CN116284021B - Compounds having therapeutic effect on bladder cancer - Google Patents
Compounds having therapeutic effect on bladder cancer Download PDFInfo
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- CN116284021B CN116284021B CN202111468318.9A CN202111468318A CN116284021B CN 116284021 B CN116284021 B CN 116284021B CN 202111468318 A CN202111468318 A CN 202111468318A CN 116284021 B CN116284021 B CN 116284021B
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- rhodamine
- bladder cancer
- cancer cells
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- 206010005003 Bladder cancer Diseases 0.000 title claims abstract description 115
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 title claims abstract description 114
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 105
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- VYXSBFYARXAAKO-UHFFFAOYSA-N ethyl 2-[3-(ethylamino)-6-ethylimino-2,7-dimethylxanthen-9-yl]benzoate;hydron;chloride Chemical compound [Cl-].C1=2C=C(C)C(NCC)=CC=2OC2=CC(=[NH+]CC)C(C)=CC2=C1C1=CC=CC=C1C(=O)OCC VYXSBFYARXAAKO-UHFFFAOYSA-N 0.000 claims abstract description 38
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a rhodamine derivative and a green catalytic synthesis method thereof, wherein rhodamine 6G hydrochloride and amine are used as main raw materials, sodium phenolate is used as an accelerator, and under the condition of stirring at room temperature in an air atmosphere by taking acetonitrile as a solvent, the rhodamine derivative is obtained with higher yield. The method has the advantages of low cost, high yield, simple operation, no pollution and the like, and has potential industrial application prospect. The method provides a cheap and green way for preparing rhodamine derivatives. The results of biological experiments on the rhodamine derivatives for inhibiting the bladder cancer cells indicate that the rhodamine derivatives have obvious and strong cell activity inhibition effect on the bladder cancer cells at the cellular level. Through later-stage mouse bladder perfusion experiments, up to 40 days of drug perfusion, rhodamine derivatives have good anticancer effect, and related mechanisms are researched, and the rhodamine derivatives 3f are found to cause bladder cancer cells to pass through mitochondrial apoptosis paths.
Description
[ field of technology ]
The invention belongs to the field of catalytic organic synthesis and biological application, and relates to rhodamine derivatives, a synthesis method and biological activity thereof; in particular to a novel method for synthesizing rhodamine derivatives by removing micromolecular ethanol through ammonolysis reaction of ester of rhodamine 6G hydrochloride and amine compound under the condition of taking sodium phenolate as an accelerator. According to the method, rhodamine 6G hydrochloride and amine compounds are used as main raw materials, sodium phenolate is used as an accelerator, and under the conditions of acetonitrile as a solvent and air atmosphere, the rhodamine derivatives can be obtained in higher yield by stirring at room temperature. The synthesized rhodamine derivative is applied to experiments for inhibiting bladder cancer cells and curing mouse bladder cancer.
[ background Art ]
Bladder cancer has been one of the most common conditions worldwide in recent decades. Bladder cancer patients have approximately 75% of non-myogenic invasive bladder cancers, including Ta, tis and stage T1. Currently, the primary treatment for non-myogenic invasive bladder cancer is transurethral cystectomy, in combination with adjuvant chemotherapy and immunotherapy to co-treat bladder cancer. The auxiliary chemotherapy is particularly important after the operation, as the residual problem of tumor cells after the operation can be solved and the curative effect can be achieved. The drugs commonly used for the treatment of bladder cancer are mitomycin C, pirarubicin, hydroxycamptothecin, epirubicin, gemcitabine, and the like. And a large amount of medicines can be used for a long time, so that the problems of certain side effects and medicine compatibility can exist. Therefore, it is important to develop a more effective drug which is convenient for real-time monitoring and can assist in treating bladder cancer. Molecular imaging has shown very excellent results in biological applications, from which tumor size, extent of spread and tumor aggregation location can be determined. The rhodamine derivative is used as a basic skeleton of fluorescence imaging, so that the rhodamine derivative is a good choice.
