A Psammaplin A derivative and its preparation method and application

Abstract

The present invention discloses a Psammaplin A derivative and its preparation method and application. The structural formula of the Psammaplin A derivative is as shown in formula (I) or (II): wherein R1 is an aromatic ring, a heterocyclic ring or a substituted heterocyclic ring; R2 is H or C 1‑5 Alkyl, R3 is H or C 1‑5 Alkyl; X is H or C 1‑5 Alkyl or C 3‑5 Cycloalkyl or aromatic ring, heterocycle or substituted heterocycle; Y is S or Se or Te, Z is S or Se or Te; n=1 to 5. The Psammaplin A derivative of the present invention has good stability, has significant inhibitory activity on IDH1 / R132H mutant enzyme activity, has no significant effect on IDH1 / WT wild-type enzyme activity, and has inhibitory activity on the proliferation of multiple tumor cell lines, thereby achieving the effect of inhibiting tumor growth, and provides an important reference for the development of anti-tumor drugs.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a Psammaplin A derivative and a preparation method and application thereof. Background Art

[0002] Isocitrate dehydrogenase (IDH) is the rate-limiting enzyme in the tricarboxylic acid cycle, catalyzing the oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-KG) and CO2. At the same time, this reaction catalyzed by IDH is also an important source of intracellular NADPH / NADH (nicotinamide adenine dinucleotide phosphate / nicotinamide adenine dinucleotide) and other substances, playing an important role in maintaining intracellular redox homeostasis. According to the catalytic characteristics, the IDH family can be divided into two categories, namely NAD + IDH3 and NADP dependent + Dependent on IDH1 and IDH2, IDH1 mutation is closely related to the occurrence and development of various tumors.

[0003] Parsons et al. found that about 12% of patients had IDH1 gene mutations from the whole-genome sequencing results of 22 patients with malignant gliomas; Mardis et al. reported that about 8% of patients with acute myeloid leukemia (AML) had IDH1 mutations; up to 20% of bile duct cancer cases had IDH1 mutations; in addition, there were also high IDH mutations in chondrosarcomas. Studies have found that IDH1 mutations mainly occur at the arginine residue (R) at position 132, and more than 80% mutate to histidine (H), that is, IDH1 / R132H mutations, and other types of IDH1 mutations are less common. IDH1 / R132H mutations are an important factor leading to the recurrence of various tumors, and patients with this mutation have an increased risk of death after relapse. Clinically, IDH1 / R132H mutations have become an important indicator for evaluating the poor prognosis of tumors such as brain gliomas, AML, bile duct cancer, and chondrosarcoma.

[0004] IDH1 / R132H mutation is a gain-of-function mutation. IDH1 / R132H mutation can catalyze the conversion of α-KG into 2-hydroxyglutarate (2-HG), significantly increasing the content of 2-HG in tumor tissues. 2-HG is similar in structure to α-KG and can competitively bind to various α-KG-dependent demethylases, inhibiting the activity of these enzymes, thereby inducing abnormal methylation of histones and DNA and promoting tumor development. 2-HG can also inhibit the differentiation of blood cells and promote the occurrence of AML by inhibiting the activity of prolyl hydroxylases; and can inhibit the aerobic glycolysis of leukemia cells by competitively inhibiting the m6A demethylase FTO. These studies have shown that 2-HG plays an important role in the occurrence and development of tumors. Therefore, targeted inhibition of IDH1 / R132H mutant protease activity, thereby inhibiting the production of 2-HG in tumor tissues and restoring the normal differentiation function of cells will provide a new strategy for the treatment of tumors with IDH1 / R132H mutations.

[0005] Currently, the only IDH1 / R132H mutation inhibitor on the market is Ivosidenib (AG-120), which can significantly inhibit the production of 2-HG and effectively promote bone marrow differentiation. It is mainly used clinically to treat relapsed or refractory AML. In 2021, the FDA approved it for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with IDH1 mutations. Given the high incidence of IDH1 mutations in patients with brain gliomas, AML, chondrosarcoma, and cholangiocarcinoma, it is necessary to continue to look for new IDH1 inhibitors to provide lead compounds or lead molecules for drug development in the field of IDH1 inhibitors.

[0006] Psammaplin A is the first bromotyrosine derivative containing a disulfide bond isolated from a sea sponge in 1987. Scientists have studied its biological activity in different aspects. Among the biological activities reported, the most important one may be its inhibitory activity against histone deacetylases (HDACs). Selenium, tellurium and sulfur belong to the oxygen family and are biological isosteres of each other, resulting in many similar properties of sulfur-containing and selenium-containing compounds. Over time, researchers have found that selenium participates in various physiological processes through at least 25 eukaryotic selenoproteins, such as glutathione peroxidase (GPX), iodothyronine deiodinase, selenoprotein P and thioredoxin reductase (TRXR). Psapmmalin A selectively induces hyperacetylation of histones, leading to upregulation of the HDAC target gene gelatin at the transcriptional level. In addition, reduced seleno-Psammaplin A showed stronger inhibitory activity than unreduced one, and cells depleted of glutathione were insensitive to seleno-Psammaplin A, indicating that seleno-Psammaplin A may exert its inhibitory effect on HDAC through reduction in cells. Psapmmalin A has important biological activity and a unique disulfide bond symmetrical structure. The strategy of replacing sulfur atoms in the molecule with selenium and tellurium has certain research value in developing selenium-tellurium active compounds. Summary of the invention

[0007] One object of the present invention is to provide a Psammaplin A derivative.

[0008] Another object of the present invention is to provide a method for preparing Psammaplin A derivatives.

[0009] Another object of the present invention is to provide the use of Psammaplin A derivatives, which can inhibit the IDH1 / R132H mutant enzyme activity and have significant inhibitory activity on cancer cell lines.

