TWI450715B - Fenbufen derivatives of cancer treatment - Google Patents

Description

Fenbufen derivatives for the treatment of cancer

The present invention relates to the synthesis of fenbufen derivatives and their use in the treatment of cancer.

Cancer, also known as malignant tumor, is a disease caused by abnormal cell proliferation. In addition to uncontrolled growth of cancer cells, cancer cells locally invade the surrounding normal tissues and even transfer to other parts of the body via the internal circulatory system or lymphatic system. There are many types of cancer, and the severity of the condition depends on where the cancer is located and the extent of malignant growth, and whether metastasis occurs. The doctor can make a diagnosis based on the biopsies of the examinee or the tissue obtained through surgery, or even the content of the biomarker. Most cancers can be treated or even cured depending on their type, location, and stage of development. Once diagnosed, cancer is usually treated in combination with surgery, chemotherapy, and radiation therapy. As scientific research progresses, many drugs for specific types of cancer have been developed, and therapeutic effects have also been enhanced. If the cancer is left untreated, usually the end result will result in death.

Cancer is now the leading cause of death worldwide. According to the World Health Organization, about 10 million people worldwide suffer from cancer every year. It is estimated that the number of new cases in the world will reach 27 million a year in 2030, and the number of deaths will reach 17 million. The situation will be accompanied by an increase in the world population. It is even more serious, which shows that the cancer medical market is huge.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a generic term for non-steroidal drugs that block the production of inflammatory substances. The mechanism of action of these drugs is mainly to inhibit cyclooxygenase (COX, including COX). -1, enzymes such as COX-2), to prevent the conversion of arachidonic acid to prostaglandins and induce an inflammatory response. NSAIDs contain a wide variety of drugs, such as aspirin, naproxen, diclofenac, ibuprofen, fenbufen, and fenbufen. In recent years, some research teams have pointed out that abnormal COX-2 enzymes are produced in some cancer tissues. It is speculated that COX-2 enzymes may be involved in cell cancer, so many NSAIDs It has also become a candidate for the development of cancer drugs.

The present invention relates to the use of fenbufen derivatives for the treatment of cancer. The fenbufen derivative disclosed in the present invention has the following chemical formula (I-1) characteristics: Wherein NR represents a guanamine-based molecule, and R represents a carboxylic acid molecule which loses a hydroxyl group by performing a guanidation reaction, and may be selected from a benzene ring-type carboxylic acid, a heterocyclic carboxylic acid, a halogen-ring carboxylic acid, and a long Chain carboxylic acid or halogen chain carboxylic acid.

The benzene ring type carboxylic acid molecule of the present invention is selected from the following molecules (A1-A23):

The heterocyclic carboxylic acid molecule of the present invention is selected from the group consisting of the following molecules (B1-B20):

The halocyclic carboxylic acid molecule of the present invention is selected from the group consisting of the following molecules (C1-C26):

The long chain carboxylic acid molecule of the present invention is selected from the group consisting of the following molecules (D1-D18):

The halogen chain carboxylic acid molecule of the present invention is selected from the following molecules (E1-E15):

Preferred fenbufen derivatives of the invention are selected from the group consisting of:

The fenbufen derivative of the present invention is toxic to cancer cells. In other words, this The cancer cells referred to in the invention refer to epithelial cell-like cancer cells, including lung cancer, breast cancer, rectal cancer, and prostate cancer cells.

The invention also provides a method for killing cancer cells by using a fenbufen derivative, the steps of which are as follows: (1) preparing a fenbufen derivative: (1-1) amidating fenbufen; (1-2) The amine group of the imipenem tail is again reacted with other carboxylic acid molecules to carry out guanidation to bind the two molecules; (2) Formulation dosage form: the product is formulated into an appropriate dosage form for use by cancer patients The appropriate dosage form referred to herein may be a spray, an oral medicinal tablet, a syrup, an ointment, an injection or any pharmaceutically acceptable pharmaceutical dosage form.

In the above method for killing cancer cells by using the fenbufen derivative, the preferred steps for preparing the fenbufen derivative are as follows: (1) preparing an amine group at both ends (or having an amine group and an azide group, respectively) (2) amidation of fenbufen by using the linker molecule; (3) reconstituting the amine group of the fenbufen tail of the amidated group with another carboxylic acid molecule to carry out amidelation to connect These two molecules.

Synthesis of fenbufen derivatives

The preparation process of the fenbufen derivative is shown in Fig. 1, and is summarized as follows: First, a butylbutane-1,4-diamine (compound 1) having an amine group at both ends is prepared. It is reacted with TfN ₃ (trifluoromethanesulfonyl azide) to oxidize the amine group at one end to an azide group (compound 2); fenbufen (compound 3) is additionally prepared to react with compound 2 in HBTU (O-benzotriazole) - N,N,N', N'-tetramethyl-uronium-hexafluorophosphate), DIEA( N,N- diisopropylethylamine) and DMSO (dimethyl sulfoxide) are subjected to guanidation to form compound 4; The nitrogen group is reduced to an amine group by hydrogen (H ₂ ) and a palladium carbon catalyst (Pd/C) to form compound 5; finally, compound 5 is further subjected to amidoximation with other carboxylic acid molecules (R ₁ COOH). The final product compound 6 was synthesized and purified. Compound 6 is the fenbufen derivative of the present invention.