Rhodamine derivatives are an important framework structure widely existing in analytical chemistry and material chemistry. The rhodamine derivative has very wide application in the aspect of biological application. Fluorescent probes based on organic small molecular rhodamine skeleton structures have become an efficient and effective technique for biological imaging. Rhodamine and its derivatives are capable of efficiently, highly selectively and rapidly recognizing various metal ions, such as iron ions, aluminum ions, mercury ions, nickel ions, chromium ions, and the like, as heavy metal ions. In addition, rhodamine derivatives are important applications in cell imaging, regulation of light of various colors, probes utilizing pH response, multifunctional polymers, and the like. Bladder cancer has become a very high prevalence disease worldwide today, and its prevalence continues to increase. Recent researches show that rhodamine derivatives have good cell imaging function, and meanwhile, the compounds have certain response to pH values, so that ring opening and ring closing functions can be realized. The rhodamine derivative has stronger anti-tumor activity, and the structure-activity relationship has good guiding significance for the design and synthesis of anti-tumor drugs.
In the past ten years, high-yield synthesis and high-efficiency biological application of rhodamine derivatives have attracted great attention in the field of scientific research. From the viewpoint of green synthesis chemistry, the amide obtained by amination of an ester bond is one of the ideal synthesis methods. The ammonolysis reaction of esters is one of the most important methods for forming amide bonds. The ammonolysis reaction of the ester is to directly utilize amino functional groups in different reaction substrates to carry out dealcoholization reaction under the condition of an accelerator so as to form an amide bond. In general, to obtain a successful dealcoholization condensation product, one or two pre-functionalized reactants are typically required, and conventional reactions require the conversion of the carboxyl group to the acid chloride, followed by reaction with an amine to give the corresponding product. But have more problems in terms of efficiency and cost effectiveness. Compared with the traditional method, the method has the advantages that the amine is directly reacted with the ester, the need of preparing the pre-functionalized material is avoided, the organic synthesis is simpler and more efficient, the shorter synthesis route and the high atom utilization efficiency are realized, a new thought and means are provided for directly utilizing simple raw materials to perform efficient and complex organic synthesis tasks, and great contribution is made to green synthesis chemistry. The traditional method for synthesizing rhodamine derivatives requires the addition of excessive amine and prefunctionalized substrate, high reaction temperature and protective gas, and is more troublesome to operate. Therefore, aiming at the defects existing in the current synthesis method, a mild reaction condition is designed, and rhodamine derivatives are successfully synthesized by utilizing a strategy of promoting rapid and efficient ester decomposition of amine by alkali. According to the method, rhodamine 6G hydrochloride and amine compounds are used as raw materials, sodium phenolate is used as an accelerator, and under the conditions of acetonitrile as a solvent and air atmosphere, the rhodamine derivatives can be obtained in a high yield by stirring at room temperature, and special equipment requirements are not required. The synthetic rhodamine derivative is subjected to an acid-base response experiment to obtain a good pH response result, and medicine molecules with good anticancer activity on bladder cancer cells are screened out from the rhodamine derivative. Finally, a plurality of groups of mice are subjected to subcutaneous experiments by using drug molecules with good drug effects, rhodamine derivative drug molecules are infused in the experiments, and in the treatment process of up to 40 days, the mice can achieve obvious treatment effects. Mice without drug infusion are increasingly ill, and infusion of our drug molecule rhodamine derivatives results in a certain therapeutic effect in mice. At present, no published literature and patent application for preparing rhodamine derivatives by using sodium phenolate as an accelerator through an ammonolysis reaction of esters at room temperature and applying the rhodamine derivatives to the treatment of bladder cancer exist at home and abroad.
