Fluorinated 1,4-naphthoquinone derivatives having cytotoxic effect on human cancer cells in culture

FIELD: chemistry.

SUBSTANCE: invention relates to an agent, which is in form of fluorinated 1,4-naphthoquinone derivatives of general formula (I) which have cytotoxic effect on human cancer cells in a culture. In general formula (I) 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH2)2, R2, R3=F; 4) R1=N(CH2CH2)2, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5R2, R3=F; 7) R1=H(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=OCH3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2NH(2-pentafluoro-1,4-naphthoqunonyl), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O; R3=F; 15) R1=NHCH2CH2OH, R2,R3=F; 16)R1, R2=OCH3, R3=F.

EFFECT: proposed compounds can be used in medicine as a base for designing drug formulations of preparations used in malignant growth therapy.

2 dwg, 4 tbl, 3 ex

 

The invention relates to the field of organic chemistry and molecular biology, namely, fluorinated derivatives of 1,4-naphthoquinone with cytotoxic activity against cancer cells in culture.

Mammalian cells typically use the reversible phosphorylation of tyrosine residues in proteins to transmit an extracellular signal to an intracellular target. With this in mind, the violation of mediators of signal transduction through phosphorylation of proteins, such as kinases and phosphatases, is associated with the development of a large number of human diseases, including cancers. It is known that Cdc25A and Cd25B phosphatase important for controlling cell cycle and activate cyclin-dependent kinases, which play an important role in the regulation of cell proliferation. Cdc25A and Cd25B phosphatase person possess oncogenic properties and hyperexpression in various cancerous human cells. In this regard, they are of interest as targets for anticancer drugs [R. Boutros, Dosier S., Ducommun C. Curr. Opin. Cell. Biol. 2006. V.18, P.185; Kristjansdottir K, Rudolf J.J. Chem. Biol., 2004. V.11. P.1043]. Among the large number of different investigated compounds only some derivatives of naphthoquinone [Eckstein J.W. Invest. New. Drugs. 2000. V.18, P.149; Pesttell KE, Ducruet A.P., Wipf P, et al. Oncogene, 2002. V.19. P.6607], and especially the naphthoquinone NSC 95397 from the National Cancer Institute library [J.S. Lazo, K. Nemoto, Pestell K.E. et al., Mol. PharmacoL, 2002. V.61. P.720] bladud the ability to effectively inhibit Cdc25A phosphatase.

It was shown that the pair-naftochinona, 7-aminoquinoline-5,8-quinone and substituted isoquinoline-5,8-quinones are core structures for the synthesis of potential inhibitors of Cdc25 phosphatases; an example of such derivative is a compound DA3003-1 [J.S. Lazo, K. Nemoto, Pestell KE et al., Mol. Pharmacol., 2002. V.61. P.720; Wipf, P., Joo C., Nguyen T., Lazo J.S. Org. Biol. Chem., 2004, V.2. P.2173]. It is shown that the derivatives of quinone inactivate Cdc25B phosphatase or Michael's reaction, either by oxidation of catalytically important residue cysteine [Brisson M, Nguyen T., P. Wipf et al, Mol. Pharmocol., 2005. V.68. R-1820]. It is known that certain substituted derivatives of the quinoline-5,8-quinone on the provisions of(2), (3) and(4) are effective inhibitors of Cdc25B phosphatase and growth of cancer cells [J. Cossy, Belotti D., Brisson M. et al. Bioorg. Med. Chem., 2006. V.14. P.6283-6287]. Crustal structure of the para-quinone part 14 is widely used in the clinic drugs and seems to be fundamental for the synthesis of new potential inhibitors of enzymes that are targets in anticancer therapy [J. Cossy, Belotti D., Brisson M. et al. Bioorg. Med. Chem., 2006. V.14. P.6283-6287].

