CN112794852B

CN112794852B - Selenium-containing organic compound and preparation method and application thereof

Info

Publication number: CN112794852B
Application number: CN202110034109.7A
Authority: CN
Inventors: 贺贤然; 钟敏
Original assignee: Jianghan University
Current assignee: Jianghan University
Priority date: 2021-01-12
Filing date: 2021-01-12
Publication date: 2021-11-30
Anticipated expiration: 2041-01-12
Also published as: CN112794852A

Abstract

The invention discloses a selenium-containing organic compound and a preparation method and application thereof, wherein the selenium-containing organic compound comprises a compound shown in a formula I, and the compound shown in the formula I has unexpected biological activity for preventing and/or treating tumors and can be effectively used for preventing and/or treating various cancers. The prepared compound shown in the formula I has cytotoxic activity to different tumor cells, particularly has good cytotoxic activity to SW480 cell strains, is superior to a control medicament 5-fluorouracil, and can play a better role in inhibiting the tumor cells. Animal experiment results show that the compound I has the effect of inhibiting tumor growth on S180-bearing mice, the tumor inhibition effect is obvious, and the antitumor effect (5mg/kg) is superior to that of a control compound 5-fluorouracil under the same dose. Thus, compound I showed higher tumor growth inhibition efficiency than 5-fluorouracil.

Description

Selenium-containing organic compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of biological medicines, in particular to a selenium-containing organic compound and a preparation method and application thereof.

Background

Malignant tumors have become a worldwide prominent public health problem today. At present, the cancer treatment modes mainly include surgical treatment, radiotherapy, chemotherapy, biological treatment and the like, wherein the chemotherapy is still the main treatment mode.

Cancer occurs as a mass of abnormal tissue in a living host organism, which receives nutrients from the host without relying on host hyperproliferation and destroys the host organism. The human organ is composed of a large number of cells. Cancer occurs when normal cells of the human body become abnormal cells and the abnormal cells divide and proliferate without examination. Although genetic factors are critically involved in the development of cancer, environmental factors also have a significant impact on whether an individual is developing cancer. Cancer is particularly prevalent in developed countries. It has been reported that the causes of cancer are increased use of pesticides, insecticides, etc. (and thus the amount of such substances remaining in foods) and consumption of processed foods containing additives such as food preservatives and colorants, increased pollution of water, soil and air, stress of modern life, reduction of activities, obesity caused by greasy dietary habits, etc. In recent years, it has also been pointed out that cancer is caused when the cell signaling system of normal cells fails, when cancer genes are activated, or when cancer suppressor genes fail.

There are many methods of treating cancer, for example, surgery, radiation therapy, chemotherapy, and immunotherapy, and the combined use of several methods can increase survival. Cancer cell metastasis between organs is a problem facing the treatment of cancer, however surgery and radiotherapy are limited for its treatment. Therefore, chemotherapy is mainly used. Chemotherapy is generally performed using anti-cancer drugs, and many chemotherapeutic drugs have been reported. These antineoplastic agents are broadly classified into the following categories: an antitumor alkylating agent represented by cyclophosphamide; an antitumor antimetabolite represented by 5-fluorouracil; antitumor antibiotics represented by doxorubicin hydrochloride; antineoplastic drugs derived from plants, represented by vincristine and paclitaxel; an anti-tumor platinum complex represented by cisplatin; and so on.

However, it is known that the toxicity of anticancer drugs acts not only on cancer cells but also on normal cells of patients, causing side effects. Therefore, development of new anticancer drugs having higher cancer cell selectivity and as little toxicity as possible is desired.

Therefore, there is still an urgent need in the art for new compounds for preventing and/or treating tumors with good effects. How to develop a new anticancer drug with higher cancer cell selectivity and as little toxicity as possible becomes a technical problem to be solved urgently.

Disclosure of Invention

The invention aims to provide a selenium-containing organic compound and a preparation method thereof, wherein the selenium-containing organic compound has unexpected biological activity for preventing and/or treating tumors and can be effectively used for preventing and/or treating various cancers.

In order to achieve the above object, an embodiment of the present invention provides a selenium-containing organic compound, which includes a compound represented by formula I:

further, the selenium-containing organic compound also comprises at least one of pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites and prodrugs of the compound shown in the formula I.