[ invention ]
The invention aims to provide rhodamine derivatives and a preparation method thereof, wherein the catalytic synthesis method uses sodium phenolate as an accelerator, and the rhodamine derivatives can be obtained with higher yield by stirring at room temperature under the conditions of acetonitrile as a solvent and air atmosphere. The rhodamine 6G hydrochloride and the amine compound are subjected to ammonolysis reaction of ester under the action of sodium phenolate serving as an accelerator, and the reaction is performed under the condition of acetonitrile solvent, so that a better reaction effect can be obtained. The method has the advantages of low cost, high yield, simple operation, no pollution and the like, and has certain feasibility for realizing the industrialized production. In order to achieve the above purpose, the present invention proposes the following technical scheme:
in order to achieve the above purpose, the present invention proposes the following technical scheme:
rhodamine derivatives I and a synthesis method thereof, wherein the rhodamine derivatives I have the following structural formula:
wherein said R is 1 Is selected from the group consisting of benzyl, 4-tert-butylbenzyl, 3, 5-dimethoxybenzyl, 4-trifluoromethylbenzyl, 2-furanmethyl, 2-picolyl, 2-thiophenoethyl, phenethyl, 3-methylphenyl, 4-nitrophenyl, indole, 3-ethylindole, gemcitabine, 2-hydroxypropyl, 2-ethylhexyl, dodecyl, cyclopropylmethyl, 2-tetrahydrofuranmethyl, 4-epoxyhexacyclic methyl, N-morpholinopropyl, 2-cyclohexenoethyl, isopropoxypropyl, cyclopropenyl, cyclobutyl, cyclopentyl and cyclohexenyl; the green catalytic synthesis method of the compound I is characterized in that sodium phenolate is used as an accelerator, rhodamine 6G hydrochloride II and an amine compound III are used as reaction raw materials, the rhodamine derivative I with higher yield can be obtained in the time of 14 hours through effective reaction in acetonitrile solvent at 25 ℃;
in the above synthetic method, the rhodamine 6G hydrochloride II and the amine compound III have the following structural formulas:
wherein said R is 1 Is selected from the group consisting of benzyl, 4-tert-butylbenzyl, 3, 5-dimethoxybenzyl, 4-trifluoromethylbenzyl, 2-furanmethyl, 2-picolyl, 2-thiophenoethyl, phenethyl, 3-methylphenyl, 4-nitrophenyl, indole, 3-ethylindole, gemcitabine, 2-hydroxypropyl, 2-ethylhexyl, dodecyl, cyclopropylmethyl, 2-tetrahydrofuranmethyl, 4-epoxyhexacyclic methyl, N-morpholinopropyl, 2-cyclohexenoethyl, isopropoxypropyl, cyclopropenyl, cyclobutyl, cyclopentyl and cyclohexenyl;
in the synthesis method, the rhodamine 6G hydrochloride II and the amine compound III which are used as raw materials are used as reaction raw materials in a ratio of 1:1.5; the using amount of the accelerator is 2 equivalents, and the organic solvent is acetonitrile; the reaction time is 14h, and the reaction temperature under illumination is 25 ℃.
The high-efficiency catalytic synthesis method of rhodamine derivatives opens up a new low-cost green path,the advantages are that: rhodamine 6G hydrochloride and amine compound sources as raw materials are wider, and target compound is produced The method has the advantages of high rate, mild reaction conditions, no need of multi-step reaction, avoidance of synthesis of acyl chloride and simple and convenient reaction operation. In addition, the rhodamine is derived The compound has good anti-bladder cancer activity, and the apoptosis mechanism of the compound is studied.
The inventor synthesizes rhodamine derivatives and carries out experiments on bladder cancer tumor cell resistance. Because the rhodamine derivative can open a loop under an acidic condition, and can close a loop under an alkaline condition. First, the synthesized compounds 3a-3aa were tested for fluorescence response in different pH environments, and the detailed results are shown in FIGS. 2A and 2B of the specification and FIG. 7 of the specification. Subsequently, the inventor screens out that 3f, 3w and 3m have good pH response values, and further tests the bladder cancer cells for toxic and side effects. Compared with the control experiment, the surface dishes added with 3f, 3w and 3m can be observed to have obvious inhibition effect on bladder cancer cells, and detailed results are shown in figure 2C of the specification. Next, the inhibition of bladder cancer cells by 3f, 3w and 3m at different pH conditions was further examined, as shown in fig. 3A and 3B of the specification, and observed under electron microscopy, as shown in fig. 3C of the specification. Since 3f has a good inhibition effect on bladder cancer cells, the inventor applies 3f to a bladder perfusion experiment of a mouse, and finds that after 40 days, the bladder tumor of the mouse has an obvious curative effect, and specific biological data are shown in an attached figure 4 of the specification. Flow cytometry shows that 3f causes early apoptosis and late apoptosis, and that apoptosis-related genes Bax, decomposed Caspase-9 (Caspase 9 enzyme) and decomposed Caspase-3 (Caspase 3 enzyme) are also detected, as shown in FIG. 5 of the specification. In addition, the inventor also researches the inhibition mechanism of 3f on bladder cancer, and the result shows that rhodamine compound 3f leads to a path of cancer cell mitochondria to undergo apoptosis,rhodamine derivative 3f enters cancer cells to act on mitochondria, and then mitochondrial membrane pore channels release apoptosis factors, so that apoptosis is caused, and the specific result is shown in figure 6 of the specification. 3f nuclear magnetic data: 1 H NMR(400MHz,CDCl 3 )δ8.18(d,J＝4.5Hz,1H),8.02(d,J＝6.8Hz,1H),7.52-7.48(m,2H),7.31(t,J＝7.4Hz,1H),7.18-7.02(m,2H),6.96-6.79(m,1H),6.29(s,2H),6.08(s,2H),4.50(s,2H),3.43(s,2H),3.20(q,J＝6.8Hz,4H),1.77(s,6H),1.32(t,J＝7.1Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ168.0,157.6,153.4,151.7,148.1,147.1,135.2,132.5,131.0,128.6,128.0,123.8,1223.0,122.8,120.8,117.4,105.5,96.4,65.2,45.5,38.2,16.5,14.7.HRMS(ESI)m/z:[M+H] + calcd for C 32 H 33 N 4 O 2 + 505.2598,Found 505.2596, the specific spectrogram is shown in figure 8 of the specification and figure 9 of the specification.