Closest to the claimed fluorinated derivatives of 1,4-naphthoquinone - prototype - is tetrafluorobenzyl 2-(2-mercaptoethanol)-3-methyl-5,6,7,8-titrator-1,4-naphthoquinone (fluorinated-Cpd 5), which has a higher activity in suppressing the growth Nerve cells than the original Cpd 5 (Ham W.. et al, 2004, Bioorg. Med. Chem. Lett., 2004, V.14. P.4103-4105). Fluorinated-Cpd 5 was obtained by the reaction of 2-methyl-3,5,6,7,8-pendaftar-1,4-naphthoquinone and 2-mercaptoethanol.

The disadvantages of the known Cpd 5 compound and its fluorinated derivative are their high toxicity, because they contain sulfur atoms - thiol groups, which are easily oxidized (exposed to oxidative stress) with the formation of toxic radicals.

An object of the invention is the creation of a less toxic fluorinated derivatives of 1,4-naphthoquinone with cytotoxic activity against cancer cells in culture, as well as less prone to reactions with the formation of toxic for the cells of radical intermediates in the processes of oxidative stress.

The goal of the project is achieved offer fluorinated derivatives of 1,4-naphthoquinone General formula

The proposed connection is produced by interaction of hexamer-1,4-naphthoquinone (II) or 2-methylpentane-1,4-naphthoquinone (III) (compound 10) with nitrogen - and kislorodoterapii nucleophiles and characterize data NMR spectroscopy1H and19F, elemental analysis or mass spectroscopy high resolution.

II R1, R2=F

III R1=CH3, R 2=F

the original connection nucleophile:

1) II, NH2C(CH3)3; 2) II, NH2CH2CH2SCH3; 3) II, NH(CH2CH3)2; 4) II, NH(CH2CH2)2O; 5) II, NH2CH2CH2CH2CH3; 6) II, NH2C6H8; 7) II, NH(CH3)CH2CH2OH; 8) II, NH2CH2CH2CH2CH3; 9) II, N(CH2CH2OH)2; 10) III, NH2C6H5; 11) II, NON3; 12) II, NH2(CH2)2SS(CH2)2NH2; 13) II, NH2C2H5; 14) II NC5H5; 15) II, NH2CH2CH2OH; 16) II, NON3.

Compared with the above-mentioned prototype of the proposed derivatives of 1,4-naphthoquinone (in the absence of sulfur atoms) to a lesser extent undergo reactions with the formation of toxic for the cells of radical intermediates in the processes of oxidative stress, as compared to non-fluorinated analogues is due to the effect of electronegative fluorine atoms. Therefore, they may be more promising compounds for targeted suppression of the development of cancer cells that synthesize high amounts of oncogenic protein kinases and phosphatases.

Table 1 shows the inventive fluorinated derivatives of 1,4-naphthoquinone and their structural formulas. Physico-chemical characterization of fluorinated derivative of the 1,4-naphthoquinone is presented in table 2. Characteristics of the NMR spectra1H and19F are presented in table 3.

The invention is illustrated by the following specific examples of receipt of the proposed connections.

Example 1.

Getting 2-ethylaminoethanol-1,4-naphthoquinone (compound 13). A mixture of 0.07 g (0.556 mmol) of ethylamine hydrobromide, 0.094 g (1.68 mmol), KOH and 2 ml of dioxane was stirred 30 min at room temperature. The precipitate was separated in a centrifuge, to the solution was added 0.1 g (0.38 mmol) of quinone (II) and stirred 2 h at 20°C. a Red precipitate was separated by centrifuge, washed with water. Got 0.106 g (97%) of the quinone. After sublimation at 150°C in vacuum 0.03 mm Hg output amounted to 0.095 g (88%), Burgundy crystals, TPL 184-185°C. Found, %: C 49.23; H 1.85; N, 4.86. C12H5F5NO2. Calculated, %: C 49.50; H 2.08; N, 4.81. An NMR spectrum, δ/ppm, J/Hz):19F 5.3 USS (F3), 24.2 DDD, 25.8 dt(F5,8), 15.1 dt, 19.8 DDT(F6,7) (J5,6I , J6,7I , J7,819.7-19.8, J5,7I , J5,8I , J6,810.1-12.1);1H 1.29 dt (CH3), 3.58 m (CH2), 5.39 USS (NH).

