CN113004183B - Sorafenib antitumor inhibition auxiliary compound and composition and application thereof - Google Patents
Sorafenib antitumor inhibition auxiliary compound and composition and application thereof Download PDFInfo
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- CN113004183B CN113004183B CN202110170904.9A CN202110170904A CN113004183B CN 113004183 B CN113004183 B CN 113004183B CN 202110170904 A CN202110170904 A CN 202110170904A CN 113004183 B CN113004183 B CN 113004183B
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- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
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- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
The invention relates to the technical field of medicines, and particularly discloses a sorafenib antitumor inhibition auxiliary compound, and a composition and application thereof. Although Ti3 has no antitumor effect, the sorafenib antitumor inhibition auxiliary compound (Ti 3) can improve and prolong the inhibition effect of sorafenib on tumor cells, reduce the drug resistance of tumors to sorafenib, and further improve the curative effect of sorafenib; the invention also provides an anticancer composition, the bioavailability of the sorafenib is improved by combining the small molecular compound Ti3 and the sorafenib, the combination of the two can enable the drug effect to generate a synergistic effect on treating tumors, and the effect is obviously superior to that of single drug.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a sorafenib antitumor inhibition auxiliary compound, and a composition and application thereof.
Background
The compound 4- (4- {3- [ 4-chloro-3- (trifluoromethyl) phenyl]Ureido } phenoxy) -N 2 -methylpyridine-2-carboxamide, also known as sorafenib, with molecular formula C 21 H 16 ClF 3 N 4 O 3 Molecular weight is 464.83. Sorafenib is a novel multi-kinase inhibitor anticancer drug jointly developed by Bayer (Bayer) in Germany and Onyx in the United states. Sorafenib tosylate was approved by the U.S. FDA for marketing for the treatment of advanced renal cell carcinoma at 20 days 12 months 2005.
Sorafenib is mainly targeted to serine/threonine kinase (Raf) and tyrosine kinase acting on tumor cells and tumor vessels, and the two kinases can influence the proliferation and angiogenesis of the tumor cells so as to inhibit the growth of tumors. Sorafenib can inhibit the activity of serine/threonine kinase of Raf-1, wild type and V599E mutant BRAF to inhibit RAF/MEK/ERK signal conduction pathway and directly inhibit tumor growth; on the other hand, it can block the formation of tumor new blood vessels by inhibiting VEGFR and PDGFR, and indirectly inhibit the growth of tumor cells.
The patients can gradually generate drug resistance along with the use time of the sorafenib, and the clinical manifestation is that part of the patients still have tumor recurrence and metastasis in the initial stage or the treatment process of the sorafenib treatment, so that the curative effect is poor.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a sorafenib antitumor inhibition auxiliary compound, a composition and an application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
in a first aspect, the invention provides a sorafenib antitumor inhibitory auxiliary compound, which has a molecular formula as follows: c 15 H 13 BrN 2 An OS; the structural formula of the compound is:
the sorafenib antitumor inhibition auxiliary compound (named as Ti 3) synthesized by the invention does not obviously inhibit a liver cancer cell line, but Ti3 can obviously improve the effects of sorafenib on inhibiting the activity of liver cancer cells and promoting the apoptosis of the liver cancer cells, and reduces the drug resistance of tumors to sorafenib.
Specific properties of Ti3 are as follows, SMLES: cc2ccccc2 (NC (= O) c1cccc (c 1) Br) = S); inChl TM ：InChl＝1S/C15H13BrN2OS/c1-10-5-2-3-8-13(10)17-15(20)18-14(19)11-6-4-7-12(16)9-11/h2-9H,1H3,(H2,17,18,19,20)；
InChlKey TM ：HEGLZZCJRVMIDM-UHFFFAOYSA-N。
In a second aspect, the present invention provides an anticancer composition comprising sorafenib and the above sorafenib antitumor adjuvant compound.
The inventor uses Ti3 and sorafenib in a combined manner, takes hepatoma cell lines Hep3B and 97L as research objects, inspects the proliferation inhibition capability of the medicament on liver cancer cells in vitro, and experiment results prove that the Ti3 and sorafenib in a combined manner can obviously improve the activity of the sorafenib in inhibiting the liver cancer cells and promote the apoptosis of the liver cancer cells, and the sorafenib has a more obvious effect of inhibiting the growth of the liver cancer cell saccule.
