WO2020170022A1 - Derivatives of aziridine-2-carboxamide as inhibitors of thioredoxin reductase, their synthesis, anti-cancer and anti-metastatic effect - Google Patents
Derivatives of aziridine-2-carboxamide as inhibitors of thioredoxin reductase, their synthesis, anti-cancer and anti-metastatic effect Download PDFInfo
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- the invention discloses novel therapeutic compounds, namely 1-acyl derivatives of aziridine-2-carboxamide and their analogues that exhibit anti-cancer and/or antiproliferative, and/or anti-metastatic properties and/or inhibition of thioredoxin reductase, as well as the application of these compounds in cancer treatment and/or prevention.
- This invention relates to the discovery of novel anti-tumor agents with the mechanism of action based on, but are not limited to, the inhibition of thioredoxin reductase, with the potential application for the treatment of tumors as connective tissue tumors, neuroblastoma and breast tumors, also may include cancers like bladder, bone, brain, central and periph-eral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva; as well as inherited cancers selected from retinom-blastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkins disease, chronic and acute myeloid leukaemia, acute lymphoblastic leukemia
- Human connective tissue fibrosarcoma has been already described in 1972 [1], and it is considered to affect humans in the age between 30 and 40 years.
- Human neuroblastoma is neuroendocrine tumor which is formed in the elements of sympathetic nervous system and affect children event at the age from 2 year.
- Human breast adenocarcinoma [3] is a type of cancer which develops mainly in breast tissues, and usually, but not always, affects women.
- TrxR Thioredoxin reductases
- ROS reactive oxygen species
- TrxRl is found in cytoplasm [5]
- TrxR3 is expressed in testis [7].
- approaches aiming to interfere with redox signaling events and disable major antioxidant systems like Trx system in the presence of ROS inducers represent promising new tactic for the development of novel anticancer agents.
- TrxRl novel anti-cancer agents
- At least one compound with TrxR inhibitory activity which is chosen from the group of compounds of the Formula I
- R represents, but are not limited to, hydrogen, linear, branched and substituted alkyl groups, including alkenyl, alkynyl, substituted and unsubstituted aryl and hetaryl groups.
- Formula I also includes enantiomers, diastereomers, tautomers and/or pharmaceutically acceptable salts, hydrates and solvates. [012] Specific compounds of the Formula I within the present invention, but are not limited to:
- compounds of this invention can contain chiral centres and compounds can be prepared in optically active (enantiomers and/or diastereomers) or racemic form.
- Compounds of this invention can also be any racemates, optically active compounds, tautomers or stereoisomeric forms of the compounds of present invention, that express above listed properties.
- the compounds of the Formula I can be in the form of a pharmaceutically acceptable salt or solvate.
- pharmaceutically acceptable refers here to the therapeutically active non-toxic salt forms, which the compounds of the Formula I are able to form.
- salts can be obtained by triturating basic forms of compounds of the Formula I with acids, for example, inorganic acids as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acids as acetic acid, propionic acid, hydroxyaceto acetic acid, 2-hydroxypropionic acid, oxopropionic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, phenylsulfonic acid, 4-methylphenylsulfonic acid, 2-hydroxybenzoic acid etc. Salts of the compounds of the Formula I can be converted back to free base form by trituration with base.
- acids for example, inorganic acids as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc.
- organic acids as acetic acid, propionic acid, hydroxyaceto acetic acid, 2-hydroxypropionic acid, o
- the target compounds 1-1 - 1-7 were synthesized by treatment of aziridine-2- carboxamide 1 with corresponding carboxylates in the presence of base (Scheme 1).
- Aziridine-2-carboxamide (1) (2.32 mmol) was suspended in MeCN (5 mL), NEt3 (2.32 mmol) was added, RM was cooled to 0 °C, corresponding acyl chloride (2.32 mmol) was added. RM was stirred at RT for 24 h, filtered. Filtrate was evaporated, acetone was added to the residue, precipitate was filtered, and filtrate was evaporated. The product was recrystallized from acetonitrile.