[ description of the drawings ]
FIG. 1 is a route diagram for preparing rhodamine derivatives.
FIG. 2 is a graph showing the fluorescence response and the inhibition effect of bladder cancer tumor cells at different pH values of rhodamine derivatives provided by the invention.
FIG. 3 is a graph showing the inhibitory effect and electron microscope of bladder cancer tumor cells under different pH values of rhodamine derivatives 3f, 3w and 3 m.
Fig. 4 is a graph of experimental data of rhodamine derivative 3f bladder perfused mice tumors provided by the invention.
Fig. 5 is a diagram of the mechanism study data of the rhodamine derivative 3f provided by the invention for inhibiting bladder cancer.
FIG. 6 is a graph showing apoptosis of bladder cancer cells caused by rhodamine derivative 3f provided by the invention.
FIG. 7 is a graph showing fluorescence response of rhodamine derivatives 3a to 3aa according to the present invention at different pH values.
Fig. 8 is a nuclear magnetic resonance spectrogram of rhodamine derivative 3f provided by the invention.
Fig. 9 is a nuclear magnetic carbon spectrum of rhodamine derivative 3f provided by the invention.
[ detailed description ] of the invention
The invention provides a high-efficiency catalytic synthesis method of rhodamine derivatives, which is shown in the accompanying drawings: rhodamine 6G hydrochloride 0.10mmol and amine 0.15mmol are added into a 10mL reaction tube, 2 equivalents of sodium phenolate and 2mL acetonitrile are added, and the mixture is effectively reacted for 14 hours at the temperature of 25 ℃ to obtain the target compound rhodamine derivative.
The rhodamine derivative provided by the invention mainly comprises the following steps of:
(1-1) cell culture: the bladder cancer cells for experiments are cultured in vitro, and after the cells grow to the logarithmic growth phase, digestion and passage are carried out.
(1-2) 96-well plates: bladder cancer cell line EJ was prepared as a single cell suspension in RPMI-1640 medium containing 10% fetal bovine serum, and 5000 cells per well were seeded into 96-well plates at a volume of 100. Mu.L per well, and the confluency of the cultured cells reached 60% -70% (typically 24 hours of culture).
(1-3) dosing treatment: after 24 hours of incubation, the old broth was gently aspirated, and the cultured cells were treated with rhodamine derivatives at different concentrations (0, 1, 5, 10, 20, 30 or 40 μm) for 24 hours of treatment with the drug, respectively; after 24 hours of incubation, old broth was gently aspirated, and cells under different pH environments (5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 or 8.5) were treated with rhodamine derivatives, respectively, for 24 hours of treatment with the drug;
(1-4) CCK-8 detection: after 24 hours of incubation, the old culture broth was gently aspirated, 90 μl of serum-free medium and 10 μl LCCK-8 detection reagent were added to each well, incubated at 37deg.C in the dark for 1 to 2 hours, then 450nm wavelength was selected, absorbance values of each well were measured on a microplate reader, the results were recorded, and a cell viability assay result graph was drawn based on the recorded results.
