CN110960519B

CN110960519B - Iodine-containing carboxylic acid compounds and application thereof in antitumor drugs

Info

Publication number: CN110960519B
Application number: CN201911377791.9A
Authority: CN
Inventors: 魏艳红; 李妮; 王海杰; 王龙胜; 朱茂春
Original assignee: Hubei University of Technology
Current assignee: Hubei University of Technology
Priority date: 2019-12-27
Filing date: 2019-12-27
Publication date: 2021-05-18
Anticipated expiration: 2039-12-27
Also published as: CN110960519A

Abstract

The invention discloses an iodic carboxylic acid compound and application thereof in antitumor drugs. Through research and experiment on the antitumor activity of the iodine-containing carboxylic acid, L4 and L5 in the compounds show certain antitumor cell proliferation activity. The inhibitory activity of L4 on human cervical cancer cells (Hela) and human liver cancer cells (HepG2) is basically equivalent to that of a positive control medicament 5-fluorouracil. L5 shows the strongest inhibition effect, can simultaneously inhibit the growth of human hepatoma cell strains (HepG2), human lung cancer cells (A549), human cervical cancer cells (Hela) and human breast cancer cells (MCF-7), has the inhibition effect basically equivalent to that of a positive control compound 5-fluorouracil, and has potential application in preparing antitumor drugs.

Description

Iodine-containing carboxylic acid compounds and application thereof in antitumor drugs

Technical Field

The invention relates to the technical field of antitumor drugs, in particular to an iodocarboxylic acid compound and application thereof in antitumor drugs.

Background

Malignant tumor is a common disease and frequently occurring disease seriously threatening human health, and the mortality rate of human caused by the malignant tumor is the second place of all disease mortality rates and becomes the second killer of cardiovascular diseases. In the early 2013, a edition of annual report on registration of tumors in 2012, published by national tumor registration center, shows that about 312 ten thousand new cancer cases occur every year in China, and the number of cancer deaths exceeds 200 ten thousand, which means that 6 people are diagnosed as cancer every 1 minute. At present, the national cancer has a serious incidence trend, and the incidence rate and the death rate are in a continuous rising trend. Cancer has become one of the major problems that threatens the life safety of human beings seriously and affects the quality of life of human beings, and the problems caused thereby have become more and more burden for the development of socioeconomic.

At present, the treatment methods of tumors mainly comprise surgical treatment, radiation treatment and drug treatment (chemotherapy), but the drug treatment is mainly used to a great extent. Most common solid tumors such as lung cancer, liver cancer, colon cancer, pancreatic cancer and the like still lack effective drugs, and a plurality of antitumor drugs generate drug resistance in the clinical application process. With the scientific and technological progress of society, the cognition of human beings on cancer is gradually clear, and methods, technologies and theories for preventing and early diagnosing certain cancers are mature, but the cancers cannot be completely cured, and the survival time of cancer patients can be prolonged only to a very limited extent. Therefore, the research and development of novel antitumor drugs are imperative, and the continuous development of novel antitumor drugs with high efficiency and low toxicity becomes a research work with important significance at present.

Iodine-containing aromatic acids are a class of organic compounds with biological activity. For example, p-iodobenzoic acid is a potent inhibitor of cinnamate-4-HYDROXYLASE (CINNAMATE 4-HYDROXYLASE), a key enzyme in the phenylpropanoid pathway for the synthesis of lignin building blocks (Dorien Van de Wouwer, et al. plant Physiology,2016,172, 198-220); the metal salt of m-iodobenzoic acid shows better inhibitory activity to Saccharomyces cerevisiae, Hansenula anomala, Escherichia coli and Bacillus subtilis (P.Koczon, et.al.J.Agric.food chem.2001,49, 2982-2986). For example, 2,3, 5-triiodobenzoic acid (TIBA) is an excellent plant growth regulator (asherman, et al. plant physiological communications, 1958,3, 27-30). 3, 5-bis (acetamido) -2,4, 6-triiodobenzoic acid, also known as diatrizoic acid (diatrizoic acid), is an important contrast agent, and is prepared into diatrizoate sodium and diatrizoate meglumine injection, which can be used for imaging urinary system, cardiovascular system, cerebrovascular system and peripheral blood vessels (I Charles, et. al.1986, US 4567034). However, the antitumor activity of the iodine-containing carboxylic acid has not been reported so far.

Disclosure of Invention

The present invention is directed to solving the above-mentioned problems, and an object of the present invention is to provide an iodocarboxylic acid compound comprising o-I-C₆H₄CO₂H,(L1)；m-I-C₆H₄CO₂H,(L2)；p-I-C₆H₄CO₂H,(L3)；3-I-4-NH₂-C₆H₃CO₂H,(L4)；3,4-I₂-C₆H₃CO₂H, (L5) and application thereof in preparing antitumor drugs.