Example 2.

Obtaining 1-(1,4-dihydro-1,4-dioxo-3-hydroxy-2-tetrathionate)pyridine betaine (compound 14). To a solution of 0.20 g (0.75 mmol) of quinone (II) in 3 ml of methanol in an atmosphere of argon was added 0.59 g (7.46 mmol) of pyridine and the mixture was stirred for 1 h at room temperature. The precipitate was separated by centrifuge, washed met the Nole (3×2 ml) and was obtained 0.22 g (90%) of the specified betaine, orange crystals, TPL 317-319°C. Found, %: C 55.59; H 1.55; N, 4.29; F 23.51. C15H5F4NO3. Calculated, %: C 55.74; H 1.56; N, 4.33; F 23.51. An NMR spectrum, δ/ ppm, J/Hz):19F 20.4 DDD, 21.9 dt (F5,8), 11.4 dt, 16.5 dt (F6,7) (J5,6I , J6,7I , J7,818.7-19.3, J5,7I , J5,8I , J6,88.3-12.8);1H 8.20 m, 8.60 TT, 8.80 D.M.

Example 3

Conducted testing of the impact of the compounds on the growth of different lines of cancer cells in culture. Cell adenocarcinoma human breast MCF-7 were grown in IMDM medium, myeloma cells human (line RPMI 6228) were grown by using RPMI 1640 with 40 µg/ml gentamycin and in the presence of 10% fetal bovine serum production company "Bilat" in an atmosphere with 5% CO2in 96-well plates.

To compare the relative activity of all compounds in the same conditions they were dissolved in DMSO at high concentrations (10 mg/ml), and then the stock solution was diluted in DMSO to obtain a series of solutions with the desired concentration. When using cell adenocarcinoma of the breast after the formation of 50-70% of the monolayer in culture medium was added investigational drugs fluorinated derivatives of 1,4-naphthoquinone (volume of added reagents was 1 / 100th of the total volume of culture medium, the amount of DMSO was 1% of final volume) and watched the growth of cells is offered by the culture for 3 days.

When using a cell line of human myeloma, which is a suspension culture, the cells are subcultured in 96-well plate in an amount of 100 μl per well, the concentration of 2x105cells/ml; after 12-24 hours added investigational drugs fluorinated derivatives of 1,4-naphthoquinone (volume of added reagents was 1 / 100th of the total volume of culture medium, the amount of DMSO was 1% of the final volume of the mixture in the hole).

Effect of fluorinated derivatives of 1,4-naphthoquinone cells MCF-7 and RPMI 6228 in culture and the suppression of their growth was performed using a test based on the ability of mitochondrial dehydrogenase to convert water-soluble 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) formazan (MTT-test), which crystallizes inside the cell. As nonviable cells enzymes are not functioning and there are no cofactors of this transformation, they are not stained with MTT. The precipitate of formazan in viable cells was dissolved in isopropanol and its quantity was determined spectrophotometrically by absorption at the wavelength of λ=560 nm.

As a positive control used cells that were grown in the absence of fluorinated derivatives of 1,4-naphthoquinone. It was found that DMSO used in concentration (1%) significant effect on the growth of RA the new cell does not have. In addition, it was found that the compounds do not affect the color of the cells in the MTT-test, if they are added to the wells with the cells immediately before conducting the test.

To evaluate the relative activity of all compounds in suppressing the growth of cancer cells were investigated according to the number of living cells on the concentration of these compounds. As an example, the drawing shows the data for three of the investigated compounds. The concentration of compounds (C50), in which there is suppression (inhibition) of cell growth by half (50%), was performed using the MTT-test. The drawing shows data for compounds 1 (s-1; 2-tert-butylaminoethyl-1,4-naphthoquinone), compound 8 (S-8; 2,8-bis(n-butylamino)-3,5,6,7-titrator-1,4-naphthoquinone) and compound 16 (C-16; 2,3-dimethoxyacetate-1,4-naphthoquinone). The number of live cells in control (incubation of cells without compounds) were taken as 100%.