In this synthesis reaction, the purpose of using a linking molecule is to allow fenbufen to be linked to other molecules by using its hydroxyl group. Therefore, in practice, as long as a compound having such a function can be used as a linking molecule, it is not limited to 4-azido-1-butylamine as described in this example; in other words, fenbufen itself has a carboxylic acid property and therefore can also directly react with other compounds in the role of R ₁ COOH in Figure 1, where In this case, the step of using the linker molecule can be omitted.

The carboxylic acid molecules attached to fenbufen in Figure 1 can be roughly classified into the following five categories: benzene ring carboxylic acids (Fig. 2, A1-A23), heterocyclic carboxylic acids (Fig. 3, B1-B20), halogen rings. Carboxylic acids (Fig. 4, C1-C26), long chain carboxylic acids (Fig. 5, D1-D18) and halogen chain carboxylic acids (Fig. 6, E1-E15). The synthesized fenbufen derivative has a total of 102 products.

Cancer cell toxicity test

When the 102 fenbufen derivatives are synthesized, the cancer cell toxicity test can be performed. The cancer cell lines used in the experiment were human lung cancer cell A549 (No. 60074, Food Industry Development Research Institute), human breast cancer cell MCF7 (No. 60436, Food Industry Development Research Institute), mouse prostate cancer cell Tramp C-1 ( National Tsinghua University, Jiang Qixun Laboratory) and mouse rectal cancer C26 (Atomic Energy Commission, Institute of Nuclear Energy). The test method was the MTT (3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) test. The control drugs used in the toxicity test were Cisl1atin (positive control group) and Benzoid acid (negative control group).

The test procedure is summarized as follows: the cells are cultured in a 96-well plate, and the MTT reagent and the test drug having a final concentration of 100 μM are added, and then the cells are cultured for a period of time to perform absorbance measurement to determine whether the drug to be tested has cells. Poisoning effect.

Figures 7 to 11 show the results of preliminary toxicity tests of 102 fenbufen derivatives, and the vertical axis represents cell survival rate (%). It can be seen from the figure that many fenbufen derivatives are toxic to these cells, and when fenbufen couples different kinds of carboxylic acids, it will cause different degrees of cytotoxicity. In addition, cell lines from different sources will also To the extent of the same compound Different sensibility.

Further analysis of the carboxylic acid species, it can be clearly seen that the best poisoning effect is polycyclic acid, followed by monocyclic acid, halocyclic acid and monocyclic acid are similar. Having said that, monocyclic acid appears to be more effective against A549 than halocyclic and polycyclic acids, while polycyclic acid is more effective against MCF7 and C26.

As for the linear acid, it can be seen that there is almost no difference in the tendency of the halogen acid and the general long chain acid for A549 and Tramp C-1. However, for MCF7 and C26, long chain acids appear to be more toxic than halogen acids. Halocycline appears to have a more toxic effect on MCF7 and C26 than on halogenated acid.

In terms of cell strain sensitivity, the 102 fenbufen derivatives disclosed by the present invention have better toxicity to C26 cell lines.

In this experiment, three compounds with particularly strong poisoning effects were also found, as shown in Figure 12, which are A23 coupled product (I-2), D5 coupled product (I-3), and C23 coupled product (I-4). ). Further determination of the IC ₅₀ values of the three derivatives for different cell lines yielded the following data:

In addition to the above three compounds, many other fenbufen derivatives can achieve an IC ₅₀ effect at a concentration of 100 μM or less, and these three compounds are only provided as experimental references.

Figure 1. Synthesis of fenbufen derivatives

Figure 2, benzene ring carboxylic acid

Figure 3. Heterocyclic carboxylic acid

Figure 4. Halocyclic carboxylic acid

Figure 5. Long chain carboxylic acid

Figure 6. Halogen chain carboxylic acid

Figure 7. Toxicity test of fenbufen coupled benzocyclic carboxylic acids for different cell lines

Figure 8. Toxicity test of fenbufen coupled heterocyclic carboxylic acids for different cell lines

Figure 9. Toxicity test of fenbufen-coupled halocyclic carboxylic acids for different cell lines

Figure 10. Toxicity test of fenbufen-coupled long-chain carboxylic acids for different cell lines

Figure 11. Toxicity test of fenbufen-coupled halogen chain carboxylic acids for different cell lines

Figure 12. Three fenbufen derivatives with better cancer cell toxicity

Claims (7)

A composition for treating cancer comprising a compound represented by the following formula (I-1) as an active ingredient Where R is selected from the following: Indicates the location of the connection. The composition of claim 1, wherein the compound is selected from the group consisting of the following molecules (I-2, I-3, I-4): The composition of claim 1, which is toxic to epithelial cell-like cancer cells. The composition according to claim 1, which is toxic to lung cancer, breast cancer, rectal cancer or prostate cancer cells. A method for preparing a fenbufen derivative for killing cancer cells, the steps of which are as follows: (1) amidoxicamylation of fenbufen; (2) amination of the amine group at the tail of fenbufen The fenbufen derivative is a compound represented by the formula (I-1) of the first aspect of the patent application by reacting with other carboxylic acid molecules to carry out amidation. According to the method of claim 5, wherein the step of preparing the amidation of the step (1) is as follows: (1-1) preparing a linked carbon chain having an amine group at one end and an azide group at the other end; 1-2) The fenbufen is aminated using this linked carbon chain. According to the method of claim 5, the method further comprises: formulating the fenbufen derivative into a suitable dosage form, wherein the appropriate dosage form can be a spray, an oral tablet, a syrup, an ointment, an injection or any Pharmaceutically acceptable pharmaceutical dosage forms.