In the scheme of the invention, the iodine-containing carboxylic acid compounds comprise o-I-C₆H₄CO₂H,(L1)；m-I-C₆H₄CO₂H,(L2)；p-I-C₆H₄CO₂H,(L3)；3-I-4-NH₂-C₆H₃CO₂H,(L4)；3,4-I₂-C₆H₃CO₂H, (L5) was evaluated for its antitumor activity.

In order to achieve the purpose, the scheme of the invention is as follows:

in a first aspect, the present invention provides an iodocarboxylic acid compound, characterized in that: comprises the following steps:

L1：o-I-C₆H₄CO₂H，

L2：m-I-C₆H₄CO₂H，

L3：p-I-C₆H₄CO₂H，

L4：3-I-4-NH₂-C₆H₃CO₂h, and

L5：3,4-I₂-C₆H₃CO₂H；

the chemical structural formulas of L1-L5 are respectively as follows:

in a second aspect, the invention provides an application of the iodine-containing carboxylic acid in preparing an antitumor drug, which is characterized in that: the compounds L1-L5 all have a certain degree of inhibitory activity on tumor cells; wherein the compound L4 only shows inhibitory effect on tumor cells Hela and HepG 2; the compound L5 shows good inhibition effect on tumor cells Hela, HepG2 and A549, and shows general inhibition activity on MCF-7.

Preferably, when the concentration of the compound L4 is 50 mug/mL, the growth inhibition rate of the HepG2 cell and the HeLa cell is 76.7 percent and 50 percent respectively; when the concentration of the compound L5 is 50 mu g/mL, the growth inhibition rates of the compound L5 on HepG2, Hela and A549 cells are 63.9%, 79.79% and 74.3% respectively, and the growth inhibition rate on MCF-7 cells also reaches 50%.

Furthermore, after any one of the compounds L1-L5 is added with pharmaceutically acceptable auxiliary materials and carriers, the compound is used for preparing an anti-tumor preparation.

Further, the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.

The scheme of the invention provides the inhibitory activity of series iodine-containing carboxylic acid on human liver cancer cells HepG2, human lung cancer cells A549, human cervical cancer cells Hela and human breast cancer cells MCF-7. The iodine-containing carboxylic acid of the present invention can be prepared into various practical agents such as granules, tablets, pills, capsules, injections, suspensions or emulsions by a conventional method.

According to the invention, through activity screening research, the compounds have the effect of inhibiting the growth of tumor cells to different degrees. The compound L4 has certain inhibitory activity on Hela and HepG2 cells, the IC50 of the Hela cells is 50 mu g/mL, which is equivalent to that of the control drug 5-Fu, and the IC50 of the HepG2 is 20 mu g/mL, which is slightly better than that of the control drug 5-Fu; the compound L5 has better inhibition effects on HepG2, A549 and Hela (IC50 is respectively 30, 40 and 35 mu g/mL), has basically equivalent inhibition activity to 5-Fu, and has poorer inhibition effect on MCF-7.

The compound is low in price and easy to obtain. The series of compounds can search for anti-tumor effect targets through structure-activity relationship research, and can foresee great application potential

Compared with the prior art, the invention has the following advantages and beneficial effects:

1. the anti-tumor activity of the iodine-containing carboxylic acid is not reported, and the iodine-containing carboxylic acid has a certain guiding effect on the development of the anti-tumor activity.

2. The antitumor drugs are searched from the compounds with similar structures, the action targets of the antitumor drugs are easy to find through the structure-activity relationship research, and certain reference significance is provided for further drug development.

Drawings

FIG. 1 shows the inhibitory activity of the series of iodine-containing carboxylic acids (50. mu.g/mL) of the present invention on various tumor cells.

FIG. 2 shows that the compounds L4 and L5 of the present invention inhibit tumor cell proliferation in a concentration-dependent manner.

FIG. 3 shows the cytopathic effect (CPE) of tumor cells induced by the effective compounds L4 and L5 of the present invention.

Detailed Description

The invention is described in further detail below with reference to the figures and specific examples.

The structures of the iodine-containing carboxylic acids used in the present invention to evaluate antitumor activity are as follows:

test tumor cells: human liver cancer cell HepG2, human lung cancer cell A549, human cervical carcinoma cell Hela and human breast cancer cell MCF-7.

Cell culture: the culture solution is prepared from a GIBCO DMEM culture medium, a GIBCO 1640 culture medium, 10% fetal calf serum and 0.01% L-glutamine. The cultured cell line was incubated at 37 ℃ with 5% CO₂The cells in logarithmic growth phase were used for the experiments after routine culture and passage under saturated humidity.

[ example 1 ] evaluation of antitumor activity in vitro (MTT method):

the above tumor cells were plated on 96-well plates respectively at 37 ℃ with 5% CO₂After the culture box is cultured to grow a monolayer, cell culture solution is discarded, cell maintenance solution containing test compounds with different concentrations is respectively added for continuous culture, cells without drug action are used as blank control, anti-tumor drug 5-fluorouracil (5-Fu) is used as positive control, each group is provided with 3 multiple holes, and continuous culture is carried out for 48 hours. The cells were visualized and individually recorded by microscope, 30. mu.L of MTT (5mg/mL) was added to each well and the culture was continued for 4h, the supernatant was discarded, 50. mu.L of DMSO was added thereto, incubation was carried out at 37 ℃ for 10min, and the absorbance at 490nm was measured by a microplate reader (A490). The average inhibition was calculated according to the following formula:

the inhibition rate (average OD490 value in cell control group-average OD490 value in drug group)/average OD490 value in cell control group) × 100%.