- Optical density (OD) determine using multichannel spectrophotometer ( Tecan multiplate reader InfinitelOO) at 540 nm. Then calculate IC50 - the concentration of tested compound providing the death of 50 % of cells by the usage of program Graph Pad Prism® 3.0. Table 1. In vitro cytotoxicity of compounds of the Formula I on monolayer tumor cell lines HT-1080 (Human connective tissue fibrosarcoma), SH-SY5Y (Human neuroblastoma) and MCF-7 (Human breast adenocarcinoma).
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Abstract
This invention relates to the novel potentially therapeutic compounds that contain l-acyl derivatives of aziridine-2-carboxamide and their analogues with the anticancer and/or antiproliferative, and/or antimetastatic properties and/or those with the thioredoxin reductase inhibitory activity as well as the application of these compounds in cancer treatment and/or prophylaxis and in the treatment of such diseases where thioredoxin reductase inhibition is crucial.
Description
Derivatives of aziridine-2-carboxamide as inhibitors of thioredoxin reductase, their synthesis, anti-cancer and anti-metastatic effect
FIELD OF THE INVENTION
[001] The invention discloses novel therapeutic compounds, namely 1-acyl derivatives of aziridine-2-carboxamide and their analogues that exhibit anti-cancer and/or antiproliferative, and/or anti-metastatic properties and/or inhibition of thioredoxin reductase, as well as the application of these compounds in cancer treatment and/or prevention.
BACKGROUND OF THE INVENTION
[002] This invention relates to the discovery of novel anti-tumor agents with the mechanism of action based on, but are not limited to, the inhibition of thioredoxin reductase, with the potential application for the treatment of tumors as connective tissue tumors, neuroblastoma and breast tumors, also may include cancers like bladder, bone, brain, central and periph-eral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva; as well as inherited cancers selected from retinom-blastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkins disease, chronic and acute myeloid leukaemia, acute lymphoblastic leukemia, Hodgkins disease, multi- pie myeloma and T-cell lymphoma; myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes. Human connective tissue fibrosarcoma has been already described in 1972 [1], and it is considered to affect humans in the age between 30 and 40 years. Human neuroblastoma is neuroendocrine tumor which is formed in the elements of sympathetic nervous system and affect children event at the age from 2 year. [2] Human breast adenocarcinoma [3] is a type of cancer which develops mainly in breast tissues, and usually, but not always, affects women.
[003] Thioredoxin reductases (TrxR, EC 1.8.1.9) are the only known enzymes that reduce the oxidized form of thioredoxin (Trx). Trx plays an important role in the maintenance of redox homeostasis in cells including the interception of reactive oxygen species (ROS). Thus, Trx is responsible for cell survival and growth but in the case of cancer Trx is also responsible for oncogenesis [4] .
[004] In mammals three TrxR isoforms are present - TrxRl, TrxR2 and TrxR3. TrxRl is found in cytoplasm [5], TrxR2 - in mitochondria [6], TrxR3 is expressed in testis [7].
[005] Since the dependency of cancer cells on the antioxidant system is a specific vulnerability, then approaches aiming to interfere with redox signaling events and disable major antioxidant systems like Trx system in the presence of ROS inducers represent promising new tactic for the development of novel anticancer agents. [8]
[006] Although the inhibitors of TrxRl are defined as novel anti-cancer agents [9], there are no anti-cancer drugs in clinical use with the mechanism of action based on the inhibition of TrxR as drug target. It is important to notice that there are only a few examples of TrxR inhibitors in literature, and most of them have milimolar of high micromolar IC50 values.
[007] We did not find any written evidencies about any of the derivatives of aziridine-2- carboxamide as the inhibitors of thioredoxin reductase and/or the application of these compounds in the investigation or treatment of any type of tumors, which is based on TrxR inhibition.
