesis of (2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl)) bis (3- (4-fluorophenyl) -2- (hydroxyimino) propanamide )

SSM-5 was obtained by using 4-fluorobenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 32%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 7.26 (m, 4H), 6.92 (t, J = 8.8 Hz, 4H), 3.87 (s, 4H), 3.54 (t, J = 6.96 Hz, 4H ), 3.01 (t, J = 6.96 Hz, 4 H) ppm

Bis (3- (4-chlorophenyl) -2- (hydroxyimino) propanamide) (SSM-6 )

SSM-6 was obtained using 4-chlorobenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 18%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 7.24 (m, 8H), 3.87 (s, 4H), 3.54 (t, J = 6.96 Hz, 4H), 3.00 (t, J = 6.96 Hz, 4H ) ppm

Example 7 Synthesis of (2E, 2'E) -N, N'- (diselanediylbis (ethane-2,1-diyl) bis (3- (4-bromophenyl) -2- (hydroxyimino) propanamide) )

According to the method of Scheme 1, SSM-7 was obtained using 4-bromobenzaldehyde as a starting material. (Total yield: 28%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 7.35 (d, J = 10.8 Hz, 4H), 7.18 (d, J = 8.48 Hz, 4H), 3.86 (s, 4H), 3.54 (t, J = 6.96 Hz, 4H), 3.00 (t, J = 6.92 Hz, 4 H) ppm

Bis (3- (3,4-difluorophenyl) -2- (hydroxyimino) propanamide) (SSM < RTI ID = 0.0 > -8)

SSM-8 was obtained by using 3,5-difluorobenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 22%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 7.15 (m, 2H), 7.09 (m, 2H), 7.05 (m, 2H), 3.86 (d, J = 5.36 Hz, 4H), 3.56 (t , J = 6.92 Hz, 4H), 3.02 (t, J = 6.96 Hz, 4 H) ppm

Bis (3- (3,4-dichlorophenyl) -2- (hydroxyimino) propanamide) (SSM < RTI ID = 0.0 > -9)

According to the method of Scheme 1, SSM-9 was obtained using 3,4-dichlorobenzaldehyde as a starting material. (Total yield: 25%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 7.41 (d, J = 2.00 Hz, 2H), 7.35 (d, J = 8.24 Hz, 2H), 7.19 (dd, J = 8.32, 2.00, 2H) , 3.87 (s, 4H), 3.55 (t, J = 6.92 Hz, 4H), 3.02 (t, J = 6.92 Hz,

Bis (3- (4-ethoxyphenyl) -2- (hydroxyimino) propanamide) (SSM-10 )

SSM-10 was obtained by using 4-ethoxybenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 27%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 11.77 (s, 2H), 8.06 (t, J = 5.88 Hz, 2H), 7.10 (d, J = 8.64 Hz, 4H), 6.78 (m, 4H ), 3.95 (q, J = 6.99 Hz, 4H), 3.72 (s, 4H), 3.44 (q, J = 6.72 Hz, = 1.28 Hz, 6 H) ppm

Example 11 Synthesis of (2E, 2'E) -N, N '- (diselanediylbis (ethane-2,1-diyl)) bis (3- (4- (benzyloxy) phenyl) -2- (hydroxyimino) propanamide SSM-11)

According to the method of Scheme 1 above, SSM-11 was obtained using 4-benzyloxybenzaldehyde as a starting material. (Total yield: 33%).

^{1 H-NMR (800MHz, DMSO} -d 6): δ = 11.78 (s, 2H), 8.07 (t, J = 5.88 Hz, 2H), 7.41 (d, J = 7.20 Hz, 4H), 7.37 (t, J = 7.60 Hz, 4H), 7.31 (t, J = 7.32 Hz, 2H), 7.11 (d, J = 8.64 Hz, 4H), 6.89 , 3.73 (s, 4H), 3.45 (q, J = 6.69 Hz, 4H)

Example 12 Synthesis of (2E, 2'E) -N, N '- (diselenediylbis (ethane-2,1-diyl) bis (2- (hydroxyimino) -3- (4-nitrophenyl) propanamide) )

SSM-12 was obtained by using 4-nitrobenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 29%).