The biological test of inducing bladder cancer cell death by rhodamine derivative, detecting cell death by using an LDH cytotoxicity detection kit mainly comprises the following experimental steps:
(2-1) cell culture: EJ cells in flask were incubated at 37℃with 5% CO 2 Is cultured in a cell culture tank until the cells are in the logarithmic growth phase.
(2-2) 96-well plates: bladder cancer cell line EJ was prepared as a single cell suspension in RPMI-1640 medium containing 10% fetal bovine serum, and 5000 cells per well were seeded into 96-well plates at a volume of 100. Mu.L per well, and the confluency of the cultured cells reached 60% -70% (typically 24 hours of culture).
(2-3) dosing treatment: after 24 hours of incubation, old broth was gently aspirated, cells under different pH environments (5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 or 8.5) were treated with rhodamine derivatives, respectively, for 24 hours of treatment with the drug, and negative and positive controls were set.
(2-4) collecting cell supernatants: after 24 hours, 10. Mu.L of Lysis Buffer,37℃and 5% CO were added to the positive control group 2 Culturing in an incubator for 30min, gently sucking out, collecting cell supernatant of each well, centrifuging, adding into a new 96-well plate, adding 100 mu L Working Solution into each well, incubating for 2 hours at room temperature in the dark, adding 50 mu L Stop Solution into each well, measuring absorbance at 490nm with an enzyme-labeled instrument, recording the result, and drawing a cell viability detection result graph according to the recorded result.
A biological experiment for inhibiting proliferation and clone formation of bladder cancer cells by rhodamine derivatives mainly comprises the following experimental steps:
(3-1) taking logarithmic phase cells, digesting with 0.25% pancreatin and gently blowing to obtain single cells, counting living cells, and adjusting cell density to 0.1X10 with DMEM medium containing 20% fetal bovine serum 4 /mL。
(3-2) preparing 0.7% and 1.2% agarose solution respectively with double distilled water, autoclaving, and placing in a water bath at 40 ℃ to keep the non-coagulated state.
(3-3) after 1.2% agarose solution and 2 XDMEM medium (containing 2 XStreptomyces and 20% fetal bovine serum) were thoroughly mixed in a ratio of 1:1, 3 mL/well was added to a six-well plate, and the mixture was allowed to solidify by cooling.
(3-4) after mixing 0.7% agarose solution and 2 XDMEM medium (containing 2 XStreptomyces and 20% fetal bovine serum) in a sterile tube at a ratio of 1:1, 0.2mL of the cell suspension was added to the tube, thoroughly mixed, and poured into a tube covered with 1.2%Double agar layers were formed in six well plates of agarose bottom. After the upper layer agar is solidified, placing the agar at 37 ℃ and 5% CO 2 Culturing in an incubator for 14 days.
(3-5) the six-well plate was placed under an inverted microscope, the number of cell clones was observed, and the formation rate was calculated.
(3-6) 1mL of 0.005% crystal violet was added to each well and the mixture was stained for 1 hour and photographed under a mirror.
At animal level, the rhodamine derivative experiment for inhibiting the growth of the bladder cancer tumor tissue mainly comprises the following experimental steps:
(4-1) taking logarithmic phase cells, digesting with 0.25% pancreatin and gently blowing to obtain single cells, counting living cells, diluting EJ tumor cell concentration to 5×10 6 100 mu L, re-suspending the cells, inoculating the cells under the right armpit of a male nude mouse with the age of 3-4 weeks, observing and waiting for the growth of tumor tissues to reach a proper size, and then carrying out subsequent experiments;
(4-2) random distribution of tumor-bearing nude mice to groups, subcutaneous injection of 22.35. Mu.M preparation 22 drug at pH 5.5,6.5,7.5,8.5, dosing every 2-3 days, recording tumor tissue volume every 5 days;
(4-3) humane sacrifice of nude mice after about 2 months, dissecting subcutaneous tumor tissue and weighing;
(4-4) after embedding tumor tissues, an antibody against proliferation-related antigen Ki-67 was selected for immunohistochemical reaction experiments.
The invention is further illustrated below in connection with specific examples of preparation:
preparation 3a
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =benzyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =benzyl), a brown solid was obtained in 96% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of bladder cancer cells, and the results show that the rhodamine derivative is at the cellular levelHas less cell activity inhibition effect on bladder cancer cells.