DESCRIPTION OF THE INVENTION
[008] We have discovered that certain derivatives of 1-acyl aziridine-2-carboxamide show TrxR inhibitory activity and high cytotoxicity, which means; they are effective antiproliferative agents with potential anti-metastatic properties against various cancer cell types with the application for the treatment of cancer.
OBJECTS OF THE INVENTION
[009] At least one compound with TrxR inhibitory activity which is chosen from the group of compounds of the Formula I
I
[010] wherein
R represents, but are not limited to, hydrogen, linear, branched and substituted alkyl groups, including alkenyl, alkynyl, substituted and unsubstituted aryl and hetaryl groups.
[Oi l] Formula I also includes enantiomers, diastereomers, tautomers and/or pharmaceutically acceptable salts, hydrates and solvates.
[012] Specific compounds of the Formula I within the present invention, but are not limited to:
l-acetylaziridine-2-carboxamide,
l-(2-methylpropanoyl)aziridine-2-carboxamide,
l-benzoylaziridine-2-carboxamide,
l-(2-iodobenzoyl)aziridine-2-carboxamide,
l-[2-(trifluoromethyl)benzoyl]aziridine-2-carboxamide,
l-(thiophen-2-ylcarbonyl)aziridine-2-carboxamide,
l-(2-furoylcarbonyl)aziridine-2-carboxamide.
DETAILED DESCRIPTION OF THE INVENTION
[013] In a search for novel anti-cancer agents with antiproliferative and/or anti-metastatic properties we have discovered that 1-acyl derivatives of aziridine-2-carboxamide of the Formula I are effective antiproliferative agents on various cancer cell types with the application in cancer treatment.
[014] We have also discovered that compounds of the Formula I inhibit enzyme thioredoxin reductase which is important for the development of cancer cells.
[015] The methods of synthesis of compounds of the Formula I are described below and shown in scheme 1. The invention is not limited to the examples that are showed here which are given for the demonstration purposes. One skilled in the art can practice the invention based on the disclosures in the present patent application.
[016] One skilled in the art can use methods that allow to make the analogues of the compounds of present invention and their derivatives that express therapeutic effect, namely higher activity and/or selectivity to target enzyme, better ability to overcome mammalian blood-brain barrier, less side effects etc.
[017] One skilled in the art will recognize that compounds of this invention can contain chiral centres and compounds can be prepared in optically active (enantiomers and/or diastereomers) or racemic form. Compounds of this invention can also be any racemates, optically active compounds, tautomers or stereoisomeric forms of the compounds of present invention, that express above listed properties.
[018] For the therapeutical use, the compounds of the Formula I can be in the form of a pharmaceutically acceptable salt or solvate. The term“pharmaceutically acceptable” refers here to the therapeutically active non-toxic salt forms, which the compounds of the Formula I are able to form. These salts can be obtained by triturating basic forms of compounds of the
Formula I with acids, for example, inorganic acids as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acids as acetic acid, propionic acid, hydroxyaceto acetic acid, 2-hydroxypropionic acid, oxopropionic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, phenylsulfonic acid, 4-methylphenylsulfonic acid, 2-hydroxybenzoic acid etc. Salts of the compounds of the Formula I can be converted back to free base form by trituration with base.
[019] The synthesis of the compounds of the Formula I is presented in details in scheme 1.
[020] The target compounds 1-1 - 1-7 were synthesized by treatment of aziridine-2- carboxamide 1 with corresponding carboxylates in the presence of base (Scheme 1).
Scheme 1.
[021] All synthesized compounds of the Formula I are not known in the literature.
EXAMPLES
General procedure of synthesis of l-acyl-2-carboxamides 1-1 - 1-7
[022] Aziridine-2-carboxamide (1) (2.32 mmol) was suspended in MeCN (5 mL), NEt3 (2.32 mmol) was added, RM was cooled to 0 °C, corresponding acyl chloride (2.32 mmol) was added. RM was stirred at RT for 24 h, filtered. Filtrate was evaporated, acetone was added to the residue, precipitate was filtered, and filtrate was evaporated. The product was recrystallized from acetonitrile.