Meanwhile, the inhibition effect of the medicament on the tumor growth in vivo is verified through a nude mouse tumorigenicity experiment. Experimental results prove that Ti3 can improve the inhibition effect of sorafenib on tumor cells.
As a preferred embodiment of the anticancer composition of the present invention, the mass concentration ratio of the sorafenib and the sorafenib antitumor adjuvant compound described above is 1.
According to in vivo and in vitro experiments, when the mass concentration ratio of the sorafenib to the sorafenib antitumor auxiliary compound is 1.
In a third aspect, the present invention provides a pharmaceutical formulation comprising the above-mentioned anti-cancer composition. Preferably, the anticancer composition of the present invention can be prepared into a pharmaceutical preparation according to the conventional technology in the art, the pharmaceutical preparation is preferably an injection preparation or an oral preparation, and according to the preparation form, the auxiliary materials selected for the preparation can adopt the conventional auxiliary materials in the art, and on the premise that the auxiliary materials do not react with the anticancer composition of the present invention or do not influence the curative effect of the drug of the present invention, the preparation method of the pharmaceutical preparation can adopt the conventional preparation method in the art.
The administration dosage of the anticancer composition of the present invention is appropriately changed depending on the administration subject, the administration route or the formulation form of the drug, but it is premised that the anticancer composition can achieve an effective blood concentration in the animal body.
In a fourth aspect, the invention provides an application of the anticancer composition in preparing tumor drugs.
As a preferred embodiment of the use according to the invention, the tumor comprises kidney, oesophagus or liver cancer. More preferably, the tumor is liver cancer.
Compared with the prior art, the invention has the following beneficial effects:
1) The invention provides a sorafenib antitumor inhibition auxiliary compound (Ti 3), which improves and prolongs the inhibition effect of sorafenib on tumor cells, reduces the drug resistance of tumors to sorafenib, and further improves the curative effect of sorafenib;
2) The invention also provides an anticancer composition, the bioavailability of the sorafenib is improved by combining the small molecular compound Ti3 and the sorafenib, the combination of the two can enable the drug effect to generate a synergistic effect on treating tumors, and the effect is obviously superior to that of single drug.
Drawings
FIG. 1 is a graph of the effect of sorafenib, ti3 alone or in combination on the activity of liver cancer cell lines;
FIG. 2 is a graph of the effect of sorafenib, ti3 alone or in combination on the apoptosis of hepatoma cell lines;
FIG. 3 is a balloon culture photoscope map and a quantitative analysis map of liver cancer cells by sorafenib and Ti3 alone or in combination;
FIG. 4 is a graph of the effect of sorafenib and Ti3 alone or in combination on tumor cell growth.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
In the following examples, hepatoma cell lines Hep3B cells were purchased from ATCC cell bank (HB-8065); hepatoma cell line 97L was from university of fudan; the CCK-8 kit was purchased from Homophilus Japan chemical (CK 04); nude mice were purchased from Beijing Wintolite (BALB/c Nude); sorafenib (i.e., sora) was purchased from seleck corporation (S7397).
Example 1 Effect of Sorafenib, ti3 alone or in combination on the Activity of liver cancer cell lines
Mixing hepatocarcinoma cell (hepatoma cell line Hep3B cell or hepatoma cell line 97L) at 8 × 10 3 Uniformly spreading the cells in a 96-well cell culture plate at a density of one cell/well, treating the cells with sorafenib with different concentrations the next day, taking 40 mu M as the highest concentration of the sorafenib substances, then carrying out 2-fold dilution, setting 10 treatment groups in total, adding the same amount of culture medium into a control group, and setting three multiple wells in each group.
The cells in the Ti3+ sorafenib combined treatment group were treated by adding 30. Mu.M Ti3 simultaneously. After 48 hours of treatment, CCK8 assays were performed and median inhibitory concentration (IC 50) values were calculated using GraphPad software. The effects of different concentrations of sorafenib and Ti3 taken alone or in combination on the activity of the hepatoma cell line Hep3B cells or the hepatoma cell line 97L are shown in tables 1-3 and figure 1.