Preparation 3b
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =4-tert-butylbenzyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =4-tert-butylbenzyl) to give a brown solid with a yield of 81%. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation 3c
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =3, 5-dimethoxybenzyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =3, 5-dimethoxybenzyl) to give a brown solid in 65% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3d
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =4-trifluoromethylbenzyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =4-trifluoromethylbenzyl) to give a brown solid in 78% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation 3e
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 1.50mmol of =2-furanmethyl), 0.2mmol of sodium phenolate and 2mL of acetonitrile are added, and the reaction is carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-furanmethyl), a brown solid was obtained in 74% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3f
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 1.50mmol of 2-picolyl), 0.2mmol of sodium phenolate and 2mL of acetonitrile were added and the reaction was carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-picolyl) to give a brown solid in 86% yield. The results of experiments on inhibiting the activity of bladder cancer cells and inducing apoptosis of bladder cancer cells by using the rhodamine derivative show that the rhodamine derivative has very remarkable cell activity inhibition effect on bladder cancer cells at the cellular level. And the mouse experiment shows that the medicine has good anti-tumor effect.
Preparation of 3g
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =2-thiophenoethyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-thiopheneethyl) to give a brown solid in 86% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation for 3h
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =phenethyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =phenethyl), a brown solid was obtained in 76% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation 3i
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 1.50mmol of 3-methylphenyl), 0.2mmol of sodium phenolate and 2mL of acetonitrile were added, and the reaction was carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =3-phenylmethyl), a brown solid was obtained in 27% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3j
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =4-nitrophenyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =4-nitrophenyl) to give a brown solid in 28% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3k
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =5-indole) 1.50mmolSodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =5-indole) to give a brown solid with a yield of 55%. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation 3l
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =3-indoloethyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =3-indoloethyl) to give a brown solid in 89% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3m
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 Gemcitabine) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =gemcitabine), a brown solid was obtained in 24% yield. The results of experiments on inhibiting the activity of bladder cancer cells and inducing apoptosis of bladder cancer cells by using the rhodamine derivative show that the rhodamine derivative has very remarkable cell activity inhibition effect on bladder cancer cells at the cellular level. And the mouse experiment shows that the medicine has good anti-tumor effect.
Preparation 3o
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =2-hydroxypropyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃The reaction was carried out for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-hydroxypropyl) to give a brown solid with a yield of 79%. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3p
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =2-ethylhexyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-ethylhexyl) to give a brown solid in 96% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3q
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =dodecyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =dodecyl), a brown solid was obtained in 96% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3r
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 1.50mmol of cyclopropylmethyl group, 0.2mmol of sodium phenolate and 2mL of acetonitrile were added, and the reaction was carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =cyclopropylmethyl), to obtainBrown solid with 85% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3s
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 1.50mmol of 2-tetrahydrofuranylmethyl group, 0.2mmol of sodium phenolate and 2mL of acetonitrile were added, and the reaction was carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-tetrahydrofuranylmethyl), a brown solid was obtained in 89% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation 3t
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 1.50mmol of 4-epoxyhexacyclic methyl group, 0.2mmol of sodium phenolate and 2mL of acetonitrile were added, and the reaction was carried out at 25℃for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =4-epoxyhexacyclic methyl) to give a brown solid in 76% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3u
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =n-morpholinoethyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =n-morpholinoethyl) to give a brown solid in 93% yield. Experiments on inhibiting the viability of bladder cancer cells by using the rhodamine derivativeAnd a biological experiment for inducing apoptosis of the bladder cancer cells, and the result shows that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3v
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =2-cyclohexenoethyl) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =2-cyclohexenoethyl) to give a brown solid in 95% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3w
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =isopropoxypropyl) 1.50mmol, 0.2mmol of sodium phenolate and 2mL of acetonitrile were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =isopropoxypropyl), to give a brown solid in 92% yield. The results of experiments on inhibiting the activity of bladder cancer cells and inducing apoptosis of bladder cancer cells by using the rhodamine derivative show that the rhodamine derivative has very remarkable cell activity inhibition effect on bladder cancer cells at the cellular level. And the mouse experiment shows that the medicine has good anti-tumor effect.