Example 1
l-Acetylaziridine-2-carboxamide (1-1)
*H NMR (DMSO-d6, 400 MHz), d, ppm: 2.18 (3H, s), 2.41 (1H, dd, 7=0.9 Hz, 7=3.0 Hz), 2.56 (1H, dd, 7=0.9 Hz, 7=6.4 Hz), 3.03 (1H, dd, 7=3.0 Hz, 7=6.4 Hz), 5.95 (1H, br. s), 6.26 (1H, br. s).
HRMS (ESI, m/z): calcd C5H8N202Na [M+Na]+ 151.0489, found 151.0583.
Example 2
l-(2-Methylpropanoyl)aziridine-2-carboxamide (I- 2)
[024] Obtained from aziridine-2-carboxamide (1) (0.20 g, 2.32 mmol), NEt (0.32 mL, 2.32 mmol) and izobutyryl chloride (0.24 mL, 2.32 mmol). Yield 117 mg (32%).
1H-NMR (DMSO-d6, 400 MHz), d, ppm: 1.03 (3H, d, 7=6.9 Hz), 1.09 (3H, d, 7=6.9 Hz), 2.27 (1H, dd, 7=2.0 Hz, 7=3.1 Hz), 2.37 (1H, dd, 7=2.0 Hz, 7=3.1 Hz), 2.46 (1H, septet, 7=6.9 Hz), 3.07 (1H, dd, 7=3.1 Hz, 7=5.5 Hz), 7.38 (1H, br. s), 7.87 (1H, br. s).
13C NMR (DMSO-d6, 100 MHz), d, ppm: 18.5, 19.6, 28.9, 35.3, 35.4, 168.7, 186.9.
HRMS (ESI, m/z): calcd C7Hi2N202Na [M+Na]+ 179.0796, found 179.0795.
Example 3
l-Benzoylaziridine-2-carboxamide (1-3)
[025] Obtained from aziridine-2-carboxamide (1) (0.20 g, 2.32 mmol), NEt (0.32 mL, 2.32 mmol) and benzoyl chloride (0.27 mL, 2.32 mmol). Yield 57 mg (44%).
*H NMR (DMSO-de, 400 MHz), d, ppm: 2.48-2.52 (1H, m), 2.59 (1H, dd, 7=1.6 Hz, 7=5.5 Hz), 3.29 (1H, dd, 7=3.1 Hz, 7=5.5 Hz), 7.34 (1H, br. s), 7.48-7.54 (2H, m), 7.58-7.63 (1H, m), 7.88-7.92 (3H, m).
13C NMR (DMSO-de, 100 MHz), d, ppm: 29.5, 37.1, 128.2, 128.5, 132.7, 133.1, 168.2, 176.1.
HRMS (ESI, m/z): calcd C10H11N2O2 [M+H]+ 191.0821, found 191.0828.
Example 4
l-(2-Iodobenzoyl)aziridine-2-carboxamide (1-4)
[026] Obtained from aziridine-2-carboxamide (1) (0.20 g, 2.32 mmol), NEt3 (0.32 mL, 2.32 mmol) and 2-iodobenzoyl chloride (0.62 mL, 2.32 mmol). Yield 258 mg (35%).
*H NMR (DMSO-de, 400 MHz), d, ppm: 2.44 (1H, dd, 7=1.5 Hz, 7=3.1 Hz), 2.57 (1H, dd, 7=1.5 Hz, 7=5.4 Hz), 3.21 (1H, dd, 7=3.1 Hz, 7=5.4 Hz), 7.22 (1H, dt, 7=1.6 Hz, 7=7.8 Hz), 7.34 (1H, br. s), 7.49 (1H, dt, 7=1.2 Hz, 7=7.8 Hz), 7.72 (1H, dt, 7=1.6 Hz, 7=7.8 Hz), 7.85 (1H, br. s), 7.98 (1H, dd, 7=1.2 Hz, 7=7.8 Hz).