TABLE 1 Effect of Sorafenib alone or in combination on the hepatoma cell line Hep3B cell Activity
TABLE 2 Effect of sorafenib alone or in combination on the Activity of 97L cells from the hepatoma cell line
TABLE 3 influence of Ti3 alone on the Activity of hepatoma cell lines Hep3B cells and 97L cells
The results in tables 1-3 and fig. 1 show that Ti3 itself does not significantly inhibit the effects of hepatoma cell lines Hep3B and 97L, but when combined with sorafenib, the effect of sorafenib in inhibiting the activity of hepatoma cells can be significantly improved.
Example 2 Effect of Sorafenib, ti3 alone or in combination on apoptosis in hepatoma cell lines
Treating liver cancer cell (hepatoma cell line Hep3B cell or hepatoma cell line 97L) at 2 × 10 5 Uniformly spreading the cells in each well in a 12-well cell culture plate, respectively treating the cells with sorafenib (5 mu M), ti3 (15/30 mu M) + sorafenib groups the next day, taking the cells in the untreated group as a control group, collecting the cells after 24 hours, and then carrying out apoptosis detection by using an apoptosis detection kit.
Analysis results show that Ti3 does not have the effect of obviously promoting apoptosis of liver cancer cell lines Hep3B and 97L, but can obviously improve the effect of sorafenib on promoting apoptosis of liver cancer cells after being combined with sorafenib (see figure 2).
Example 3 Effect of Sorafenib, ti3 alone or in combination on growth of balloon of hepatoma cells
Mixing the liver cancer cells at 2 × 10 3 Cell/well density was plated in 24-well low-adhesion culture plates, fresh serum-free medium was added, and the content of CO was 5% at 37 ℃% 2 The incubation was continued for about 10 days to form cell balloons. Counting standards are set according to the size of the saccule according to the observation results, the saccule forming number of different groups of cells is recorded, and then detection analysis is carried out.
The analysis result shows that after Ti3 and sorafenib are combined, the effect of sorafenib on inhibiting the growth of the hepatoma cell balloon is more obvious (see figure 3).
Example 4 nude mouse tumorigenesis experiment
Will be 5X 10 6 The cells/mouse were injected into the subcutaneous part of the right hind limb of nude mice, and after 3-4 weeks, tumor formation was observed, and then tumor mice were divided into four groups: placebo control group, sorafenib group (25 mg/kg mouse weight), ti3 group (10 mg/kg mouse weight), sorafenib + Ti3 group (sorafenib: 25mg/kg mouse weight; ti3:10mg/kg mouse weight), 5 mice per group were treated with drugs by oral administration (gavage). Twice a week, one month after drug treatment, samples were taken and statistically analyzed (t-test)Experiment).
The analysis result shows that the effect of the Ti3 alone is not obviously different from that of a placebo control group; when Ti3 and sorafenib are used together, the effect of sorafenib on inhibiting tumor growth is more obvious (see figure 4).
The invention provides a sorafenib antitumor inhibition auxiliary compound (Ti 3), although Ti3 has no antitumor effect, the invention can improve and prolong the inhibition effect of sorafenib on tumor cells, reduce the drug resistance of tumors to sorafenib and further improve the curative effect of sorafenib; the invention also provides an anticancer composition, the bioavailability of the sorafenib is improved by combining the small molecular compound Ti3 and the sorafenib, the combination of the two can enable the drug effect to generate a synergistic effect on treating tumors, and the effect is obviously superior to that of single drug.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (5)
1. An anticancer composition, which is characterized by comprising sorafenib and a sorafenib antitumor inhibition auxiliary compound, wherein the formula of the sorafenib antitumor inhibition auxiliary compound is as follows: c 15 H 13 BrN 2 An OS; the structural formula of the sorafenib antitumor inhibition auxiliary compound is as follows:
the ratio of the content of the sorafenib to the content of the sorafenib antitumor inhibitor auxiliary compound is 1.
2. A pharmaceutical formulation comprising the anti-cancer composition of claim 1.
3. The pharmaceutical formulation of claim 2, further comprising a pharmaceutical excipient.
4. The pharmaceutical preparation according to claim 3, wherein the pharmaceutical preparation is in the form of an oral preparation or an injectable preparation.
5. The use of the anticancer composition of claim 1 in the preparation of a liver cancer medicament.
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| CN113004183B true CN113004183B (en) | 2023-03-14 |
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