阅读说明：本技术 一种四氢喹啉类化合物的抗肿瘤作用 (Antineoplastic effect of tetrahydroquinoline compound ) 是由 王贯 陈亿 张帅 牟一 李代萍 于 2021-11-05 设计创作，主要内容包括：本发明涉及一种四氢喹啉类化合物的抗恶性黑色素瘤作用,属于抗肿瘤药学技术领域。本发明解决的技术问题是发现了一种四氢喹啉类化合物具有显著的酪氨酸酶活性抑制和抗恶性黑色素瘤的作用。化合物的结构如下所示,化合物具有抗恶性黑色素瘤的作用。(The invention relates to an anti-malignant melanoma effect of tetrahydroquinoline compounds, belonging to the technical field of antitumor medicine. The technical problem to be solved by the invention is to find that the tetrahydroquinoline compound has obvious tyrosinase activity inhibition and malignant melanoma resistance. The structure of the compound is shown as follows, and the compound has the function of resisting malignant melanoma.)

1. The compound with the structural formula shown as the formula I has the effect of resisting malignant melanoma:

2. use according to claim 1, characterized in that: a pharmaceutical composition contains a compound of formula I and a pharmaceutically acceptable salt, and is used for resisting malignant melanoma.

3. Use according to claim 2, characterized in that: the disease is malignant melanoma.

Technical Field

The invention relates to an anti-malignant melanoma effect of tetrahydroquinoline compounds, belonging to the technical field of antitumor medicine.

Background

Malignant melanoma is a highly invasive tumor formed by aberrant expression of melanocytes of the skin. Malignant melanoma is one of the most common tumors and is also one of the most malignant skin cancers. Pigmentation is an important feature of malignant melanoma. The research shows that the pigmentation is closely related to the abnormal expression of tyrosinase activity. Tyrosinase (EC 1.14.18.1), one of the key rate-limiting enzymes in melanin synthesis, is a type III copper ion-containing metalloprotease whose active center contains 2 copper ions and 6 histidines, and is commonly found in plants, animals, and humans. Melanin in the human body can protect the skin from harmful effects caused by environmental factors such as ultraviolet radiation, oxidative stress, and the like. However, excessive accumulation of melanin also causes many pigmentation diseases such as freckles, age spots, melasma, and the like. Therefore, tyrosinase is a key target for treating pigmentation diseases and malignant melanoma, and the tyrosinase inhibitor can be used as a candidate drug for resisting malignant melanoma.

In view of the important relationship between tyrosinase and pigmentation diseases and the occurrence and treatment of malignant melanoma, the research on tyrosinase inhibitors has been widely focused on by domestic researchers. However, at present, tyrosinase inhibitors such as kojic acid, arbutin, hydroquinone, azelaic acid and the like are commonly used as effective components of whitening cosmetics, and researches show that most of the tyrosinase inhibitors have certain side effects and cannot be widely applied. Therefore, the finding of the tyrosinase inhibitor with high efficiency and high selectivity plays an important role in treating diseases such as pigmentation diseases, malignant melanoma and the like.

Disclosure of Invention

The invention relates to an anti-malignant melanoma effect of tetrahydroquinoline compounds.

The application of the invention is characterized in that: the disease is malignant melanoma.

Furthermore, the anti-tumor drug is a targeted tyrosinase inhibitor and can play a role in resisting malignant melanoma by inhibiting tyrosinase.

The anti-tumor drug is preferably a drug for resisting malignant melanoma.

Description of the figures

Table 1 shows the results of tyrosinase inhibitory activity test and antitumor cell proliferation activity of compound I.

TABLE 1 tyrosinase inhibitory Activity test and antitumor cell proliferation Activity test results for Compound I

Fig. 1 shows the effect of compound concentration on tyrosinase inhibitory activity, and data are expressed as mean inhibition (n-3).

FIG. 2 is a kinetic experiment of the compound on tyrosinase inhibition, and the inhibition type of the compound is judged to be non-competitive inhibition according to a Lineweaver-Burk double reciprocal diagram.

Detailed Description

The above object of the present invention is achieved by the following technical solutions:

the compound is a tetrahydroquinoline compound, and the structure of the compound is shown as the following formula I:

the following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.

Test example 1 half inhibition test of tyrosinase by the Compound

A total of 0.1mL of the reaction system, 50. mu.L (10. mu.M, 30. mu.M) of the sample solution and 25. mu.L of 1mM tyrosinase solution, were added to a 0.5mL centrifuge tube, reacted at 25 ℃ for 20 minutes, then 25. mu. L2.5U/. mu. L L-Tyrosine solution was added rapidly, mixed well, and the change in Optical Density (OD) was measured at 492nm over 5 min. The experiment was repeated three times and the inhibition rate was calculated. A solvent control was phosphate buffer supplemented with 50. mu.L DMSO, and a blank control was phosphate buffer supplemented with 75. mu.L DMSO and 25. mu.L of 2.5U/. mu. L L-Tyrosine. The inhibition ratio was calculated by the following formula:

inhibition ratio%_vehicle-ΔOD_compound)/(ΔOD_vehicle-ΔOD_blank)*100％

Wherein, Δ OD_compoundΔ OD being the value of change in optical density value after inhibitor treatment_vehicleAs a change in the value of the optical density of the solvent control, Δ OD_blankThe change value of blank control optical density value.

Testing the tyrosinase inhibition rate under different concentration sample solutions, then drawing a dose response curve, namely a curve of the tyrosinase activity change along with the change of the inhibitor concentration, and obtaining the IC of the compound according to the dose response curve₅₀. The results are shown in Table 1 and FIG. 1. Kojic acid was used as a positive control drug.

As is apparent from Table 1 and FIG. 1, the compound has significantly stronger inhibitory activity on tyrosinase, better inhibitory activity than kojic acid, and is a dose-dependent inhibitory effect. Thus, compound I is a potent tyrosinase inhibitor.

Test example 2 inhibition mechanism of tyrosinase by the Compound

Two series of 1 different sample concentrations (30. mu.M) and no sample were appropriately selected, and the dosage of the substrate L-tyrosine solution was varied to measure the Δ OD values of the initial enzyme catalysis velocity at various substrate concentrations of 1000nM, 667nM, 444nM, 296nM, 198nM, 132nM, 88nM, 59nM and 39nM, respectively. In the concentration of L-tyrosine (. mu.mol/L) reciprocal 1/[ S ]]Tyrosinase catalytic activity Δ OD_{Sample (A)}Interaction plot of reciprocal 1/V, inhibition constant (K)_i) Can be calculated by a Lineweaver-Burk double reciprocal diagram. The results are shown in FIG. 2. Experimental results show that the compound I has stronger inhibitory activity on tyrosinase and is a non-competitive tyrosinase inhibitor.

Experimental example 3 antiproliferative assay of melanoma cells with Compounds

The results of the antiproliferative activity test using malignant melanoma cells are shown in Table 1. After B16F10 cells are treated by the compound, the half inhibitory concentration on malignant melanoma cells is determined, and the result shows that the compound I has obvious and strong antiproliferative activity on the malignant melanoma cells.

The combination of the experiments shows that the compound I has good tyrosinase inhibitory activity, can exert good malignant melanoma resistance, provides a powerful reference for the targeted therapy of tumors, and has wide application prospects.