13C NMR (DMSO-de, 100 MHz), d, ppm: 30.2, 36.9, 128.1, 130.0, 132.3, 138.4, 140.8, 167.8, 176.5.
HRMS (ESI, m/z): calcd C10H10N2O2I [M+H]+ 316.9787, found 316.9794.
Example 5
l-[2-(Trifluoromethyl)benzoyl]aziridine-2-carboxamide (1-5)
[027] Obtained from aziridine-2-carboxamide (1) (0.20 g, 2.32 mmol), NEt3 (0.32 mL, 2.32 mmol) and 2-(trifluoromethyl)benzoyl chloride (0.28 mL, 2.32 mmol). Yield 53 mg (11%).
*H NMR (DMSO-d6, 400 MHz), d, ppm: 2.45 (1H, dd, 7=1.6 Hz, 7=3.1 Hz), 2.55 (1H, dd, 7=1.6 Hz, 7=5.6 Hz), 3.17 (1H, dd, 7=3.1 Hz, 7=5.6 Hz), 7.37 (1H, br. s), 7.70-7.75 (1H, m), 7.78 (1H, dt, 7=1.3 Hz, 7=7.4 Hz), 7.82-7.87 (3H, m).
HRMS (ESI, m/z): calcd C11H10N2O2F3 [M+H]+ 259.0694, found 259.0688.
Example 6
l-(Tiophen-2-ylcarbonyl)aziridine-2-carboxamide (1-6)
[028] Obtained from aziridine-2-carboxamide (1) (0.20 g, 2.32 mmol), NEt3 (0.32 mL, 2.32 mmol) and 2-thiophenecarbonyl chloride (0.25 mL, 2.32 mmol). Yield 41 mg (46%).
*H NMR (DMSO-d6, 400 MHz), d, ppm: 2.49-2.51 (1H, m), 2.61 (1H, dd, /=1.7 Hz, 7=5.7 Hz), 3.29 (1H, dd, 7=3.3 Hz, 7=5.7 Hz), 7.21 (1H, dd, 7=3.7 Hz, 7=4.8 Hz), 7.40 (1H, br. s), 7.72 (1H, dd, 7=1.2 Hz, 7=3.7 Hz), 7.90 (1H, dd, 7=1.2 Hz, 7=4.8 Hz), 7.94 (1H, br. s).
13C NMR (DMSO-de, 100 MHz), d, ppm: 29.8, 37.1, 128.2, 131.6, 133.1, 137.9, 168.1, 170.7.
HRMS (ESI, m/z): calcd C8H9N2O2S [M+H]+ 197.0385, found 197.0394.
Example 7
l-(Furan-2-ylcarbonyl)aziridine-2-carboxamide (1-7)
[029] Obtained from aziridine-2-carboxamide (1) (0.20 g, 2.32 mmol), NEt3 (0.32 mL, 2.32 mmol) and 2-furoyl chloride (0.23 mL, 2.32 mmol). Yield 60 mg (14%).
*H NMR (DMSO-d6, 400 MHz), d, ppm: 2.46 (1H, dd, 7=1.6 Hz, 7=3.3 Hz), 2.57 (1H, dd, 7=1.6 Hz, 7=5.4 Hz), 3.28 (1H, dd, 7=3.3 Hz, 7=5.4 Hz), 6.67 (1H, dd, 7=1.6 Hz, 7=3.5 Hz), 7.19 (1H, dd, 7=0.8 Hz, 7=3.5 Hz), 7.38 (1H, br. s), 7.90 (1H, dd, 7=0.8 Hz, 7=1.6 Hz), 7.93 (1H, br. s).