[0010] In order to achieve the above-mentioned invention object, the present invention adopts the following technical solutions:

[0011] The present invention provides a Psammaplin A derivative having a structural formula shown in formula (I) or formula (II):

[0012]

[0013] Wherein, R1 is an aromatic ring, a heterocyclic ring or a substituted heterocyclic ring;

[0014] R2 is H or C 1-5 Alkyl, R3 is H or C 1-5 alkyl;

[0015] X is H or C1-5 Alkyl or C 3-5 Cycloalkyl or aromatic ring, heterocyclic ring or substituted heterocyclic ring;

[0016] Y is S or Se or Te, Z is S or Se or Te;

[0017] n=1~5.

[0018] Furthermore, the Psammaplin A derivative has a structural formula shown in formula (I) or formula (II):

[0019]

[0020] wherein R1 is a benzene ring or a substituted benzene ring, 2-furan, 3-furan, 5-bromo-2-furan, 2 or 3-pyrrole, 2 or 3-thiophene, 5-bromo-2-thiophene, 5-chloro-2-thiophene, 4-pyridine, 2 or 4-imidazole, 3-pyrazole, 5-thiazole or 2-bromo-5-thiazole; R2 is H or methyl; R3 is H or methyl;

[0021] X is H, C 1-5 Alkyl, C 3-5 Cycloalkyl, benzene ring or substituted benzene ring, 2-furan, 3-furan, 5-bromo-2-furan, 2 or 3-pyrrole, 2 or 3-thiophene, 5-bromo-2-thiophene, 5-chloro-2-thiophene, 4-pyridine, 2 or 4-imidazole, 3-pyrazole, 5-thiazole or 2-bromo-5-thiazole;

[0022] Y is S or Se or Te; Z is S or Se or Te; n=1 or 2;

[0023] The number of substituents on the substituted benzene ring is 1 to 5, and the substituents are H, -OH, -OCH3, F, Cl, Br, I, -NO2, -CN, 3,5-di-fluoro-benzyloxy, 2-fluoro-benzyloxy, 3-fluoro-benzyloxy, 4-cyano-benzyloxy or 4-trifluoromethyl-benzyloxy.

[0024] Furthermore, the Psammaplin A derivatives are specifically:

[0025] Compound 002: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-2-yl)propionamide);

[0026] Compound 003: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(3-(furan-2-yl)-2-(hydroxyimino)propionamide);

[0027] Compound 004: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(1H-pyrrol-2-yl)propionamide);

[0028] Compound 005: (E)-3-(3-bromo-4-hydroxyphenyl)-N-(2-((1-((E)-3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido)-2-methylpropan-2-yl)disulfanyl)ethyl)-2-(hydroxyimino)propionamide;

[0029] Compound 006: (2E,2'E)-N,N'-(disulfanediylbis(2-methylpropane-2,1-diyl))bis(3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamide);

[0030] Compound 007: (E)-N-(1,2-dithiolan-4-yl)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionamide;

[0031] Compound 008: (E)-3-(3-bromo-4-hydroxyphenyl)-N-(1,2-dithiolan-4-yl)-2-(hydroxyimino)propionamide;

[0032] Compound 009: (E)-3-(4-((4-cyanobenzyl)oxy)phenyl)-N-(1,2-dithiolan-4-yl)-2-(hydroxyimino)propanamide;

[0033] Compound 010: (E)-N-(1,2-dithiolan-4-yl)-3-(3-fluorophenyl)-2-(hydroxyimino)propionamide;

[0034] Compound 011: (2E, 2′E)-N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(3-(5-bromothiophen-2-yl)-2-(hydroxyimino)propylamine);

[0035] Compound 012: (2E, 2′E)-N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(3-(5-chlorothiophen-2-yl)-2-(hydroxyimino)propylamine);

[0036] Compound 013: (2E, 2′E)-N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(3-(5-bromofuran-2-yl)-2-(hydroxyimino)propylamine);

[0037] Compound 014: (2E, 2'E)-N, N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(5-methylfuran-2-yl)propionamide);

[0038] Compound 015: (2E, 2'E)-N, N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-3-yl)propionamide);

[0039] Compound 016: (E)-N-(1,2-dithiocyclohexane-4-yl)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionamide;

[0040] Compound 017: (E)-3-(3-bromo-4-hydroxyphenyl)-N-(1,2-dithiocyclohexane-4-yl)-2-(hydroxyimino)propionamide;

[0041] Compound 018: (E)-N-(1,2-dithiocyclohexane-4-yl)-3-(3-fluorophenyl)-2-(hydroxyimino)propionamide;

[0042] Compound 105: (2E,2'E)-N,N'-(diselenediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-2-yl)propionamide);

[0043] Compound 106: (2E,2'E)-N,N'-(diselenediylbis(ethane-2,1-diyl))bis(3-(furan-2-yl)-2-(hydroxyimino)propionamide);

[0044] Compound 108: (E)-N-(1,2-diselenocyclopentane-4-yl)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionamide;

[0045] Compound 109: (E)-2-(hydroxyimino)-3-(4-hydroxyphenyl)-N-(1-thio-2-selenocyclopentane-4-yl)propanamide;

[0046] Compound 110: (E)-3-(3-bromo-4-hydroxyphenyl)-N-(1,2-diselenocyclopentane-4-yl)-2-(hydroxyimino)propionamide;

[0047] Compound 111: (E)-3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)-N-(1-thio-2-selenocyclopentane-4-yl)propanamide;

[0048] Compound 112: (2E, 2′E)-N, N′-(diselenodiylbis(ethane-2,1-diyl))bis(3-(5-bromothiophen-2-yl)-2-(hydroxyimino)propionamide);

[0049] Compound 113: (2E, 2′E)-N, N′-(diselenediylbis(ethane-2,1-diyl))bis(3-(5-chlorothiophen-2-yl)-2-(hydroxyimino)propionamide);

[0050] Compound 114: (2E, 2′E)-N, N′-(diselenodiylbis(ethane-2,1-diyl))bis(3-(5-bromofuran-2-yl)-2-(hydroxyimino)propionamide);

[0051] Compound 115: (2E, 2'E)-N, N'-(diselendiylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(5-methylfuran-2-yl)propionamide);

[0052] Compound 116: (2E,2′E)-N,N′-(diselenediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-3-yl)propionamide);

[0053] Compound 117: (E)-N-(1,2-diselenocyclohexane-4-yl)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionamide;

[0054] Compound 118: (E)-3-(3-bromo-4-hydroxyphenyl)-N-(1,2-diselenocyclohexane-4-yl)-2-(hydroxyimino)propionamide;

[0055] Compound 119: (E)-N-(1,2-Diselenohexan-4-yl)-3-(3-fluorophenyl)-2-(hydroxyimino)propanamide.