The embodiment of the invention also provides a pharmaceutical composition, which comprises:

an effective amount of said selenium-containing organic compound,

at least one pharmaceutically acceptable excipient or carrier.

The embodiment of the invention also provides a preparation method of the selenium-containing organic compound, which comprises the following steps:

carrying out chlorine substitution reaction on the compound shown in the formula IV and a chlorinated reagent to obtain a compound shown in a formula III;

reacting the compound shown in the formula III with potassium selenocyanate under the action of a catalyst to obtain a compound shown in a formula II;

reacting the compound shown in the formula II with trifluoromethyl trimethylsilane to obtain a compound shown in the formula I;

further, the chlorinating agent comprises one of thionyl chloride, chlorosulfonic acid and tert-butyl hypochlorite.

Further, the mass ratio of the compound shown in the formula III to the potassium selenocyanate is 1 (1-2).

Further, the catalyst is potassium iodide, and the weight ratio of the compound shown in the formula III to the potassium iodide is 1: (1-2).

Further, the mass ratio of the compound shown in the formula II to the trifluoromethyl trimethylsilane is 1: (1-2).

The embodiment of the invention also provides application of the selenium-containing organic compound and the pharmaceutical composition in preparing medicines for preventing and/or treating tumors.

Further, the tumor includes at least one of colon cancer, breast cancer, prostate cancer, cervical cancer, liver cancer, and lung cancer.

One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

according to the selenium-containing organic compound and the preparation method thereof provided by the embodiment of the invention, the compound shown in the formula I has unexpected biological activity for preventing and/or treating tumors, and can be effectively used for preventing and/or treating various cancers. The prepared compound shown in the formula I has cytotoxic activity to different tumor cells, particularly has good cytotoxic activity to SW480 cell strains, is superior to a control medicament 5-fluorouracil, and can play a better role in inhibiting the tumor cells. Animal experiment results show that the compound I has the effect of inhibiting tumor growth on S180-bearing mice, the tumor inhibition effect is obvious, and the anti-tumor effect is better than that of a control compound 5-fluorouracil under the same dosage (5 mg/kg). Thus, compound I exhibited a higher tumor growth inhibition efficiency than 5-fluorouracil.

Drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on the drawings without creative efforts.

Fig. 1 is a flow chart of a method for preparing a selenium-containing organic compound according to embodiment 1 of the present invention.

Detailed Description

The embodiments of the present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the embodiments of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that the present embodiments and examples are illustrative of the present invention and are not to be construed as limiting the present invention.

Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention belong. If there is a conflict, the present specification will control.

Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the examples of the present invention are commercially available or can be obtained by an existing method.

The embodiment of the invention provides a preparation method of a selenium-containing organic compound, which has the following general idea:

according to an exemplary embodiment of the present invention, there is provided a selenium-containing organic compound comprising a compound represented by formula I:

as an alternative embodiment, the selenium-containing organic compound further includes at least one of pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites and prodrugs of the compound of formula I.

The compounds of formula I of the present embodiments may exist in the form of their pharmaceutically acceptable salts. The pharmaceutically acceptable salts are salts of the compounds of formula I with inorganic or organic acids. Such inorganic or organic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid; acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic or toluenesulfonic acid.

According to another exemplary embodiment of the present embodiments, there is provided a pharmaceutical composition comprising: an effective amount of said selenium-containing organic compound, and at least one pharmaceutically acceptable excipient or carrier.

By "pharmaceutically acceptable excipient or carrier" is meant a medium commonly accepted in the art for delivering biologically active agents to an animal, particularly a mammal, and includes, i.e., adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.

"pharmaceutical composition" means a mixture containing one or more compounds of formula I, as described herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, and other chemical components, such as pharmaceutically acceptable excipients or carriers. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity. In the pharmaceutical compositions of the embodiments of the present invention, other pharmaceutically active ingredients may be further included in addition to the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the invention may be prepared by conventional techniques, for example as described in Remington: the method described in The Science and Practice of Pharmacy, 19 th edition, 1995, which is incorporated herein by reference. The compositions may be presented in conventional forms, such as capsules, tablets, aerosols, solutions, suspensions or topical application forms.