13C NMR (DMSO-d6, 100 MHz), d, ppm: 29.2, 36.7, 112.1, 116.5, 146.7, 147.7, 166.6, 168.2.
HRMS (ESI, m/z): calcd C8H9N203 [M+H]+ 181.0613, found 181.0615
[030] The compounds obtained of the Formula I (1-1 - 1-7) showed inhibition of cancer cell culture growth (cytotoxicity) as well as inhibition of TrxRl.
Cell and cell culture viability
[031] Determination of cytotoxicity in vitro was performed on monolayer tumor cell lines FIT- 1080 (Human connective tissue fibrosarcoma), SH-SY5Y (Human neuroblastoma), MCF- -7 (Human breast adenocarcinoma). The results are summarized in Table 1.
[032] Almost all compounds of the Formula I showed better cytotoxic effect on all three cell lines than anticancer agent Leakadine 1 (Table 1) which is known in literature. Almost all compounds of the Formula I showed moderate to high cytotoxic (antiproliferative) effect on all three cell lines. One compound of the Formula I (1-5) showed very good cytotoxic effect on HT-1080 cells with IC50 values lower than 200 mM (Table 1).
[033] One compounds of the Formula I (1-5) showed very good cytotoxic effect on SH- SY5Y cells with IC50 values lower than 200 pM (Table 1). In turn cytotoxicity on MCF-7 cells was somewhat lower, where best IC50 values exhibited three compounds of the Formula
I (1-4, 1-5 and 1-6) (Table 1).
[034] In vitro cytotoxicity test: Cells were seeded on a 96-well plate in DMEM medium supplemented with 10% fetal bovine serum and 4 mM glutamine together with tested compound and then cultivated in thermostat 72 hours. Cell viability was measured by colouring with MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). After incubation with tested compound the medium was replaced with new one containing 0.2 mg/ml MTT. After incubated 3 hours in thermostat at 37°C with 5% CO2, removal of medium, the dye was extracted with 0.2 ml DMSO. Optical density (OD) determine using multichannel spectrophotometer ( Tecan multiplate reader InfinitelOO) at 540 nm. Then calculate IC50 - the concentration of tested compound providing the death of 50 % of cells by the usage of program Graph Pad Prism® 3.0.
Table 1. In vitro cytotoxicity of compounds of the Formula I on monolayer tumor cell lines HT-1080 (Human connective tissue fibrosarcoma), SH-SY5Y (Human neuroblastoma) and MCF-7 (Human breast adenocarcinoma).
[035] All compounds of the Formula I showed moderate to very good TrxR inhibitory activity at the inhibitor concentration 200 mM (Table 2). At the inhibitor concentration 50 mM two compounds of the Formula I showed TrxR inhibitory (Table 2).
[036] It is important to mention that anticancer agent Leakadine 1 which is known in literature practically does not inhibit TrxR (Table 2).
[037] Thioredoxin reductase inhibition screening in vitro·. SHSY5Y cells (ATCC) were cultivated in DMEM medium (Sigma) supplemented with 10% fetal bovine serum and 4 mM glutamine in incubator with 37°C and 5 % CO2. Cells in concentration 1x10 harvested and washed twice with ice-cold PBS. Then cells were lysed by 50 mM pottasium-phosphate buffer with 1 mM EDTA, pH 7.4. Lysates were clarified by microcentrifugation at 14,000 rpm, 4 °C. TrxR activity with tested compounds were determined by Thioredoxin Reductase Assay kit (kat.Nr.10007892, Cayman Chemical). The compound (10-50-200 pM) with TrxR were incubated in 96-well plate 30 min. Then detection due was added and reaction progress was monitored at 405 nm for 10 min. The compound inhibitory effect was calculated as % relative to control.
Table 2. TrxR inhibition data of compounds of the Formula I.
ne - no effect; nt - not determined.