[0056] The present invention also provides a method for preparing the Psammaplin A derivatives, comprising the following steps:

[0057] (1) Synthesis of oxime propionic acid intermediates: Using formaldehyde with different substituents as raw materials, oxime propionic acid intermediates with different substituents are obtained through condensation, reduction, decarboxylation and hydrolysis; wherein the substituent R is

[0058]

[0059] (2) Synthetic amine intermediates 2a, 2b, 2c, 2d, 2e, 2f or 2g, whose structural formulas are:

[0060]

[0061] (3) coupling the oxime propionic acid intermediate described in step (1) with the amine intermediate described in step (2) to obtain compound 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 or 119.

[0062] The present invention also provides the use of the Psammaplin A derivatives in the preparation of mutation inhibitors.

[0063] Furthermore, the mutation is an IDH1 / R132H mutation.

[0064] Furthermore, the mutation inhibitor contains at least one of Psammaplin A derivatives 105, 106, 112, 113, 116, 114 and 115.

[0065] The present invention also provides the use of any one of the Psammaplin A derivatives in the preparation of anti-tumor drugs.

[0066] Furthermore, the drug contains at least one of Psammaplin A derivatives 002, 003, 004, 005, 006, 009, 011, 012, 013, 014, 015, 105, 106, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 and 119.

[0067] Furthermore, the tumor is a tumor caused by IDH1 / R132H mutation, specifically glioma, colon cancer, chondrosarcoma, bile duct carcinoma, and acute myeloid leukemia.

[0068] Compared with the prior art, the advantages and positive effects of the present invention are:

[0069] The present invention designs and synthesizes a series of heterocyclic Psammaplin A derivatives, replaces disulfide bonds with diselenide bonds to obtain compounds with better activity, and synthesizes a series of asymmetric Psammaplin A derivatives by synthesizing amines of five-membered and six-membered cyclic disulfide bonds and diselenide bonds, as well as synthesizing Psammaplin A derivatives with methyl substitution at the ortho-position of the sulfur atom of the disulfide bond. The Psammaplin A derivatives of the present invention improve the stability of the original Psammaplin A and retain its biological activity. These derivatives have significant inhibitory activity on the IDH1 / R132H mutant enzyme activity, but have no significant effect on the IDH1 wild-type enzyme activity, and have inhibitory activity on the proliferation of multiple tumor cell lines, thereby achieving the effect of inhibiting tumor growth, which not only provides a new structure and idea for the design of novel IDH1 / R132H inhibitors, but also provides an important theoretical reference for the development of anti-tumor drugs based on IDH1 / R132H. DETAILED DESCRIPTION

[0070] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0071] Example 1

[0072] This example aims to synthesize the corresponding oxime propionic acid intermediate, using the general method for synthesizing seleno-psammaplin A (Hong S. et al., Tetrahedron Letters, 2012, 53, 4209-4211), using formaldehyde with different substituents as raw materials to prepare oxime propionic acid intermediates with different substituents. When R is a heterocycle, the reaction process is shown in the following formula, the aldehyde group and ethyl acetoacetate are condensed by Knoevenagel, the double bond is reduced by tri-n-butyltin hydride, and nitrosation and decarboxylation are performed to obtain α-ketoximate esters, and finally the ester group is hydrolyzed under alkaline conditions to obtain oxime propionic acid intermediates with different substituents.

[0073]

[0074] Example 2

[0075] This example aims to synthesize a series of amine intermediates containing disulfide and diselenide bonds.

[0076] 1. Preparation of selenocystamine hydrochloride 2a

[0077]

[0078] In a 100mL three-necked flask, dissolve solid NaOH (0.8g, 20mmol) in 10mL water, add selenium powder (1.2g, 15mmol) and hexadecyltrimethylammonium bromide (48mg, 0.15mmol). Weigh NaBH4 (75mg, 2.0mmol) and solid NaOH (0.1g, 0.25mmol), add 5mL water to dissolve under ice bath cooling, add this solution dropwise to the above selenium solution under nitrogen protection, react at room temperature for 1h, then react at 90℃ for half an hour to complete the reaction, and obtain a characteristic brown-red alkaline aqueous solution, which can be used for the next step of diselenide synthesis without treatment.

[0079] NaOH (0.8 g, 20 mmol) was dissolved in 3 mL of water, and 2-chloroethylamine hydrochloride (2.1 g, 15 mmol) was dissolved in 3 mL of water, and then added dropwise to the above solution, and reacted at 40°C for 5 h. After the reaction was completed, the residual selenoic acid was removed by filtration, and the pH of the filtrate was adjusted to acidic with 1 M hydrochloric acid, and the solvent was evaporated under reduced pressure, and methanol was added to dissolve, filtered, and the solvent was evaporated to obtain 1.6 g of crude selenocystamine hydrochloride 2a, with a yield of 43%.

[0080] 2. Preparation of 2,2'-disulfanediylbis(2-methylpropane-1-amine) hydrochloride 2b

[0081]

[0082] 1-Amino-2-methylpropane-2-thiol (500 mg, 2.3 mmol) was dissolved in 30 mL of methanol, and iodine (585 mg, 2.3 mmol) was dissolved in 30 mL of methanol. The mixture was added dropwise to the above solution and stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, and the mixture was diluted with 100 mL of ethyl acetate, washed with 100 mL of water, washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a light yellow solid 2b (330 mg, 69%).