Typical compositions comprise a compound of formula I of the present invention or a salt thereof and a pharmaceutically acceptable excipient or carrier. For example, the active compound is typically mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet (sachet), paper or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, the carrier can be a solid, semi-solid, or liquid material that serves as a carrier, excipient, or medium for the active compound. The active compound may be adsorbed on a particulate solid carrier (e.g. contained in a sachet). Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

The formulations may be mixed with adjuvants which do not deleteriously react with the active compound. These additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffering and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.

The route of administration may be any route which is effective for transporting a compound of formula I of the present invention to the appropriate or desired site of action, for example, oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal or parenteral routes, such as rectal, depot (depot), subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments, with the oral route being preferred.

If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule as a powder or pellet, or it may be in the form of a troche (troche) or lozenge. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

Injectable dosage forms typically comprise an aqueous or oily suspension, which may be formulated using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in the form of a solution phase or a suspension prepared with a solvent or diluent. Acceptable solvents or carriers include sterile water, ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Preferably, the oil or fatty acid is non-volatile and comprises a natural or synthetic oil, a fatty acid, a monoglyceride, diglyceride, or triglyceride.

For injection, the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For injections, the formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these agents. The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or in multi-dose containers.

The formulations of the present invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by methods well known in the art. Thus, the formulation may also be formulated for controlled release or slow release.

According to another exemplary embodiment of the present invention, there is provided a method for preparing the selenium-containing organic compound, the method including:

s1, carrying out a chlorine substitution reaction on the compound shown in the formula IV and a chlorinated reagent to obtain a compound shown in a formula III;

as an alternative embodiment, the chlorinating agent comprises one of thionyl chloride, chlorosulfonic acid, and tert-butyl hypochlorite. The ratio of the compound of formula III to thionyl chloride is 1: (1-6), the reaction temperature is 0-60 ℃, and the reaction time is 2-12 h; under the reaction condition, the chlorine substitution reaction is complete.

S2, reacting the compound shown in the formula III with potassium selenocyanate under the action of a catalyst to obtain a compound shown in a formula II;

specifically, the method comprises the following steps:

dissolving the compound shown in the formula III in an organic solvent, adding potassium selenocyanate and a catalyst potassium iodide, heating for reaction, and purifying to obtain the compound shown in the formula I.

The mass ratio of the compound shown in the formula III to the potassium selenocyanate is 1: (1-2), wherein the weight ratio of the compound shown in the formula III to the potassium iodide is 1: (1-2). The mass ratio is favorable for the reaction to be complete. If the potassium selenocyanate is too much or too little, the reaction is not favorable for being complete; if the potassium iodide is added too little to be beneficial to the reaction, the potassium iodide is added too much to cause waste;

the heating reaction temperature is 0-50 ℃, and the heating reaction time is 12-24 h. The reaction conditions are favorable for the complete reaction, and if the reaction temperature is lower than 0 ℃ or higher than 50 ℃, the reaction is unfavorable for the complete reaction.

S3, reacting the compound shown in the formula II with trifluoromethyl trimethylsilane to obtain a compound shown in the formula I;

as an alternative embodiment, the mass ratio of the compound of formula II to trifluoromethyltrimethylsilane is 1: (1-2), the reaction temperature is 0-40 ℃, and the reaction time is 2-6 h; this mass ratio and reaction temperature are favorable for the completion of the reaction.

The preparation method provided by the embodiment of the invention is simple, has high yield, and can easily prepare the compound shown in the formula I.

According to another exemplary embodiment of the present invention, there is provided a use of the selenium-containing organic compound and the pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of tumors.

The compounds of the embodiments of the invention are useful for treating, preventing or ameliorating diseases, disorders or conditions, including tumors and cancers. The term "cancer", as used herein, refers to an uncontrolled abnormal growth of cells and under certain conditions is capable of metastasizing (spreading). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (e.g., thyroid), prostate, skin (melanoma), or hematologic tumors (e.g., non-leukemias).

The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians/monkeys, equines, bovines, porcines, canines, felines, and the like) and most preferably refer to humans.