[038] All compounds of the Formula I that are described here have the correlation between the TrxR inhibitory activity and antiproliferative properties but one compounds of the Formula I (1-6) should be particularly highlighted as it have very good cytotoxic properties on all cancer cell lines described here (FIT- 1080, SH-SY5Y and MCF-7) as well as good TrxR inhibitory activity.
[039] It was discovered that several compounds of the Formula I in in vivo studies on mice (Balb/c mice with implanted breast cancer cells 4T1) exhibit anti-metastatic activity reducing metastasis up to 80% or more, where good results were observed for compounds 1-1 - 1-7, with best activity for compound 1-6.
REFERENCES
1. Rasheed, S. et al. Cancer 1974, 33, 1027-1033.
2. Strenger, V. et al. Pediatr. Blood Cancer 2007, 48, 504-509.
3. Auer, G. et al. Cell. Oncology 2004, 26, 171-172.
4. Tonissen K.F.; Di Trapani G. Mol. Nutr. Food Res. 2009, 53, 87-103.
5. Gasdaska P.Y.; Gasdaska J.R.; Cochran S.; Powis G. FEBS Lett 1995, 373, 5-9.
6. Lee S.R.; Kim J.R.; Kwon K.S.; Yoon H.W. et al. J. Biol. Chem. 1999, 274, 4722-4734.
7. Sun Q.A.; Kirnarsky L.; Sherman S.; Gladyshev V.N. Proc. Natl. Acad. Sci. USA 2001,
98, 3673-3678.
8. Panieri E.; Santoro M.M. Cell Death Dis. 2016, 7(6), e2253. doi: 10.1038/cddis.2016.105
9. Nguyena P.; Awwada R.T.; Smarta D.D.K.; Spitzb D.R.; Giusa D. Cancer Lett. 2006, 236, 164-174.
Claims
1. Compounds of the Formula I
R represents, but are not limited to, hydrogen, linear, branched and substituted alkyl groups, including alkenyl, alkynyl, substituted and unsubstituted aryl and hetaryl groups;
as well as their enantiomers, diastereomers, tautomers and/or pharmaceutically acceptable salts, hydrates and solvates;
with proviso that R is not 4-N02-phenyl- or CH3-CO-CH2- group.
2. The compound according to Claim 1, wherein the compound is selected from the group comprising:
1 -acetylaziridine-2-carboxamide,
l-(2-methylpropanoyl)aziridine-2-carboxamide,
1 -benzoylaziridine-2-carboxamide,
l-(2-iodobenzoyl)aziridine-2-carboxamide,
l-[2-(trifluoromethyl)benzoyl]aziridine-2-carboxamide,
l-(thiophen-2-ylcarbonyl)aziridine-2-carboxamide,
l-(2-furoylcarbonyl)aziridine-2-carboxamide.
3. The compound according to Claim 1 and 2 for use as thioredoxin reductase (TrxR) inhibitors for the treatment or prevention of diseases such as connective tissue tumors, neuroblastoma and breast tumors, also including cancers like bladder, bone, brain, central and periph-eral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva; as well as inherited cancers selected from retinom-blastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkins
disease, chronic and acute myeloid leukaemia, acute lymphoblastic leukemia, Hodgkins disease, multiple myeloma and T-cell lymphoma; myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, as well as including reduction or prevention of metastasis.
4. The compound according to the Claim 1 or 2, wherein compound is used together with one or more chemotherapeutic agents, surgery, chemotherapy, radiotherapy, immunotherapy or combination thereof.