[0083] 3. Preparation of 1,2-dithiocyclopentyl-4-amine hydrochloride 2c

[0084]

[0085] The synthesis of 1,2-cyclopentanedisulfide-4-amine hydrochloride 2c and 2d, 2e, 2f, and 2g can all refer to the synthesis method of Zeisel, L et al. (Zeisel L. et al., Chem. 2022, 8(5), 1493-1517). In the synthesis of 2c, the amino group of serinol is first protected with a Boc protecting group, and then reacted with methanesulfonyl chloride to introduce a methanesulfonyl group, and then reacted with potassium thioacetate to obtain a thioacetyl disubstituted product. The thioester bond is broken by sodium hydroxide treatment, and the dithiol group is oxidized to a ring by iodine or air, and finally the Boc protecting group is removed to obtain the product 2c.

[0086] 4. Preparation of 1,2-diselenocyclopentyl-4-amine hydrochloride 2d

[0087]

[0088] The synthesis of 1,2-cyclopentadienyl diselenide-4-amine hydrochloride 2d is similar to that of 2c, except that potassium selenocyanide is used as the replacement, followed by treatment with sodium hydroxide or potassium hydroxide and oxidation in air to form a cyclic diselenide, and finally the Boc protecting group is removed to obtain 2d.

[0089] 5. Preparation of 1-thio-2-selenocyclopentyl-4-amine hydrochloride 2e

[0090]

[0091] The synthesis of 1-thio-2-selenocyclopentyl-4-amine hydrochloride 2e is to first replace the methylsulfonyl group with 1 equivalent of potassium thioacetate, and then replace the other methylsulfonyl group with potassium selenocyanate. The mixture is also treated with alkali and oxidized with air to form a five-membered seleniumsulfur ring, and 2e can be obtained by removing the Boc protecting group.

[0092] 6. Preparation of 1,2-dithiocyclohexyl-4-amine hydrochloride 2f

[0093]

[0094] 1,2-Dithiocyclohexyl-4-amine hydrochloride 2f is a six-membered cyclic amine. Its synthesis is similar to the above amines. First, aspartic acid is used as the raw material to form an acyl chloride with thionyl chloride, which is then reacted with solvent methanol for double esterification. The amino group is then protected by Boc, and the ester group is reduced to a hydroxyl group with lithium aluminum hydride. The subsequent synthesis is the same as that of 2c.

[0095] 7. Preparation of 2 g of 1,2-diselenocyclohexyl-4-amine hydrochloride

[0096]

[0097] The synthesis of 1,2-diselencyclohexyl-4-amine hydrochloride 2g is the same as 2d, and potassium selenocyanate is also used for substitution to obtain six-membered cyclic diselenamine 2g.

[0098] Example 3

[0099] This example aims to prepare heterocyclic Psammaplin A derivatives. Compounds 002, 003, 004, 011, 012, 013, 014 and 015 can be obtained by coupling different oxime propionic acids prepared in Examples 1 and 2 with cystamine hydrochloride.

[0100]

[0101] i) Preparation of Compound 002:

[0102] 1a (200 mg, 1.1 mmol) was dissolved in 15 mL To the 1,4-dioxane solution, DCC (245 mg, 1.2 mmol) and NHS (137 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature for 2 h. Cystamine hydrochloride (122 mg, 0.55 mmol) and triethylamine (0.5 mL, 2.5 mmol) were added to the reaction solution, and the mixture was stirred at room temperature overnight. The mixture was filtered, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated brine (100 mL), and the organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and column chromatography (DCM:EA=10:1) was performed to obtain a white solid compound (2E, 2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-2-yl)propionamide)002 (115 mg, 0.24 mmol, 44%). 1 H NMR (400MHz, DMSO-d6) δ11.97 (s, 2H), 8.08 (t, J = 5.9Hz, 2H), 7.24 (dd, J = 5.1, 1.3Hz, 2H), 6.85 (dd, J=5.2,3.4Hz,2H),6.78)dd,J=3.3,1.3Hz,2H),3.94(s,4H),3.45–3.34(m,4H),2.86-2.73(m,4H).

[0103] ii) Preparation of Compound 003

[0104] Intermediate 1b and cystamine hydrochloride can be subjected to acid-amine condensation according to the above method to obtain compound 003.

[0105] iii) Preparation of Compound 004

[0106] Intermediate 1c is condensed with cystamine hydrochloride to obtain compound 004. 1 H NMR (400MHz, DMSO-d6) δ11.75(s,2H),10.29(s,2H),8.05(t,J=6.0Hz,2H),6.48(dd,J=2.7,1.3Hz,2H), 5.79(d,J=2.9Hz,2H),5.61(d,J=2.3Hz,2H),3.69(s,4H),3.39(q,J=6.6Hz,4H),2.78(t,J=6.9Hz,4H). 13C NMR (101MHz, DMSO-D6) δ164.02,151.61,125.83,116.85,107.73,105.98,38.73,37.37,22.16.

[0107] iv) Preparation of Compound 011

[0108] Intermediate 1d is condensed with cystamine hydrochloride to obtain compound 011. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,2H),8.10(t,J=5.7Hz,2H),6.95(d,J=3.7Hz,2H),6.6 4(d,J=3.7Hz,2H),3.88(s,4H),3.39(m,J=7.8,6.0,3.0Hz,4H),2.79(t,J=6.9Hz,4H). 13 C NMR (101MHz, DMSO-D6) δ163.24,150.70,140.68,130.20,127.59,109.63,37.38,33.88,24.45.

[0109] v) Preparation of Compound 012

[0110] Intermediate 1e can be condensed with cystamine hydrochloride to obtain compound 012. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,2H),8.09(t,J=5.9Hz,2H),6.84(d,J=3.7Hz,2H),6.66(d ,J=3.7Hz,2H),3.93–3.77(m,4H),3.39(dt,J=7.6,6.1Hz,4H),2.78(t,J=7.6,6.2Hz,4H). 13 C NMR (101MHz, DMSO-D6) δ163.24,150.70,138.01,126.66,126.58,38.73,37.39,24.49.

[0111] ⅵ) Preparation of Compound 013

[0112] Intermediate 1f is condensed with cystamine hydrochloride to obtain compound 013. 1H NMR (400MHz, DMSO-d6) δ12.02(s,2H),8.13(dt,J=6.0,3.0Hz,2H),6.38(d,J=3.3Hz,2 H),6.03(d,J=3.2Hz,2H),3.79(s,4H),3.44–3.36(m,4H),2.79(dd,J=7.6,6.2Hz,4H). 13 C NMR (101MHz, DMSO-D6) δ163.29,152.80,152.77,149.07,119.28,112.99,109.89,38.73,37.39,22.93.

