Статья опубликована в рамках: XXXIII Международной научно-практической конференции «Естественные науки и медицина: теория и практика» (Россия, г. Новосибирск, 12 апреля 2021 г.)
Наука: Химия
Секция: Органическая химия
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SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF 6-(TERT-BUTYL)-2-OXO-1,2,5,6,7,8-HEXAHYDROQUINOLINE-3,4-DICARBONITRILE
The dicyanopyridine fragment is included in the structure of compounds exhibiting different biological activities. In work [1], the authors investigated the antitumor activity of dicyanopyridine derivatives against the cell lines of human liver carcinoma (HEPG2) and cervical carcinoma (HELA) in-vivo. According to the study data, the introduction of dicyanopyridine derivatives increases the lifespan of mice in comparison with the control group by 25-69%. The work [2] showed the antiproliferative activity of dicyanopyridines against the cell lines of breast carcinoma (MCF-7), colon cancer (HCT116), and lung carcinoma (A549) with an IC50 activity of <10 μM for most derivatives. At the same time, one representative exceeds the activity of the drug Paclitaxel by 2 times.
The presence of an oxo group in the second position of the pyridine ring in combination with the carbonitrile function makes it possible to use cyanopyridones as an inhibitor of the Pim-1 protooncogene [3] and as an agent against the growth of the NT-29 human colon adenocarcinoma tumor cell line [4].
In this work, we present the results of a study of the antiproliferative activity of 6-(tert-butyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3,4-dicarbonitrile 2, the synthesis of which was carried out on the basis of the reaction 1-(5- (tert-butyl)-2-oxocyclohexyl)ethane-1,1,2,2-tetracarbonitrile with water in an acidic medium (Scheme 1) [5, 6].
Scheme 1. Синтез 6-(tert-butyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3,4-dicarbonitrile
The mechanism of the antriproliferative action of 2-oxopyridines is associated with the inhibition of PIM-1 kinase due to the creation of an H-bonding network by the carbonyl group and NH-fragment of the pyridine ring with a conservative water molecule interacting with the PIM-1 catalytic residues of Asp186 kinase and with the PIM-1 catalytic residue kinase Lys67 [3, 4]. In addition, cyano groups are also prone to the formation of hydrogen bonds and can bind DNA molecules, amino acid residues such as serine and arginine [7], which leads to disruption of the activity of a number of enzymes and disruption of nitrogen metabolism. In this regard, three drugs of alkylating action were selected as a comparison: hydroxycarbamide, busulfan, cisplatin.
The antiproliferative activity of compound 2 was studied at the National Institute of Oncology (USA). For the research, an in vitro model was used, which allows standardizing the experimental conditions for repeated series according to the “NCI-60 One-Dose Screen” method [8]. The studies were carried out on 59 cell lines obtained from tumors of the lungs, colon, brain, ovaries, kidneys, prostate, breast, as well as human leukemia and melanoma.
Table 1.
The results of a study of the antiproliferative activity of compounds at a concentration 10-5 M (on the One-Dose Screen program)
|
Compound |
Inhibition of the growth of cell lines, % |
||||||||
|
leukemia (6 lines) |
lung cancer (9 lines) |
colon cancer (7 lines) |
brain cancer (6 lines) |
melanomas (8 lines) |
ovarian cancer (7 lines) |
kidney cancer (8 lines) |
prostate cancer (2 lines) |
breast cancer (6 lines) |
|
|
2 |
2.57 ± 3.99 |
–2.61 ± 7.69 |
–2.94 ± 8.86 |
1.18 ± 6.37 |
–6.04 ± 10.89 |
–6.87 ± 11.87 |
–2.31 ± 6.53 |
–0.85 ± 7.79 |
4.21 ± 4.43 |
|
hydroxycarbamide, subst. 100.0, Nativa |
35.01 ± 5.62 |
32.76 ± 3.26 |
26.17 ± 2.65 |
39.42 ± 4.01 |
33.76 ± 6.22 |
38.97 ± 6.40 |
46.50 ± 10.86 |
35.35 ± 7.95 |
41.20 ± 18.43 |
|
busulfan, "Mielosan", subst., Pharmacon |
– |
– |
– |
– |
18.80 ± 1.98 |
– |
– |
– |
– |
|
cisplatin, lyoph. for injection 0.01, Lance-Pharm |
– |
32.1 ± 2.15 |
– |
13.90 ± 1.31 |
14.2 ± 1.10 |
26.90 ± 1.87 |
18.10 ± 1.72 |
19.90 ± 2.05 |
10.90 ± 1.03 |
Note: The effects of all studied substances are significantly significant at p <0.05.
Statistical processing of the experimental material was carried out using a two-sample Student's t-test for independent samples. The effect was considered significant at p <0.05 (Table 1).
Thus, in the course of this study, it was shown that 6- (tert-butyl) -2-oxo-1,2,5,6,7,8-hexahydroquinoline-3,4-dicarbonitrile 2 suppresses the growth of leukemia cell lines (to a greater extent degree of the K-562 and SR line), brain cancer (mostly the SNB-75 line), prostate cancer (mostly the PC-3 line), and breast cancer (mostly the MCF7 line).
Synthesis, study of the chemical and physical properties of new heterocyclic compounds, as well as the study of their biological activity is one of the scientific directions of our team [9-23].
This work was supported by a grant from the President of the Russian Federation for state support of young Russian scientists, agreement number No. 075-15-2020-229 (MK-269.2020.3).
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