^{1 H-NMR (800MHz, CD} 3 OD): δ = 8.09 (d, J = 8.72 Hz, 4H), 7.49 (d, J = 8.80 Hz, 4H), 4.02 (s, 4H), 3.55 (t, J = 6.92 Hz, 4H), 3.02 (t, J = 6.92 Hz, 4 H) ppm

Example 13. (2E, 2'E) -N, N'- (diselanediylbis (ethane-2,1-diyl)) bis (3- (4- (tert- butyl) phenyl) -2- (hydroxyimino) propanamide ) ≪ / RTI > (SSM-13)

SSM-13 was obtained by using 4-tert-butoxybenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 19%).

^{1 H-NMR (800MHz, DMSO} -d 6): δ = 11.79 (s, 2H), 8.07 (t, J = 5.88 Hz, 2H), 7.25 (d, J = 8.40 H, 4H), 7.11 (d, J = 8.16 Hz, 4H), 3.77 (s, 4H), 3.45 (q, J = 6.69 Hz, 4H), 3.01

Example 14 Synthesis of (2E, 2'E) -N, N'- (diselanediylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3- (naphthalen- -14)

SSM-14 was obtained by using 4-2'-naphthylbenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 27%).

^{1 H-NMR (800MHz, DMSO} -d 6): δ = 11.93 (s, 1H), 8.15 (t, J = 5.84 Hz, 1H), 7.82 (m, 2H), 7.80 (m, 4H), 7.67 ( J = 6.8 Hz, 4H), 3.01 (t, J = 7.08 (s, 2H), 7.45 Hz, 4 H) ppm

Example 15 Preparation of (E) -3- (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2- (phenylthio) selanyl) ethyl) propanamide

SSM-15 was obtained using selenosamapline A (1) as a starting material according to the method of Scheme X above. (Total yield: 56%).

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.50-7.53 (m, 2H), 7.34 (d, J = 1.8 Hz, 1H), 7.24 (dd, J = 8.3, 6.9 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.04 (dd, J = 8.3, 2.3 Hz, 1H), 6.73 6.9 Hz, 2H), 3.01 (t, J = 6.9 Hz, 2H) ppm

Example 16 Preparation of (E) -3- (3-chloro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2- (phenylthio) selanyl) ethyl) propanamide

SSM-16 was obtained using the selenosamphlin A derivative (2) as a starting material according to the method of Scheme X above. (Total yield: 64%)

^{1 H -NMR (400 MHz, CD} 3 OD): δ 7.50-7.53 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.0, 6.6 Hz, 2H), 7.17 (d, J = 7.3 Hz, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.71 7.1 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H) ppm

Example 17 Preparation of (E) -3- (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2- (phenylthio) selanyl) ethyl) propanamide

SSM-17 was obtained using the selenosamphlin A derivative (3) as a starting material according to the method of Scheme X above. (Total yield: 62%)

^{1 H -NMR (400 MHz, CD} 3 OD): δ 7.50-7.53 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.0, 6.6 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.91 (dd, J = 8.5, 2.1 Hz, 1H), 6.70 7.1 Hz, 2H), 2.98 (t, J = 6.9 Hz, 2H) ppm

Example 18 Preparation of (E) -2- (hydroxyimino) -3-phenyl-N- (2 - (phenylthio) selanyl) ethyl) propanamide (SSM-18)

SSM-18 was obtained using the selenosamphlin A derivative (4) as a starting material according to the method of Scheme X above. (Total yield: 37%).

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.50-7.53 (m, 2H), 7.09-7.27 (m, 8H), 3.87 (d, J = 5.1 Hz, 2H), 3.56 (t, J = 6.9 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H) ppm

Example 19 Preparation of (E) -3- (4-fluorophenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

According to the method of Scheme X above, SSM-19 was obtained using selenosamapline A derivative (5) as a starting material. (Total yield: 51%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.51-7.53 (m, 2H), 7.16-7.27 (m, 5H), 6.91 (t, J = 9.0 Hz, 2H), 3.84 (s, 2H) , 3.57 (t, J = 6.9 Hz, 2H), 3.01 (t, J = 7.1 Hz, 2H) ppm

Example 20 Preparation of (E) -3- (4-chlorophenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