The test results show that the compounds L4 and L5 have the best inhibitory activity. The IC50 of the compound L4 for the tumor cell Hela is 50 mug/mL, and the IC50 for the tumor cell HepG2 is 20 mug/mL, which is slightly better than that of the positive control drug 5-Fu. The compound L5 has better inhibition effect on tumor cells Hela, HepG2 and A549(IC50 is 35, 30 and 40 mu g/mL respectively), has basically equivalent inhibition activity on 5-Fu, and has poorer inhibition effect on MCF-7. The half inhibitory concentration IC50 is shown in table 1 below.

TABLE 1 series of inhibitory activities of iodocarboxylic acids on different tumor cells

In table 1:^aIC 50: half inhibitory concentration.^b5-Fu, 5-fluorouracil, positive control.

The inhibitory activity of the 50. mu.g/mL series of iodine-containing carboxylic acids on different tumor cells is shown in FIG. 1. Compound No. L4 showed the strongest antitumor activity against HepG2 tumor cells. The compound L5 shows strong inhibition effect on MCF-7 tumor cells and other tumor cells at 50 μ g/mL. The positive control drug 5-Fu shows relatively uniform inhibition effect on the tumor cells.

The concentration-dependent inhibition activity of representative compounds L4, L5 on different tumor cells is shown in fig. 2. The compound L4 showed concentration-dependent inhibitory activity on HepG2 cells and the compound L5 on Hela, HepG2, A549 and MCF-7 cells.

[ example 2 ]

In this example, the cytopathic effect of HepG2 and Hela cells caused by compound L4, and the cytopathic effect of three tumor cells of Hela, HepG2 and a549 caused by compound L5 were recorded by further taking a picture with a microscope. The specific implementation method comprises the following steps:

hela, HepG2 and A549 cells in logarithmic growth phase were plated in 96-well plates respectively at 37 ℃ with 5% CO₂Culturing in incubator, removing cell culture solution, adding cell maintenance solution containing compounds of 50 μ g/mL L4 and 50 μ g/mL L5, culturing, observing with microscope at 48 hr, and photographingA cytopathic condition.

The pathological effect of the compound on tumor cells is shown in figure 3. The untreated tumor cells grow well, adhere firmly, are full in shape and have clear edge boundaries. Treatment with 50. mu.g/mL L4 and 50. mu.g/mL L5 compounds for 48h resulted in apoptosis of tumor cells, which were rounded off in different forms and shed from the culture plates. The strong growth inhibition effect of the L4 and L5 compounds on tumor cells can be seen.

In conclusion, the series of iodine-containing carboxylic acids L4 and L5 have good effects of inhibiting the proliferation of different tumor cells, wherein L5 has stronger and broader-spectrum inhibition effect and shows great application potential. If further studied clinically, it is hopeful to prepare a drug effective against tumor diseases.

Claims

1. The application of the iodine-containing carboxylic acid compounds in preparing the antitumor drugs is characterized in that: the compounds include the following:

L4：3-I-4-NH₂-C₆H₃CO₂h, and

L5：3,4-I₂-C₆H₃CO₂H；

the chemical structural formulas of L4-L5 are respectively as follows:

the compounds L4-L5 all have a certain degree of inhibitory activity on tumor cells; wherein the compound L4 only shows inhibitory effect on tumor cells Hela and HepG 2; the compound L5 has good inhibition effect on tumor cells Hela, HepG2 and A549, and has general inhibition activity on MCF-7;

when the concentration of the compound L4 is 50 mug/mL, the growth inhibition rates of the compound L4 on HepG2 cells and Hela cells are 76.7% and 50% respectively; when the concentration of the compound L5 is 50 mu g/mL, the growth inhibition rates of the compound L5 on HepG2, Hela and A549 cells are 63.9%, 79.79% and 74.3% respectively, and the growth inhibition rate on MCF-7 cells also reaches 50%.

2. The use of the iodine-containing carboxylic acids as claimed in claim 1, in preparing antitumor drugs, characterized in that: after pharmaceutically acceptable auxiliary materials and carriers are added into the compound L4, the compound L4 is used for preparing a preparation for inhibiting the activity of tumor cells Hela or/and HepG 2.

3. The use of the iodine-containing carboxylic acids as claimed in claim 1, in preparing antitumor drugs, characterized in that: after pharmaceutically acceptable auxiliary materials and carriers are added into the compound L5, the compound L5 is used for preparing a preparation for inhibiting the activity of tumor cells Hela, HepG2 or/and A549.

4. The use of the iodine carboxylic acid compounds according to claim 2 or 3, wherein: the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.