The term "treatment" as used herein includes the term "effective amount" which means an amount of a drug or pharmaceutical agent (i.e., a compound of the invention) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of: the amount results in improved treatment, cure, prevention, or alleviation of the disease, disorder, or side effect, or reduces the rate of progression of the disease or disorder, as compared to a corresponding subject not receiving the above amount. An effective amount may be administered in one or more administrations, administrations or dosages and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.

Preferably, the tumor is selected from colon cancer, breast cancer, prostate cancer, cervical cancer, liver cancer and lung cancer; particularly preferably, the tumor is selected from breast cancer, colorectal cancer, ascites tumors including sarcoma and liver cancer; particularly preferably, the tumor is sarcoma or liver cancer.

The compounds of formula I of the present embodiments are effective over a wide dosage range. For example, in the treatment of adults, a dosage of about 0.01 to about 5000mg, preferably about 0.1 to about 2000mg, more preferably about 0.2 to about 2000mg per day may be used. Typical dosages are from about 0.1mg to about 1000mg per day. When selecting a patient treatment regimen, it may often be necessary to start with a higher dose and reduce the dose when the condition is controlled. The precise dosage will depend upon the mode of administration, the desired treatment, the form of administration, the subject to be treated and the weight of the subject to be treated, as well as the preferences and experience of the attending physician.

In general, the compounds of formula I of the present invention are dispensed in unit dosage forms containing from about 0.05mg to about 1000mg of the active ingredient per unit dose and a pharmaceutically acceptable carrier.

In general, dosage forms suitable for oral, nasal, pulmonary or transdermal administration include from about 100 μ g to about 1250mg, preferably from about 150 μ g to about 500mg, more preferably from about 1.5mg to about 250mg of the compound of formula I in admixture with a pharmaceutically acceptable carrier or diluent.

The dosage form may be administered once daily, or more than once daily, e.g., twice daily or three times daily. Alternatively, the dosage form may be administered less frequently than once daily, for example every other day or weekly, if deemed appropriate by the prescribing physician.

The pharmaceutical compositions of the embodiments of the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquids or gels. Tablets and capsules for oral administration may be in a form suitable for unit dose administration and may contain conventional excipients, such as: binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, silica, talc, polyethylene glycol or silicon dioxide; disintegrants such as potato starch; acceptable lubricants such as sodium lauryl sulfate. The tablets may be coated according to known methods of conventional pharmaceutical practice. The oral liquid preparation can be made into aqueous or oily suspension, solution, emulsion, syrup or tincture, or made into a dry substance, and reconstituted with water or other suitable carrier before use. These liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats and oils). Emulsifying agents (e.g. lecithin, sorbitol monooleate or acacia), non-aqueous vehicles (including edible oils such as almond oil, fractionated coconut oil, fats and oils such as glycerol, propylene glycol or ethanol), preservatives (e.g. methyl or propyl p-hydroxybenzoic acid or sorbic acid), and if desired conventional flavours or colouring agents.

The dosage may vary with the method and dosage form of administration, as well as the age, weight, condition and sensitivity of the patient. In the case of oral administration, an effective daily dosage range, for example, may be from 20mg to 1 g. Single dose units containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of from 20mg to 200mg may conveniently be employed to meet the daily dosage requirements. The dosages and dosage units used may be outside the ranges indicated above.

The percentage of active substance in the pharmaceutical composition of the present invention is variable because the pharmaceutical formulation must be formulated in a suitable proportion of the dosage to achieve the desired therapeutic effect. In general, the pharmaceutical preparations of the invention can be administered orally or by injection in an amount of 0.1 to 15 mg of the compound of formula I per day per 70kg of body weight. The following examples are for the purpose of illustrating certain aspects of the invention and should not be construed as limiting the scope of the invention in any way.

The selenium-containing organic compound, the preparation method and the application thereof will be described in detail below with reference to examples and experimental data.

EXAMPLE 1 Compounds of formula I and methods for their preparation

The compound of formula I is prepared according to the reaction equation shown below, which specifically comprises:

synthesis of Compounds of formula III

In a three-hole flask, 110 mg of compound of formula IV was dissolved in 5ml of thionyl chloride at 0 ℃ and stirred well, heated to 50 ℃ and stirred for 5 hours more, TLC showed complete reaction, spun dry and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give compound of formula III (150 mg) in 85% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃)δ:7.89(bs,1H,-NH),7.42(d,2H,J＝7.8Hz,ArH), 7.32(t,2H,J＝7.8Hz,ArH),7.24(t,1H,J＝7.8Hz,ArH),4.91(s,2H,-CH₂),3.79(s,3H,-CH₃), 2.21-2.23(m,2H,-CH₂),2.02-2.04(m,2H,-CH₂).