[0113] ⅶ) Preparation of Compound 014

[0114] The intermediate 1g is condensed with cystamine hydrochloride to obtain compound 014. 1 H NMR (400MHz, DMSO-d6) δ11.88(s,2H),8.08(t,J=5.8Hz,2H),5.86(dd,J=3.0,1.3Hz,2H),5.79( d,J=3.0Hz,2H),3.74(s,4H),3.39(ddt,J=7.7,6.0,3.0Hz,4H),2.86–2.73(t,4H),2.13(s,6H). 13 C NMR (101MHz, DMSO-D6) δ163.50,150.29,149.87,148.34,107.31,106.96,38.69,37.42,22.78,13.78.

[0115] VIII) Preparation of Compound 015

[0116] Intermediate 1h is condensed with cystamine hydrochloride to obtain compound 015. 1 H NMR (400MHz, DMSO-d6) δ11.81(s,2H),8.05(t,J=5.8Hz,2H),7.36(dd,J=4.9,2.9Hz,2H),7.06(dd,J=2.9, 1.3Hz, 2H), 6.90 (dd, J=4.9, 1.3Hz, 2H), 3.76 (s, 4H), 3.39 (ddt, J=7.8, 6.0, 3.0Hz, 4H), 2.84–2.74 (t, 4H). 13 C NMR (101MHz, DMSO-D6) δ163.78,152.01,136.67,136.64,129.18,126.21,122.37,38.68,37.44,24.39.

[0117] Example 4

[0118] This example aims to prepare seleno-Psammaplin A derivatives. Compounds 105, 106, 112, 113, 114, 115 and 116 can be obtained by coupling different oxime propionic acids prepared in Examples 1 and 2 with selenocystamine hydrochloride (2a).

[0119]

[0120] i) Preparation of Compound 105

[0121] Compound 105 can be prepared by condensing 1a with the prepared selenocystamine hydrochloride 2a.

[0122] ii) Preparation of Compound 106

[0123] Compound 106 can be prepared by condensing 1b with the prepared selenocystamine hydrochloride 2a. 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.12(t,J=5.8Hz,2H),7.43(d,J=1.7Hz,1H),6.28(dd,J=3 .2,1.9Hz,2H),5.95(d,J=3.2Hz,2H),3.80(s,3H),3.43(q,J=6.7Hz,4H),2.98(t,J=7.1Hz,3H). 13 C NMR (101MHz, DMSO-D6) δ163.37,150.28,149.78,141.91,111.08,106.69,28.65,22.75.

[0124] iii) Preparation of Compound 112

[0125] Compound 112 can be prepared by condensing 1d with the prepared selenocystamine hydrochloride 2a. 1 H NMR (400MHz, DMSO-d6) δ12.07(s,2H),8.12(td,J=5.9,1.7Hz,2H),6.95(d,J=3.7Hz,2H ),6.64(d,J=3.7Hz,2H),3.88(s,4H),3.43(m,J=6.7,3.0Hz,4H),2.98(t,J=7.1Hz,4H). 13 C NMR (101MHz, DMSO-D6)163.13,150.69,140.69,130.20,127.59,109.63,33.87,28.62,24.45.

[0126] iv) Preparation of Compound 113

[0127] Intermediate 1e and selenocystamine hydrochloride 2a can be subjected to acid-amine condensation according to the above method to obtain compound 113. 1 HNMR(400MHz,DMSO-d6)δ12.08(s,2H),8.12(t,J=5.9Hz,2H),6.84(d,J=3.8Hz,2H),6.6 6(d,J=3.7Hz,2H),3.90–3.82(m,4H),3.43(q,J=7.4,6.6Hz,4H),2.98(t,J=7.1Hz,4H). 13 C NMR (101MHz, DMSO-D6) δ163.14,157.23,150.74,138.02,126.65,126.58,33.88,28.63,24.50.

[0128] v) Preparation of Compound 114

[0129] Intermediate 1f and selenocystamine hydrochloride 2a can be subjected to acid-amine condensation according to the above method to obtain compound 114. 1 HNMR(400MHz,DMSO-d6)δ12.01(s,2H),8.15(t,J=5.7Hz,2H),6.38(d,J=3.3Hz,2H),6 .03(d,J=3.2Hz,2H),3.79(s,4H),3.43(tt,J=6.6,3.0Hz,4H),2.99(t,J=7.1Hz,4H). 13 CNMR(101MHz,DMSO-D6)δ163.19,152.80,149.07,119.28,112.98,109.90,33.88,28.64,25.00.

[0130] ⅵ) Preparation of Compound 115

[0131] Intermediate 1g and selenocystamine hydrochloride 2a can be subjected to acid-amine condensation according to the above method to obtain compound 115. 1 HNMR(400MHz,DMSO-d6)δ11.89(s,1H),8.11(t,J=5.9Hz,1H),5.86(d,J=3.0Hz,1H ), 5.79 (d, J = 3.0Hz, 1H), 3.74 (s, 2H), 3.42 (q, J = 6.6Hz, 2H), 2.98 (t, J = 7.1Hz, 2H). 13C NMR (101MHz, DMSO-D6) δ163.43,150.29,149.95,148.34,107.32,106.96,28.69,22.78,13.78.

[0132] ⅶ) Preparation of Compound 116

[0133] Intermediate 1h and selenocystamine hydrochloride 2a can be subjected to acid-amine condensation according to the above method to obtain compound 116. 1 HNMR(400MHz,DMSO-d6)δ11.80(s,1H),8.07(d,J=1.4Hz,1H),7.37(s,1H),7.06(dd,J=3.0,1.3Hz ,2H),6.90(dd,J=4.9,1.3Hz,2H),3.76(s,4H),3.42(tt,J=6.7,3.0Hz,4H),2.98(t,J=7.1Hz,4H). 13 C NMR (101MHz, DMSO-D6) δ163.19,152.80,119.28,112.98,109.90,33.88,28.64,25.00.