SSM-20 was obtained by using the selenosamphlin A derivative (6) as a starting material according to the method of Scheme X above. (Total yield: 71%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.51-7.53 (m, 2H), 7.17-7.27 (m, 7H), 3.84 (s, 2H), 3.57 (t, J = 6.9 Hz, 2H) , 3.01 (t, J = 6.9 Hz, 2H) ppm

Example 21 Preparation of (E) -3- (4-bromophenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

SSM-21 was obtained using the selenosamphlin A derivative (7) as a starting material according to the method of Scheme X above. (Total yield: 34%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.52 (d, J = 7.4 Hz, 2H), 7.15-7.35 (m, 7H), 3.83 (s, 2H), 3.57 (t, J = 6.9 Hz , 2H), 3.01 (t, J = 6.9 Hz, 2H) ppm

Example 22 Preparation of (E) -3- (3,4-difluorophenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

SSM-22 was obtained by using the selenosamphlin A derivative (8) as a starting material according to the method of Scheme X above. (Total yield: 35%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.51-7.53 (m, 2H), 7.04-7.27 (m, 6H), 3.84 (s, 2H), 3.58 (t, J = 6.9 Hz, 2H) , 3.02 (t, J = 7.1 Hz, 2H) ppm

Preparation of (E) -3- (3,4-dichlorophenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

SSM-23 was obtained using the selenosamphlin A derivative (9) as a starting material according to the method of Scheme X above.

(Total yield: 26%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.50-7.53 (m, 2H), 7.40 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.23-7.27 (m, 2H), 7.16-7.20 (m, 2H), 3.84 (s, 2H), 3.58 (t, J = 6.9 Hz, 2H), 3.02

Example 24 Preparation of (E) -3- (4-ethoxyphenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

SSM-24 was obtained using the selenosamphlin A derivative (10) as a starting material according to the method of Scheme X above. (Total yield: 40%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.51-7.53 (m, 2H), 7.12-7.27 (m, 5H), 6.73 (d, J = 8.7 Hz, 2H), 3.94 (q, J = J = 7.1 Hz, 2H), 3.79 (s, 2H), 3.56 (t, J = 7.1 Hz, 2H), 2.99

Preparation of (E) -3- (4- (benzyloxy) phenyl) -2- (hydroxyimino) -N- (2 - (phenylthio) selanyl) ethyl) propanamide

SSM-25 was obtained using the selenosamphlin A derivative (11) as a starting material according to the method of Scheme X above. (Total yield: 41%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.52 (dt, J = 7.0, 1.4 Hz, 2H), 7.14-7.39 (m, 9H), 6.82 (dd, J = 6.7, 2.1 Hz, 2H) , 4.98 (d, J = 12.4 Hz, 2H), 3.80 (d, J = 4.1 Hz, 2H), 3.55

Example 26 Preparation of (E) -2- (hydroxyimino) -3- (4-nitrophenyl) -N- (2- (phenylthio) selanyl) ethyl) propanamide

SSM-26 was obtained using the selenosamapline A derivative (12) as a starting material according to the method of Scheme X above. (Total yield: 37%)

4.8 (d, J = 2.8 Hz, ¹ H-NMR (400 MHz, CD ₃ OD):? 8.06-8.09 (m, 2H), 7.46-7.53 (m, 4H), 7.17-7.27 2H), 3.58 (t, / = 6.9 Hz, 2H), 3.02 (t,

Example 27 Preparation of (E) -3- (4- (tert-butyl) phenyl) -2- (hydroxyimino) -N- (2- (phenylthio) selanyl) ethyl) propanamide

According to the method of Scheme X, SSM-27 was obtained using selenosamapline A derivative (13) as a starting material. (Total yield: 52%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.51-7.53 (m, 2H), 7.34 (d, J = 2.3 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H), 7.17 (t J = 7.3 Hz, 1H), 7.04 (dd, J = 8.5, 2.1 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 3.75 , 2H), 3.01 (t, J = 6.9 Hz, 2H) ppm

Example 28 Preparation of (E) -2- (hydroxyimino) -3- (naphthalen-2-yl) -N- (2- (phenylthio) selanyl) ethyl) propanamide

SSM-28 was obtained using the selenosamphlin A derivative (14) as a starting material according to the method of Scheme X above. (Total yield: 61%)

^{1 H-NMR (400 MHz,} CD 3 OD): δ 7.67-7.76 (m, 4H), 7.48-7.50 (m, 2H), 7.36-7.41 (m, 3H), 7.19-7.23 (m, 2H), (S, 2H), 3.57 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 1.26

The form of the substituent X of the compounds prepared in Example 1-28 is shown in FIG.