HRMS[ESI]Calculated value (M +1)⁺317.1210; found 317.1223.

Synthesis of compounds of formula II

150 mg of compound of formula III was dissolved in 5ml acetonitrile, followed by the addition of potassium selenocyanate (82 mg), potassium iodide (80 mg), heating to 40 ℃ and stirring for 2 hours, TLC showed complete reaction, after the reaction was cooled to room temperature, 20 ml water, 10 ml dichloromethane were added, the aqueous phase was separated, extracted 2 times with dichloromethane (15 ml 2), the combined organic phases were dried over anhydrous sodium sulfate, spun dry, and the crude product was purified by preparative TLC (DCM/MeOH ═ 7:1) to give II (70 mg) as a pale yellow solid in 45% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃)δ:7.82(bs,1H,-NH),7.39(d,2H,J＝7.8Hz,ArH), 7.30(t,2H,J＝7.8Hz,ArH),7.22(t,1H,J＝7.8Hz,ArH),4.88(s,2H,-CH₂),3.75(s,3H,-CH₃), 2.28-2.30(m,2H,-CH₂),2.12-2.14(m,2H,-CH₂).

HRMS[ESI]Calculated value (M +1)⁺388.0718; found 388.0721.

Synthesis of Compounds of formula I

100 mg of the compound of formula II was dissolved in 5ml of anhydrous tetrahydrofuran, and trifluoromethyl trimethylsilane (120 mg), tetrabutylammonium fluoride (100 mg) were added in that order, stirred at room temperature for 6 hours, TLC showed completion of the reaction, after the reaction liquid cooled to room temperature, 20 ml of water and 10 ml of ethyl acetate were added, the layers were separated, the aqueous phase was extracted 2 times with ethyl acetate (15 ml 2), the combined organic phases were dried over anhydrous sodium sulfate, spun dry, and the crude product was purified by preparative TLC (DCM/MeOH ═ 3:1) to give white solid I (60 mg) in 50% yield.

Nuclear magnetic resonance¹H NMR(400MHz,CDCl₃)δ:7.88(bs,1H,-NH),7.45(d,2H,J＝7.8Hz,ArH), 7.35(t,2H,J＝7.8Hz,ArH),7.30(t,1H,J＝7.8Hz,ArH),4.95(s,2H,-CH₂),3.88(s,3H,-CH₃), 2.32-2.41(m,2H,-CH₂),2.10-2.12(m,2H,-CH₂).

HRMS[ESI]Calculated value (M +1)⁺431.0700; found 431.0721.

EXAMPLE 1 Effect of Compounds of formula I on tumor cell survival

Log phase cells were taken at 3X 10 per well⁴Inoculating on a 96-well plate, adding 200. mu.L of DMEM medium to each well, removing the supernatant after 12h, adding the compound I prepared in example 3 to each well, and culturing for 24h according to a blank group and an addition group (the concentrations are 0,2.5,5,10,20,30 and 50. mu.M respectively), and removing the supernatant. mu.L of MTT-containing solution prepared by dissolving MTT (thiazole blue, Biyuntian reagent) in phosphate buffer (PBS, pH 7.3) at a concentration of 0.5mg/mL was added thereto and incubated for 4 hours, and then 100. mu.L of dimethyl sulfoxide (DMSO) was added to each well, followed by shaking for 1 hour to measure the OD (optical density) value at 570nm on a microplate reader. Fitting and calculating the gradient dosage of each tumor cell line and the corresponding proliferation inhibition rate to obtain a nonlinear regression equation, IC₅₀The value is the amount of the drug added when the tumor cell line proliferation inhibition rate is 50%. Wherein, the proliferation inhibition ratio = (blank OD value-administered OD value)/blank OD value. The results show that the activity of the tumor cells is obviously reduced after the medicine is added. The experiment respectively detects the cytotoxic activity of human colon cancer cells HCT116, SW480 and HT29, the cell strains are purchased from ATCC, 5-fluorouracil is a positive control drug, and specific results are shown in Table 1.