[0134] Example 5

[0135] This example aims to prepare a Psammaplin A derivative with a methyl group substituted at the α-position of the sulfur atom to increase the steric hindrance of the disulfide bond and improve the stability of Psammaplin A.

[0136] i) Preparation of Compound 005:

[0137]

[0138] 1. Preparation of 2-(pyridin-2-yldisulfanyl)ethylamine-1-amine a

[0139] Under nitrogen protection, cysteamine hydrochloride (1.0 g, 8.8 mmol) in methanol (12 mL) was added dropwise to a solution of 2,2'-disulfide dipyridine (2.9 g, 13.2 mmol) in methanol (32 mL). The yellow mixture was stirred at room temperature for 2.5 h, the solvent was evaporated in vacuo, and the desired compound a was obtained by purification by column chromatography (DCM: MeOH = 10: 1) as a light yellow solid (1.5 g, 8.1 mmol, 90%).

[0140] 2. Preparation of (E)-3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)-N-(2-(pyridin-2-yldisulfanyl) b

[0141] 1k (500 mg, 1.8 mmol) was dissolved in 15 mL of 1,4-dioxane solution, and DCC (413 mg, 2 mmol) and NHS (230 mg, 2 mmol) were added. The mixture was stirred at room temperature for 2 h. A (335 mg, 1.8 mmol) and triethylamine (0.8 mL, 5.4 mmol) were added to the reaction solution, and the mixture was stirred at room temperature overnight. The mixture was filtered, and water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM: MeOH = 50: 1) to obtain b (482 mg, 1.1 mmol, 60%).

[0142] 3. Preparation of (E)-N-(2-((1-amino-2-methylpropan-2-yl)disulfanyl)ethyl)-3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamide c

[0143] To a solution of b (482 mg, 1.1 mmol) in DMF (20 mL) was added dropwise a methanol solution (5 mL) of 1-amino-2-methylpropane-2-thiol (250 mg, 1.1 mmol) and stirred at room temperature for 1 h. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM:MeOH=8:1) to obtain a light yellow solid c (147 mg, 0.3 mmol, 31%).

[0144] 4. Preparation of Compound 005

[0145] The synthesis of compound 005 was carried out by acid-amine condensation of acid intermediate 1k and prepared amine intermediate c, with a yield of 67%. The NMR data are as follows:

[0146] 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),11.81(s,1H),10.00(d,J=3.2Hz,2H),8.05(t,J=5.9Hz,1H),7.79(t,J=6.4Hz,1H),7.25(s,1H),7.0 3–6.91(m,2H),6.79(d,J=8.3Hz,2H),3.65(d,J=9.1Hz,4H),3.40–3.31(m,2H),3.28(d,J=6.5Hz,2H),2.76(t,J=6.9Hz,2H),1.13(s,6H). 13C NMR (101MHz, DMSO-D6) δ164.02,163.77,152.91,152.88,152.41,152.34,133.33,129. 69,129.31,116.67,116.58,109.41,109.38,51.87,47.62,38.95,38.79,28.23,25.66.

[0147] ii) Preparation of Compound 006

[0148]

[0149] The preparation method of compound 006 is the same as the synthesis method of 002. Intermediate 1k and amine 2b are condensed to synthesize compound 006. The NMR data are as follows:

[0150] 1 H NMR (400MHz, DMSO-d6) δ11.90(s,2H),10.00(s,2H),7.78(t,J=6.5Hz,2H),7.24(d,J=2.1Hz,2H),6 .97(dd,J=8.4,2.1Hz,2H),6.79(d,J=8.3Hz,2H),3.66(s,4H),3.22(d,J=6.5Hz,4H),1.12(s,12H). 13 C NMR (101MHz, DMSO-D6) δ163.97,152.91,152.38,133.31,129.68,129.19,116.68,109.41,50.63,48.38,28.25,26.11.

[0151] Example 6

[0152] This embodiment aims to introduce a five-membered cyclic selenium sulfide-substituted chain diamine into the structure of the Psammaplin A analog, so that the original dimer is transformed into a monomer while retaining the disulfide bond and diselenide bond structures.

[0153] i) Preparation of Compound 007:

[0154]

[0155] Compound 007 can be prepared by condensing intermediate 11 with amine 2c. 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.17(s,1H),7.77(d,J=7.9Hz,1H),6.96(d,J =8.5Hz,2H),6.65–6.42(m,2H),4.87–4.76(m,1H),3.64(s,2H),3.25–3.06(m,4H). 13 C NMR (101MHz, DMSO-D6) δ163.36,156.19,152.41,130.33,127.11,115.58,115.49,55.93,43.34,33.88,28.47,25.00.

[0156] ii) Preparation of Compound 108:

[0157] The intermediate 11 is condensed with amine 2d to give compound 108. 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),9.16(s,1H),7.55(d,J=8.3Hz,1H),6.97(d,J=8.3Hz,2H),6.60(d,J =8.0Hz,2H),5.01(mt,J=3.0Hz,1H),3.65(s,2H),3.41(ddd,J=33.6,10.0,4.4Hz,2H),3.18–3.00(m,2H).

[0158] iii) Preparation of Compound 109:

[0159] Compound 109 can be prepared by condensing intermediate 11 with amine 2e.

[0160] iv) Preparation of Compound 008:

[0161]

[0162] Compound 008 can be prepared by condensing intermediate 1k with amine 2c. 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.03(s,1H),7.82(d,J=7.8Hz,1H),7.26(s,1H),6.99( d,J=8.4Hz,1H),6.80(d,J=8.0Hz,1H),4.83(d,J=4.9Hz,1H),3.65(s,2H),3.27–3.09(m,4H).

[0163] v) Preparation of Compound 110:

[0164] Intermediate 1b can be condensed with amine 2d to give compound 110.

[0165] vi) Preparation of Compound 111:

[0166] Intermediate 1b can be reacted with amine 2e to give compound 111.