Using such curves was determined by the concentration (C50), in which there is suppression (inhibition) of cell growth by half. Data on the impact of the claimed compounds (inhibition of 50%, With50) on the growth of cancer cells of human myeloma (RPMI 6228) and human adenocarcinoma (MCF-7)and control cells (murine fibroblast line LMTK after incubation for 48 h are shown in t the blitz 4.

From table 4 it is seen that the compounds inhibit the growth of cancer cells myeloma (RPMI 6228) and human adenocarcinoma (MCF-7) in culture at concentrations of 0.1 and 7.5 μg/ ml Most of the new fluorinated derivatives of 1,4-naphthoquinone (compounds 1-7, 9, 13, 15-16) shows similar values With50(0.1 to 2.5 μg/ml) in the case of two types of cancer cells (RPMI 6228 and MCF-7), while compounds 8, 10 and 12 inhibit the growth of these cells in higher concentrations (4,0-7,5 µg/ml), and the connection 11 shows a significant difference in the inhibition of cell line RPMI 6228 (1 μg/ml) and line MCF-7 (6.7 ág/ml).

Fluorinated derivatives of 1,4-naphthoquinone are inhibitors Cdc25A and Cd25B phosphatases that play an important role in the regulation of cell proliferation and hyperexpression in various cancerous human cells. Since the modification of kinases leading to cell death, fluorinated derivatives of 1,4-naphthoquinone show cytotoxicity (as well as other known anti-cancer drugs) in both cancer and normal somatic mammalian cells. However, fluorinated 1,4-naftochinona largely inhibit it the cancer cells and not normal mammalian cells.

Table 4 also shows that the suppression of cell growth by 50% using compounds 1, 2, 6 and 8 occurs at concentrations of 1.8-5.6 times more than the low, than of fibroblast cells. There is a connection (5, 7 and 9), which inhibit the growth of cancer cells of two types (RPMI 6228 and MCF-7) with approximately the same efficiency, and suppression of cell growth of fibroblasts occurs only at concentrations of 6.9-14 times higher. At the same time, two compounds (3 and 4), showing approximately the same effect on cell lines RPMI 6228 and MCF-7 (C50=1.3 to about 2.2 μg/ml), at high concentration (25 µg/ml) only 10-20% inhibit the growth of fibroblast cells, suggesting that they inhibit the growth of fibroblast cells by 50% at concentrations of more than 11,4-19.2 times higher than in the case of cancer cells. Some compounds (10 and 12) inhibit the growth of RPMI 6228 and MCF-7 cancer cells at relatively high concentrations (4,0-7,5 µg/ml), but exhibit poor growth inhibition of fibroblast cells (30-35%) high concentration (25 μg/ml), which may also be a potential basis for their potential use in cancer therapy. Part of the new compounds (11, 13-16) shows a very strong difference in the effects on cancer cell lines RPMI 6228 and MCF-7, inhibiting the growth of RPMI 6228 at concentrations of 3.8-24 times lower than MCF-7. In this regard, the ratio of the values With50for cells, fibroblasts and cancer cells lines for these compounds varies from 1 to 25. The data obtained indicate that h is of some new fluorinated derivatives of 1,4-naphthoquinone can be universal for suppression of cancer cells of various types, while others may be more promising for a specific effect only for a certain type of the best known variety of cancer cells. Thus, the proposed new fluorinated derivatives of 1,4-naphthoquinone are effective inhibitors of the growth of cancer cells and are potentially promising for their use in cancer therapy.

The tool, which represents a fluorinated derivatives of 1,4-naphthoquinone General formula

where 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH3)2, R2, R3=F; 4) R1=N(CH2CH2)2O, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5, R2, R3=F; 7) R1-N(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=Co3, R2, R3 =F; 12) R1=NH(CH2)2SS(CH2)2HN(2-pendaftar-1,4-naphtohinone), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O-, R3=F; 15) R1=NHCH2CH2OH, R2, R3=F; 16) R1, R2=Co3, R3=F possessing cytotoxic activity towards cancer cells in culture.



 

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< / BR>
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