5. Pharmaceutical composition which is intended for parental or peroral administration, and contains therapeutically active amount of compound according to Claim 1 or 2 and pharmaceutically acceptable diluents, carriers, or excipients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-19-08 LV15518B (en) | 2019-02-18 | AZIRIDINE-2-CARBOXAMIDE DERIVATIVES AS THIOREDOXIN REDUCTASE INHIBITORS WITH ANTI-CANCER AND ANTIMETASTIC ACTIVITY AND THEIR SYNTHESIS | |
| LVP-19-08A LV15518A (en) | 2019-02-18 | 2019-02-18 | Derivatives of aziridine-2-carboxamide as inhibitors of thioredoxin reductase, their synthesis, anti-cancer and anti-metastatic effect |
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| Publication Number | Publication Date |
|---|---|
| WO2020170022A1 true WO2020170022A1 (en) | 2020-08-27 |
Family
ID=65598692
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2019/060350 WO2020170022A1 (en) | 2019-02-18 | 2019-12-02 | Derivatives of aziridine-2-carboxamide as inhibitors of thioredoxin reductase, their synthesis, anti-cancer and anti-metastatic effect |
Country Status (2)
| Country | Link |
|---|---|
| LV (1) | LV15518A (en) |
| WO (1) | WO2020170022A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267174A (en) * | 1977-07-11 | 1981-05-12 | Boehringer Mannheim, Gmbh | Immune-stimulating and cancerostatic 1-acyl-2-cyanoaziridines |
| JPH11322593A (en) * | 1998-03-19 | 1999-11-24 | Sagami Chem Res Center | Anticancer agent and tubuline inhibitor containing acetamide derivative, and new acetamide derivative |
-
2019
- 2019-02-18 LV LVP-19-08A patent/LV15518A/en unknown
- 2019-12-02 WO PCT/IB2019/060350 patent/WO2020170022A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267174A (en) * | 1977-07-11 | 1981-05-12 | Boehringer Mannheim, Gmbh | Immune-stimulating and cancerostatic 1-acyl-2-cyanoaziridines |
| JPH11322593A (en) * | 1998-03-19 | 1999-11-24 | Sagami Chem Res Center | Anticancer agent and tubuline inhibitor containing acetamide derivative, and new acetamide derivative |
Non-Patent Citations (11)
| Title |
|---|
| AUER, G. ET AL., CELL. ONCOLOGY, vol. 26, 2004, pages 171 - 172 |
| GASDASKA P.Y.GASDASKA J.R.COCHRAN S.POWIS G., FEBS LETT, vol. 373, 1995, pages 5 - 9 |
| KATO, TETSUZO ET AL.: "Ketene and its derivatives. XLII. Ring-expansion of 1-acetoacetylaziridines", YAKUGAKU ZASSHI = JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 91, no. 3, 1 January 1971 (1971-01-01) - 1971, pages 384 - 392, XP002794830, ISSN: 0031-6903 * |
| KUNATH A ET AL: "Influence of the kind of the alcoholic modifier on chiral separation on a Chiralpak AD column", JOURNAL OF CHROMATOGRAPHY A, ELSEVIER, AMSTERDAM, NL, vol. 728, no. 1, 29 March 1996 (1996-03-29), pages 249 - 257, XP004039456, ISSN: 0021-9673, DOI: 10.1016/0021-9673(95)00891-8 * |
| LEE S.R.KIM J.R.KWON K.S.YOON H.W. ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 4722 - 4734 |
| NGUYENA P.AWWADA R.T.SMARTA D.D.K.SPITZB D.R.GIUSA D., CANCER LETT., vol. 236, 2006, pages 164 - 174 |
| PANIERI E.SANTORO M.M., CELL DEATH DIS., vol. 7, no. 6, 2016, pages e2253 |
| RASHEED, S. ET AL., CANCER, vol. 33, 1974, pages 1027 - 1033 |
| STRENGER, V. ET AL., PEDIATR. BLOOD CANCER, vol. 48, 2007, pages 504 - 509 |
| SUN Q.A.KIRNARSKY L.SHERMAN S.GLADYSHEV V.N., PROC. NATL. ACAD. SCI. USA, vol. 98, 2001, pages 3673 - 3678 |
| TONISSEN K.F.DI TRAPANI G., MOL. NUTR. FOOD RES., vol. 53, 2009, pages 87 - 103 |
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| LV15518A (en) | 2020-08-20 |
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