[0167] vii) Preparation of Compound 009:

[0168]

[0169] Intermediate 1i is reacted with amine 2e to obtain compound 009. 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),7.82(d,J=8.0Hz,2H),7.78(d,J=8.1Hz,1H),7.58(d,J=8.0Hz,2H),7.10(d,J=8.3H z,2H),6.87(d,J=8.2Hz,2H),5.14(s,2H),4.82(dt,J=8.8,4.7Hz,1H),3.70(s,2H),3.17(ddd,J=40.0,11.4,4.8Hz,4H). 13 C NMR (101MHz, DMSO-D6) δ163.29,156.89,152.09,143.62,132.96,130.45,129.58,128.53,119.32,115.21,110.93,68.68,55.95,43.34,28.53.

[0170] viii) Preparation of Compound 010:

[0171] Intermediate 1j is reacted with amine 2e to obtain compound 010. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),7.86(d,J=7.8Hz,1H),7.27(tdd,J=7.7,6.3,1.3Hz,1H ),7.07–6.84(m,3H),4.83(dddd,J=9.8,8.1,5.5,4.2Hz,1H),3.79(s,2H),3.28–3.01(m,4H). 13C NMR (101MHz, DMSO-D6) δ163.82,163.18,161.40,151.33,139.93,130.78,130.7 0,125.41,116.08,115.87,113.66,113.46,56.01,55.90,43.33,43.30,29.25.

[0172] Example 7

[0173] This embodiment aims to introduce a six-membered cyclic selenium sulfide-substituted chain diamine into the structure of the Psammaplin A analog, so that the original dimer is transformed into a monomer while retaining the disulfide bond and diselenide bond structures.

[0174] i) Preparation of Compound 016:

[0175]

[0176] Intermediate 1a is reacted with amine 2f to obtain compound 016. 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.15(s,1H),7.99(d,J=8.5Hz,1H),6.96(d,J=8.4Hz,2H),6.59(dd, J=8.4,1.6Hz,2H),3.89(s,1H),3.64(s,2H),3.07–2.86(m,2H),2.77(d,J=8.9Hz,2H),2.06–1.75(m,2H).

[0177] ii) Preparation of Compound 117:

[0178] Intermediate 1a can be condensed with amine 2g to obtain compound 117. 1 H NMR (400MHz, DMSO-d6) δ11.73(s,1H),9.15(s,1H),7.99(d,J=8.5Hz,1H),6.96(d,J=8.1Hz,2H),6.59(d,J =8.2Hz,1H),3.95(m,J=9.6Hz,1H),3.64(s,2H),3.27–3.05(m,2H),3.02–2.85(m,2H),2.12–1.85(m,2H).

[0179] iii) Preparation of Compound 017:

[0180]

[0181] Intermediate 1k is reacted with amine 2f to give compound 017.1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),10.02(s,1H),8.05(d,J=8.4Hz,1H),7.25(d,J=2.1Hz,1H),6.98(dd,J=8.4,2.2Hz ,1H),6.79(dd,J=8.3,2.4Hz,1H),3.90(s,1H),3.65(s,2H),3.07–2.87(m,2H),2.77(d,J=8.8Hz,2H),2.04–1.72(m,2H).

[0182] iv) Preparation of Compound 118:

[0183] Intermediate 1k can be condensed with amine 2g to obtain compound 118. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),10.02(s,1H),8.04(d,J=8.7Hz,1H),7.26(s,1H),6.98(d,J=8.4Hz,1H),6.80 (d,J=8.3Hz,1H),3.95(m,J=10.0Hz,1H),3.65(s,2H),3.13(m,J=12.0Hz,2H),3.02–2.86(m,2H),2.18–1.85(m,2H).

[0184] v) Preparation of Compound 018:

[0185]

[0186] Intermediate 1j is reacted with amine 2f to obtain compound 018.

[0187] vi) Preparation of Compound 119:

[0188] Intermediate 1j is reacted with amine 2g to give compound 119. 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.08(d,J=8.3Hz,1H),7.27(q,J=7.5Hz,1H),6.98(dd,J=16.5,8.6H z,3H),3.96(m,J=10.0,9.5Hz,1H),3.79(s,2H),3.28–3.08(m,2H),3.03–2.89(m,2H),2.14–1.84(m,2H).

[0189] Example 8: Effects of compounds on IDH1 / R132H mutation and IDH1 / WT enzyme activity

[0190] Experimental methods:

[0191] Using M- The total protein of U-87 cells overexpressing IDH1 / R132H or IDH1 / WT was extracted with protein lysate, and the protein content was detected by BCA method. IDH1 / R132H activity detection: The protein lysate was incubated with a series of concentrations of compounds for 30 minutes, and then added to 200 μL of reaction solution (100 mM Tris-HCl [pH 7.5], 1.3 mM MnCl2, 0.01 mM NADPH, 0.5 mM α-ketoglutarate) and incubated for 2 hours. The consumption of NADPH was detected at 340 nm using an ELISA reader, and 3 replicates were performed in each well. GraphPad Prism 7 was used to calculate the IC of the series of compounds against IDH1 / R132H enzyme activity 50 value.

[0192] Experimental results:

[0193] Table 1 IC50 values ​​(μM) of some compounds against IDH1 / R132H and IDH1 / WT enzyme activities

[0194]

[0195]

[0196]

[0197] As shown in Table 1, the compounds of the present invention showed different levels of inhibitory activity against IDH1 / R132H mutant enzyme activity, among which JYK-105, JYK-106 and JYK-115 had more prominent inhibitory activity against IDH1 / R132H enzyme activity, but had no obvious inhibitory activity against IDH1 / WT enzyme activity, showing strong selectivity. The IC50 of the inhibitory activity of positive drugs AG-120 and AGI-5198 against IDH1 / R132H mutant enzyme activity were 0.0834 and 0.0647 μM, respectively, and the IC50 of the inhibitory activity against IDH1 / WT enzyme activity were both greater than >10 μM.

