CN109316479B - Preparation of naphthol compound and application of naphthol compound in cancer treatment - Google Patents
Preparation of naphthol compound and application of naphthol compound in cancer treatment Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention belongs to the field of medical biology, and discloses a design and preparation method of a brand new naphthol compound and application of the compound or biologically acceptable salt thereof as an active ingredient in the aspects of cell growth regulation mechanism and cancer treatment. Biological activity tests show that the compound has remarkable inhibition effect on STAT3 cell signal transduction in tumor cells, and has remarkable antagonism effect on proliferation of various cancer cells such as lung cancer, breast cancer, colon cancer, leukemia and the like. The compound has potential significance for clinical treatment of cancer and research on cancer mechanism, has great development potential and has good application prospect.
Description
Technical Field
The invention relates to the field of medical biology, in particular to a preparation method of naphthol compounds and application thereof in the aspect of cancer treatment.
Background
Recent cancer data in China released by the national cancer center in 2017 shows that there are 429 ten thousand new cancer cases per year in China, accounting for 20% of the global new cases, and 281 ten thousand deaths (clinical and rehabilitation of Chinese tumor, 2017 (5): 574-574). No innovative target exists in 5 anticancer new drugs on the market in the CFDA batch in China in 2017, few targeting new drugs are created in China, and the research and development level of the targeting original drugs in China is totally reflected to fall behind Europe and America. How to achieve double creation in the aspect of drug development (biological targets are new targets and novel compounds which are related to diseases and are used for clinical treatment for the first time) is a test stone for testing the actual research and development of our Chinese medicine. The novel target spot and the potential drug lead compound are sought, breakthrough is made in the specific tumor treatment field, and the method is urgent for medical research and development scientific researchers. STAT3-JAK signaling pathways have a positive regulatory effect on tumor cell growth, STAT3 proteins have been favored as biological targets for the treatment of cancer for nearly ten years, and by 2017, the us FDA approved more than 30 STAT3 signaling pathway-inhibiting anticancer drugs in clinical testing (Johnson D E, et al, nature Reviews Clinical Oncology, 2018, 15 (4): 234). The STAT3 inhibitor anticancer targeting medicine has the characteristics of novel target point, wide anticancer spectrum and the like, and recent clinical test results show that the medicine has great development potential and wide market space in the aspect of future clinical treatment of tumors. The applicant discovers that the naphthol compounds such as SMBAA002, SMBAA007 and the like belong to STAT3 inhibitors, the mechanism of inhibiting STAT3 activation of the compounds is clear, and the effect of inhibiting tumor cell growth is obvious. The compound is developed by Ruida medical science and technology Co.Ltd.
Because of its unique structural features, the naphthol compound can be combined with protein sites related to tumor diseases in organisms through polar bonds and atoms in the structure and can perform hydrogen bonding with receptors. On the other hand, the aromatic ring in the structure and enzyme and receptor related to tumor diseases form aromatic ring stacking effect, thereby achieving the purpose of inhibiting proliferation of tumor cells.
Disclosure of Invention
The invention mainly solves the technical problem of providing a naphthol compound with a structure of formula I and application of the naphthol compound in tumor cell inhibition.
In order to achieve the above object, the present invention provides the following technical solutions:
a naphthol compound with a structure of formula I,
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 each independently selected from: hydrogen, halogen, nitro, alkyl, cyano, aryl;
r5 is selected from: -H, -OH;
p=0 or 1 and,
x is-CH 2 -、-(CH 2 ) 2 -、-CO-、-CH 2 -CO-，-(CH 2 ) 2 -CO-, etc.;
m=0 or 1,
y is-CH 2 -、-(CH 2 ) 2 -、-CO-、-CH 2 -CO-、-(CH 2 ) 2 -CO-, etc.;
a is selected from:etc., wherein n=0, 1, 2, 3;
the term "halogen" as used herein means fluorine, chlorine, bromine or iodine, with preferred halogen groups being fluorine, chlorine or bromine. Further, more specifically, the naphthol compound of the present invention is one of the following compounds:
the invention also provides a preparation method of the naphthol compound of the formula I, which comprises the following steps:
the compound has the general formula I (wherein X= -CO-, -CH 2 -CO-、-(CH 2 ) 2 -CO-、Y＝-CH 2 -、-(CH 2 ) 2 -、R 5 The process comprises the steps of synthesizing the raw materials by a route shown in a scheme 1, forming an etherification intermediate by Mitsunobu reaction, hydrolyzing the raw materials by a strong alkali solution to generate corresponding carboxylic acid, purifying the carboxylic acid, performing an acylation reaction to generate corresponding acyl chloride, and finally synthesizing the target compound in an alkali environment.
Scheme 1
1a：X＝-CO-，Y＝-CH 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1b：X＝-CO-，Y＝-CH 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1c：X＝-CO-，Y＝-CH 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1d：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1e：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1f：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
Specific groups for X, Y and E include, but are not limited to, those groups/compounds described above as 1a,1b,1c,1d,1E,1f, and other compounds readily understood by those skilled in the art to be synthesized using scheme 1. The particular compounds and X, Y, E in schemes 2-3 below are defined as above, including but not limited to these particular compound components. The same should be understood for the case of the synthetic process/procedure defined in the claims, which should not be taken as limiting, but rather not limiting to the specific compounds in the procedure.