Example 29 Measurement of Inhibitory Effect of Selenosamphilin A Derivative Compound on In vitro Lung Cancer and Colorectal Cancer Cell Lines

In order to confirm the growth inhibitory effects of the samples prepared in Examples 1-28 on human lung cancer and colon cancer cell lines in vitro, experiments were conducted as described below (Lee SK et al 2008) Chem Biol Interact 115: 215-28). Human lung cancer cell line A549 and colon cancer cell line HCT116 were purchased from American Cell Line Bank (ATCC, Manassas, VA, USA).

A549 and HCT116 cells were incubated with 10% fetal bovine serum (FBS, 100 units / mL penicillin, 100 μg / mL streptomycin and 250 ng / mL amphotericin ratio 1 to 2 times per week at 37 ° C, 5% CO ₂ , using a Roswell Park Memorial Institute (RPMI) medium 1640, RPMI 1640) containing amphotericin B All cells were lysed from liquid nitrogen and then used in the experiment after passage over 3 times.

The effects of the compounds obtained in Examples 1 to 28 on cell growth were determined by the sulforhodamine B (SRB) method (Lee et al (1998) Chemico-Biol Interact 115: 215-228).

In detail, the lung cancer and colon cancer cell lines used in the present invention were subcultured in RPMI medium containing 10% FBS, 1% PSF, etc., and 10 μl of a sample dissolved in 10% DMSO in each well of a 96- 190 μl (5 × 10 ⁴ cells / ml) of the cell suspension was added and cultured for 3 days. 190 μl of the cell suspension was added to at least 16 wells and incubated for 30 minutes, and used as a zero-day control before the experiment. The cultured cells were fixed with 10% TCA (trichloroacetic acid), stained with SRB solution, dissolved in 10 mM Tris-base, and then absorbed at 515 nm. 10% DMSO was used as a control, and the cell survival rate according to the treatment of each test substance was measured using the following equation (1).

[Equation 1]

% Survival rate = (OD (0-day)) / (OD (10% DMSO) -OD (0-day)) X 100

When the control group without the sample was taken as 100%, the value of the sample treatment group was expressed as a percentage of the control group, and the treatment of each test substance was calculated by the mean value ± SEM of the double or triple test. The IC ₅₀ value is the concentration of the test substance relative to the 50% survival rate. The effects of the compounds obtained in Examples 1 and 2 on lung cancer and colon cancer cell lines are shown in Tables 2 and 3 below.

The experimental results are shown in Tables 2 and 3. As shown in Tables 2 and 3, SSM-1, SSM-2, SSM-3, SSM-4, SSM- -10, and SSM-12 showed 20-60 times more cancer cell growth inhibitory activity than samaplirin A itself, and it was observed that the inhibitory activity was higher than that of the control compound Etoposide.

compound	A549-LC 50 ([mu] M)	HCT116-LC 50 ([mu] M)
Etoposide	0.42	0.90
Samapillin A	1.76	0.61
SSM-1	0.03	0.01
SSM-2	0.05	0.02
SSM-3	0.06	0.05
SSM-4	0.08	0.09
SSM-5	0.10	0.11
SSM-6	0.25	0.28
SSM-7	0.32	0.30
SSM-8	0.20	0.19
SSM-9	0.28	0.52
SSM-10	0.05	0.07
SSM-11	0.14	0.10
SSM-12	0.09	0.09
SSM-13	0.10	0.13
SSM-14	0.38	0.12

compound	A549-LC 50 ([mu] M)	HCT116-LC 50 ([mu] M)
Etoposide	0.71	0.61
Samapillin A	1.76	0.61
SSM-15	0.10	0.01
SSM-16	0.11	0.09
SSM-17	0.29	0.20
SSM-18	0.28	0.13
SSM-19	0.49	0.33
SSM-20	0.49	0.33
SSM-21	0.51	0.18
SSM-22	0.48	0.31
SSM-23	0.28	0.05
SSM-24	0.33	0.13
SSM-25	0.18	0.08
SSM-26	0.12	0.12
SSM-27	0.11	0.02
SSM-28	0.12	0.02

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

The present invention confirms excellent anticancer activity against various human cancer cells of novel selenosamphilin A and its derivatives and a superior growth inhibitory effect as compared with existing samaplirin A. The novel compounds of the present invention are useful for prevention and treatment of cancer, It is expected that it can be usefully used as a pharmaceutical composition for treatment.