Preparation of 3x
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =cyclopropane) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =cyclopropane), a brown solid was obtained in 86% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the rhodamine derivative is used for inhibiting the activity of the bladder cancer cellsThe result shows that the rhodamine derivative has smaller cell activity inhibition effect on bladder cancer cells at the cellular level.
Preparation of 3y
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =cyclobutane) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =butane change), a brown solid was obtained in 90% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation of 3z
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =cyclopentane) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =cyclopentane), a brown solid was obtained in 87% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
Preparation 3aa
A10 mL reaction tube was charged with rhodamine 6G hydrochloride 0.0mmol and amine (R 1 =cyclohexane) 1.50mmol, sodium phenolate 0.2mmol and acetonitrile 2mL were added and the reaction was carried out at 25 ℃ for 14h. After the reaction is finished, obtaining rhodamine derivative (R) through column chromatography separation 1 =cyclohexane), a brown solid was obtained in 68% yield. The rhodamine derivative is subjected to experiments for inhibiting the activity of bladder cancer cells and biological experiments for inducing the apoptosis of the bladder cancer cells, and the results show that the rhodamine derivative has smaller cell activity inhibition effect on the bladder cancer cells at the cellular level.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (4)
1. Rhodamine derivative I, its characterized in that, its structural formula is as follows:
wherein R is 1 Selected from the group consisting of 4-tert-butylbenzyl, 3, 5-dimethoxybenzyl, 4-trifluoromethylbenzyl, 2-furanmethyl, phenethyl, 3-methylphenyl, 4-nitrophenyl, 2-hydroxypropyl, 2-ethylhexyl, dodecyl, cyclopropylmethyl, 2-tetrahydrofuranmethyl, 4-epoxyhexacyclic methyl, N-morpholinopropyl, 2-cyclohexenoethyl, and isopropoxypropyl.
2. The method for synthesizing rhodamine derivative I according to claim 1, wherein sodium phenolate is used as an accelerator, rhodamine 6G hydrochloride II and amine compound III are used as reaction raw materials, and the ratio of the rhodamine 6G hydrochloride II to the amine compound III is 1:1.5; the using amount of the accelerator is 2 equivalents, and the organic solvent is acetonitrile; the reaction time is 14h, and the reaction temperature under illumination is 25 ℃;
wherein the amine compound III has the following structural formula: r is R 1 -NH 2 。
3. Use of rhodamine derivatives I as defined in claim 1 for the preparation of a medicament having an anti-bladder cancer activity.
4. Application of rhodamine derivative I in preparation of medicines with anti-bladder cancer activity is characterized in thatThe structural formula is as follows:wherein R is 1 Selected from benzyl, picolyl, 2-thiophenoethyl, cyclopropanyl, cyclobutylalkyl, cyclopentanyl, cyclohexenyl.
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| CN111875611A (en) * | 2020-05-21 | 2020-11-03 | 湖南师范大学 | Fluorescent probe for reduction and activation of anticancer platinum prodrug and preparation method and application thereof |
| KR20210117762A (en) * | 2020-03-20 | 2021-09-29 | 주식회사 이노파마스크린 | A screening method for plk-1 inhibitor and plk-1 inhibitor therefrom, use of the same |
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| CN111875611A (en) * | 2020-05-21 | 2020-11-03 | 湖南师范大学 | Fluorescent probe for reduction and activation of anticancer platinum prodrug and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| "Comparison of rhodamine 6G, rhodamine B and rhodamine 101 spirolactam based fluorescent probes: A case of pH detection";Fei Deng et al.;《Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy》;20211126;第268卷;第120662-120670页 * |
| Dingheng Lu et al.."A pH-Dependent rhodamine fluorophore with antiproliferative activity of bladder cancer in Vitro/Vivo and apoptosis mechanism".《European Journal of Medicinal Chemistry》.2022,第236卷第114293-114306页. * |
| Dipankar Das et al.."A differentially selective probe for trivalent chemosensor upon single excitation with cell imaging application: potential applications in combinatorial logic circuit and memory devices".《Photochem. Photobiol. Sci.》.2012,第18卷第242-252页. * |
| 含氮杂环化合物的合成及其抗肿瘤活性研究;阳天宝;《湖南大学博士学位论文》;20220301;全文 * |
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