TABLE 1

The experimental results in table 1 show that the prepared compound I has cytotoxic activity against different tumor cells, especially has good cytotoxic activity against SW480 cell lines, is superior to the control drug 5-fluorouracil, and can play a better role in tumor cell inhibition.

EXAMPLE 2 in vivo antitumor Activity of Compounds of formula I

The experimental animal selects SPF level male Kunming mouse with the body mass of 19-22g, which is provided by animal experiment center of Wuhan university, tumor strain mouse S180 sarcoma is introduced by pharmaceutical research institute of Chinese medical academy of sciences, the seed is frozen and preserved in laboratory at low temperature, the S180 cell for experiment is cell suspension for 4 th generation after recovery, and the positive control drug selects 5-fluorouracil.

The S180 tumor-bearing mouse model is established by aseptically extracting ascites from S180 mice, counting the cell suspension under a microscope, and adjusting the cell concentration to 2.0 × 10⁷and/mL, 0.2mL of the S180 ascites tumor fluid was inoculated subcutaneously in the right armpit of the mouse aseptically, and 20 healthy mice were divided into groups at random according to body weight.

Administration method and calculation of tumor inhibition rate administration was started on day 2 after tumor cell inoculation in mice, and the mice were randomly divided into 3 dose groups of high, medium and low compound I, positive control group (5-fluorouracil, 1.5mg/kg) and negative control group according to body weight, administered intraperitoneally 1 time per day with administration volume of 0.5 mL/mouse, experimental administration time of 9 days, animals were sacrificed 24h after the last administration, body mass was weighed, tumor mass was dissected and mass was weighed, and tumor growth inhibition rate was calculated according to the following formula.

TABLE 2 inhibitory Effect of Compound I on mouse S180

As can be seen from the animal experiment results in Table 2, the compound I has the effect of inhibiting tumor growth on S180-bearing mice, and the tumor inhibition effect is obvious, and the anti-tumor effect is better than that of the control compound 5-fluorouracil under the same dose (5 mg/kg).

Thus, compound I exhibits a higher tumor growth inhibition efficiency than 5-fluorouracil finally, it is also noted that the terms "comprises", "comprises" or any other variation thereof are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but also other elements not expressly listed or inherent to such process, method, article, or apparatus.

While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including the preferred embodiment and all such alterations and modifications as fall within the true scope of the embodiments of the invention.

It will be apparent to those skilled in the art that various modifications and variations can be made in the embodiments of the present invention without departing from the spirit or scope of the embodiments of the invention. Thus, if such modifications and variations of the embodiments of the present invention fall within the scope of the claims of the embodiments of the present invention and their equivalents, the embodiments of the present invention are intended to include such modifications and variations as well.

Claims

1. A selenium-containing organic compound is characterized by comprising a compound shown as a formula I and a pharmaceutically acceptable salt of the compound shown as the formula I;

。

2. a pharmaceutical composition, comprising:

an effective amount of the selenium-containing organic compound of claim 1,

at least one pharmaceutically acceptable excipient or carrier.

3. A method of preparing the selenium-containing organic compound of claim 1, comprising:

。

4. the method of claim 3, wherein the chlorinating agent comprises one of thionyl chloride, chlorosulfonic acid, and tert-butyl hypochlorite.

5. The method for preparing the selenium-containing organic compound as claimed in claim 3, wherein the mass ratio of the compound represented by the formula III to the potassium selenocyanate is 1 (1-2).

6. The method according to claim 5, wherein the catalyst is potassium iodide, and the weight ratio of the compound of formula III to the potassium iodide is 1 (1-2).

7. The method according to claim 3, wherein the mass ratio of the compound represented by formula II to the trifluoromethyltrimethylsilane is 1 (1-2).

8. Use of a selenium-containing organic compound according to claim 1 and a pharmaceutical composition according to claim 2 for the preparation of a medicament for the prevention and/or treatment of tumors.

9. The use of claim 8, wherein the tumor comprises at least one of colon cancer, breast cancer, prostate cancer, cervical cancer, liver cancer, and lung cancer.