Claims (11)

1. A selenosamphiline A represented by the following formula (1) or (2) and a derivative thereof, an isomer thereof or a pharmaceutically acceptable salt thereof:

   [Chemical Formula 1]

   

   (2)

   

   (In the formulas (1) and (2)

   Wherein X is hydrogen, C _1-5 alkyl,

   

   , 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

   Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

   When R ₃ and R ₄ are connected to each other through a ring,

   

   (n = 1, 2, 3);

   When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl to be)
2. The method according to claim 1,

   X is

   

   Or 2-naphthyl;

   Wherein R ₁ , R ₂ , and R ₅ are each independently hydrogen;

   R ₃ is hydrogen, hydroxy, ethoxy, t-butyl, fluoro, chloro, bromo, nitro, or benzyl;

   Wherein said R < ₄ > is hydrogen, bromo, chloro, or fluoro; selenosamphilin A and its derivatives, isomers or pharmaceutically acceptable salts thereof.
3. The method according to claim 1,

   Wherein said selenosamphilin A and its derivatives are any one selected from the group consisting of the following compounds: selenosamphilin A and its derivatives, isomers thereof or pharmaceutically acceptable salts thereof:

   (3-bromo-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Minino) propanamide);

   (3-chloro-4-hydroxyphenyl) -2- (hydroxyimino (2-ethylhexyl) ) Propane amide);

   (3-fluoro-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Minino) propanamide);

   (2E, 2'E) -N, N '- (diesterediylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3-phenylpropanamide);

   (3- (4-fluorophenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ;

   (2E, 2'E) -N, N '- (dicentylene diylbis (ethane-2,1-diyl)) bis (3- (4-chlorophenyl) -2- (hydroxyimino) propanamide);

   (3- (4-bromophenyl) -2- (hydroxyimino) propanamide) (2E, 2'E) -N, N'- (decenylene diylbis ;

   Bis (3- (3,4-difluorophenyl) -2- (hydroxyimino) propane-2-carboxylic acid (2E, 2'E) Propanamide);

   (2E, 2'E) -N, N '- (diesterediylbis (ethane-2,1-diyl)) bis (3,4-dichlorophenyl) -2- (hydroxyimino) propanamide;

   (3- (4-ethoxyphenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ;

   (4-benzyloxy) phenyl) -2- (hydroxyimino) propanamide (2E, 2'E) -N, N'- (decenylene diylbis );

   (2E, 2'E) -N, N '- (dicentylene diylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3- (4-nitrophenyl) propanamide);

   (3-tert-butylphenyl) -2- (hydroxyimino) propane (2E, 2'E) -N, N'- (dicentylene diylbis amides);

   (2- (hydroxyimino) -3- (naphthalen-2-yl) propanamide) bis (2E, 2'E) -N, N ' ;

   (E) -3- (3-bromo-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (3-Chloro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (3-fluoro-4-hydroxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -2- (hydroxyimino) -3-phenyl-N- (2 - ((phenylthio) cyanyl) ethyl) propanamide (;

   (E) -3- (4-fluorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (4-chlorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (4-bromophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (3,4-difluorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (3,4-Dichlorophenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (4-ethoxyphenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (4- (benzyloxy) phenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -2- (hydroxyimino) -3- (4-nitrophenyl) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide;

   (E) -3- (4- (tert-butyl) phenyl) -2- (hydroxyimino) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide; And

   (E) -2- (hydroxyimino) -3- (naphthalen-2-yl) -N- (2 - ((phenylthio) celanyl) ethyl) propanamide.
4. The method of claim 3,

   Wherein said selenosamphilin A and its derivatives are any one selected from the group consisting of the following compounds: selenosamphilin A and its derivatives, isomers thereof or pharmaceutically acceptable salts thereof:

   (3-bromo-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Minino) propanamide);

   (3-chloro-4-hydroxyphenyl) -2- (hydroxyimino (2-ethylhexyl) ) Propane amide);

   (3-fluoro-4-hydroxyphenyl) -2- (hydroxy-2-ethylhexyl) Minino) propanamide);

   (2E, 2'E) -N, N '- (diesterediylbis (ethane-2,1-diyl)) bis (2- (hydroxyimino) -3-phenylpropanamide);

   (3- (4-ethoxyphenyl) -2- (hydroxyimino) propanamide) bis (2E, 2'E) -N, N ' ; And

   Bis (2- (hydroxyimino) -3- (4-nitrophenyl) propanamide), N, N '- (dicenediylbis (ethane-2,1-diyl)) bis (2E, 2'E).
5. Synthesizing a compound represented by the following formula (4) by adding 2,2'-diseleninediyldiethanamine to a compound represented by the following formula (3); And

   And a step of synthesizing selenosamphilin A represented by the following formula (1) and a derivative thereof by performing a hydrolysis reaction of the compound represented by the formula (4): Selenosamphafiline A represented by the following formula : ≪

   (3)

   

   [Chemical Formula 4]

   

   [Chemical Formula 1]

   

   (In the above formulas (1), (3) and (4)

   Wherein X is hydrogen, C _1-5 alkyl,

   

   , 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

   Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

   When R ₃ and R ₄ are connected to each other through a ring,

   

   (n = 1, 2, 3);

   When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl to be)
6. A method for producing selenosamphyllin A represented by the following formula (2), comprising the step of synthesizing selenosamphilin A represented by the following formula (2) and a derivative thereof by adding dithiothreitol to a compound represented by the following formula Preparation of derivatives:

   [Chemical Formula 1]

   

   (2)

   

   (In the formulas (1) and (2)

   Wherein X is hydrogen, C _1-5 alkyl,

   

   , 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

   Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

   When R ₃ and R ₄ are connected to each other through a ring,

   

   (n = 1, 2, 3);

   When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl to be)
7. The method according to claim 5 or 6,

   X is

   

   Or 2-naphthyl;

   R ₁ , R ₂ , and R ₅ are each independently hydrogen;

   R ₃ is hydrogen, hydroxy, ethoxy, t-butyl, fluoro, chloro, bromo, nitro, or benzyl;

   Wherein R < ₄ > is hydrogen, bromo, chloro, or fluoro.
8. A pharmaceutical composition for preventing or treating cancer, comprising selenosamphilin A and a derivative thereof, an isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.
9. 9. The method of claim 8,

   A pharmaceutical composition for preventing or treating cancer, wherein the cancer is lung cancer or colon cancer.
10. A method for preventing or treating cancer, comprising administering to a subject a pharmaceutical composition comprising selenosamphilin A represented by the following formula (1) or (2) and a derivative thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Way.

    [Chemical Formula 1]

    

    (2)

    

    (In the formulas (1) and (2)

    Wherein X is hydrogen, C _1-5 alkyl,

    

    , 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

    Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

    When R ₃ and R ₄ are connected to each other through a ring,

    

    (n = 1, 2, 3);

    When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl to be)
11. Use of a pharmaceutical composition comprising selenosamphilin A represented by the following formula (1) or (2) and derivatives thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for cancer prevention or treatment.

    [Chemical Formula 1]

    

    (2)

    

    (In the formulas (1) and (2)

    Wherein X is hydrogen, C _1-5 alkyl,

    

    , 1-naphthyl, 2-naphthyl, or 9-anthracenyl;

    Wherein each of R ₁ to R ₅ is independently hydrogen, nitro, halogen, cyan, hydroxy, dimethylamino, methylsulfonylamide, trifluoromethyl, C _1-5 alkyl, C _1-3 alkoxy, Aryl, phenoxy, or benzyloxy;

    When R ₃ and R ₄ are connected to each other through a ring,

    

    (n = 1, 2, 3);

    When any one of R ₁ to R ₅ is phenoxy or benzyl, the substituent of the aromatic ring may be C _1-3 alkyl, C _1-3 alkoxy, halogen, trifluoromethyl, or t-butyl to be)

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