[0198] Example 9: Determination of the inhibitory activity of the compounds on the proliferation of malignant glioma cell lines U87-IDH1 / R132H and U87-IDH1 / WT

[0199] Experimental methods:

[0200] 10,000 IDH1 / WT or IDH1 / R132H overexpressing U-87 cells were resuspended in 100 μL culture medium and seeded in 96-well plates. They were incubated in a 37°C carbon dioxide incubator for 24 hours to adhere to the wall. The next day, different concentrations of compounds were diluted in 100 μL culture medium and added to the cells, and incubated for 48 hours. The MTT method was used to detect the effects of the compounds on the proliferation of the two cell types. GraphPad Prism 7 was used to calculate the IC50 values ​​of the compounds against cell proliferation. The experiment was repeated 3 times.

[0201] Experimental results:

[0202] Table 2 IC50 values ​​(μM) of some compounds for inhibiting proliferation of IDH1 mutant and wild-type cells

[0203] Compound No. U-87 IDH1 / R132H cells U-87 IDH1 / WT cells 105 19.63 19.2 106 15.9 75.93 AG120 >40 >40 AG15198 >40 >40

[0204] The results are shown in Table 2. The compounds JYK-105 and JYK-106 of the present invention can both show certain inhibitory activity on cell proliferation after acting on the two types of cells for 48 hours.

[0205] Example 10: Determination of the proliferation inhibitory activity of compounds on other tumor cell lines

[0206] Experimental methods:

[0207] Using the same method as in Test Example 2, the present invention also determined the proliferation inhibitory activity of the compound on human colon cancer cell HCT116 (40 μM), human glioma cell U-87 IDH1 / R132H (40 μM), human leukemia cell MV4-11 (5 μM) and other cells for 72 hours.

[0208] Table 3 Inhibition rate of some compounds on proliferation of various tumor cells

[0209]

[0210]

[0211] The results are shown in Table 3. The compounds of the present invention showed a certain inhibitory effect on the proliferation of HCT116, U87-IDH1 / R132H and MV4-11 cells.

[0212] According to the knowledge of those skilled in the art, brain glioma, AML, bile duct cancer, chondrosarcoma and other tumors all have different degrees of IDH1 / R132H mutations, and are important indicators of poor prognosis of the above-related diseases. The present invention has proved through experiments that the compounds of the present invention have an inhibitory effect on the IDH1 / R132H enzyme, so the compounds provided by the present invention can be used as IDH1 / R132H inhibitors for the treatment of brain glioma, AML, bile duct cancer, chondrosarcoma and other tumors.

[0213] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for a person skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to replace some of the technical features therein by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions claimed to be protected by the present invention.

Claims

1. A Psammaplin A derivative, characterized in that: The Psammaplin A derivatives are specifically: Compound 002: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-2-yl)propionamide); Compound 003: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(3-(furan-2-yl)-2-(hydroxyimino)propionamide); Compound 004: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(1H-pyrrol-2-yl)propionamide); Compound 011: (2E,2′E)-N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(3-(5-bromothiophen-2-yl)-2-(hydroxyimino)propylamine); Compound 012: (2E,2′E)-N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(3-(5-chlorothiophen-2-yl)-2-(hydroxyimino)propylamine); Compound 013: (2E,2′E)-N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(3-(5-bromofuran-2-yl)-2-(hydroxyimino)propylamine); Compound 014: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(5-methylfuran-2-yl)propionamide); Compound 015: (2E,2'E)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-3-yl)propionamide); Compound 105: (2E,2'E)-N,N'-(diselenediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-2-yl)propionamide); Compound 106: (2E,2'E)-N,N'-(diselendiylbis(ethane-2,1-diyl))bis(3-(furan-2-yl)-2-(hydroxyimino)propionamide); Compound 112: (2E,2′E)-N,N′-(diselendiylbis(ethane-2,1-diyl))bis(3-(5-bromothiophen-2-yl)-2-(hydroxyimino)propionamide); Compound 113: (2E,2′E)-N,N′-(diselenediylbis(ethane-2,1-diyl))bis(3-(5-chlorothiophen-2-yl)-2-(hydroxyimino)propionamide); Compound 114: (2E,2′E)-N,N′-(diselenodiylbis(ethane-2,1-diyl))bis(3-(5-bromofuran-2-yl)-2-(hydroxyimino)propionamide); Compound 115: (2E,2'E)-N,N'-(diselendiylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(5-methylfuran-2-yl)propionamide); Compound 116: (2E,2′E)-N,N′-(Diselenediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-3-yl)propionamide).

2. Use of the Psammaplin A derivative according to claim 1 in the preparation of a mutation inhibitor, characterized in that: The mutation is an IDH1 / R132H mutation.

3. Use of the Psammaplin A derivative according to claim 2 in the preparation of a mutation inhibitor, characterized in that: The mutation inhibitor contains at least one of the following compounds; (2E,2'E)-N,N'-(diselenodiylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-2-yl)propionamide); (2E,2'E)-N,N'-(diselenodiylbis(ethane-2,1-diyl))bis(3-(furan-2-yl)-2-(hydroxyimino)propionamide); (2E,2′E)-N,N′-(diselendiylbis(ethane-2,1-diyl))bis(3-(5-bromothiophen-2-yl)-2-(hydroxyimino)propionamide); (2E,2′E)-N,N′-(diselendiylbis(ethane-2,1-diyl))bis(3-(5-chlorothien-2-yl)-2-(hydroxyimino)propionamide); (2E,2′E)-N,N′-(diselenodiylbis(ethane-2,1-diyl))bis(3-(5-bromofuran-2-yl)-2-(hydroxyimino)propionamide); (2E,2'E)-N,N'-(diselendiylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(5-methylfuran-2-yl)propionamide); (2E,2'E)-N,N'-(Diselenediylbis(ethane-2,1-diyl))bis(2-(hydroxyimino)-3-(thiophen-3-yl)propionamide).

4. Use of the Psammaplin A derivative according to claim 1 in the preparation of anti-tumor drugs.

5. The use of the Psammaplin A derivative according to claim 4 in the preparation of anti-tumor drugs, characterized in that: The tumor is a tumor caused by IDH1 / R132H mutation, specifically glioma, colon cancer, chondrosarcoma, bile duct cancer, and acute myeloid leukemia.

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