The compound has the general formula I (wherein X= -CH 2 -、-(CH 2 ) 2 -、Y＝-CH 2 -、-(CH 2 ) 2 -、R 5 = -H) can be synthesized by the route shown in scheme 2, starting materials undergo Mitsunobu reaction to form an etherified intermediate, and finally the target compound is synthesized in a strong base environment.
Scheme 2
3a：X＝-(CH 2 ) 2 -，Y＝-CH 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
3b：X＝-(CH 2 ) 2 -，Y＝-CH 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
3c：X＝-(CH 2 ) 2 -，Y＝-CH 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
3d：X＝-(CH 2 ) 2 -，Y＝-(CH 2 ) 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
3e：X＝-(CH 2 ) 2 -，Y＝-(CH 2 ) 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
3f：X＝-(CH 2 ) 2 -，Y＝-(CH 2 ) 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
The compound has the general formula I (wherein X= -CO-, -CH 2 -CO-、-(CH 2 ) 2 -CO-、Y＝-CH 2 -、-(CH 2 ) 2 -，R 5 The process comprises the steps of synthesizing the target compound by a route shown in a scheme 3, wherein raw materials are amide intermediates synthesized by the scheme 1, oxidizing the amide intermediates by hydrogen peroxide to generate quinoid intermediates, and finally synthesizing the target compound by Michael addition in dilute alkali.
Scheme 3
2a：X＝-CO-，Y＝-CH 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2b：X＝-CO-，Y＝-CH 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2c：X＝-CO-，Y＝-CH 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2d：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2e：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2f：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
It is another object of the present invention to provide a compound for inhibiting proliferation of tumor cells, which contains a naphthol compound of formula I or a biologically acceptable salt thereof as an active ingredient. Any of the naphthol compounds synthesized by the above method may be used, and only one of them may be contained, or a plurality of kinds of them may be contained for composite application.
Further, the biologically acceptable salt refers to a salt of the compound of formula I with at least one of acetic acid, dihydroacetic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.
The object of the present invention is to find new compounds with high STAT3 inhibition and with lower toxicity.
The invention also relates to application of the novel naphthol compound with the structure shown in the formula I, pharmaceutically acceptable salt thereof, solvate of the derivative or solvate of the salt in preparation of medicines for treating or assisting in treating and/or preventing lung cancer, colon cancer, breast cancer and leukemia of mammals. In particular, the mammal is a human.
The invention also relates to application of the novel naphthol compound with the structure shown in the formula I, pharmaceutically acceptable salt thereof, solvate of the derivative or solvate of the salt in preparation of medicines for treating or assisting in treating and/or preventing tumors mediated by STAT3 or tumor cell proliferation and migration driven by STAT3 in mammals. In particular, the mammal is a human.
One aspect of the invention relates to the use of the novel naphthol compounds having the structure of formula I, the pharmaceutically acceptable salts thereof, the solvates of said derivatives, or the solvates of said salts for the manufacture of a medicament for the treatment and/or prophylaxis of diseases associated with STAT3 cell signaling in a mammal. In particular, the mammal is a human.
According to the present invention, it is fully contemplated that the compounds of the present invention may be used to treat tumors caused by abnormally high expression of STAT 3. STAT 3-related tumors include all other cancers such as lung cancer, breast cancer, colorectal cancer, leukemia, and the like.
Various terms and phrases used herein have the ordinary and customary meaning as understood by those skilled in the art, and even though they are still intended to be more fully described and explained herein, the terms and phrases used herein are to be understood and to have a meaning inconsistent with the ordinary and customary meaning as set forth herein.
In the process according to the invention for the synthesis of the compounds of the formula I, the various starting materials used for the reaction are preparable by the person skilled in the art according to the prior art, or can be prepared by methods known from the literature, or can be obtained commercially. The intermediates, raw materials, reagents, reaction conditions and the like used in the above reaction schemes may be appropriately changed according to the knowledge already known to those skilled in the art.
Drawings
FIG. 1 is a drawing of the general formula I.
FIG. 2 is a hydrochloride nuclear magnetic resonance spectrum of Compound 1 a.
FIG. 3 is a nuclear magnetic resonance spectrum of Compound 2 a.
FIG. 4 is a graph showing the experimental results of the virtual molecular docking of compound SMBAA002 with the SH2 domain of STAT3 protein in example 3, wherein compound SMBAA002 is presented on the action interface of the SH2 domain of STAT3 protein, no non-polar hydrogen atom (H) is labeled, and key amino acids interacting with the SMBAA002 molecule are arranged above the SH2 interval of STAT3 protein: lysine 591 and arginine 609 and serine 611, 613, 636 and glutamic acid 612, 638, labeled with LYS591, ARG609, SER611, GLU612, SER613, SER636 and GLU638, respectively; the β -sheet, α -helix and random coil of the SH2 domain of STAT3 protein are represented by the slow straight band, helical band and tubule, respectively. The results of virtual docking show that the compound SMBaA002 has strong interactions with the phosphorylation site ARG609 of the SH2 domain of STAT3 protein, the specific amino acid GLU638 and the drug hydrophobic selection cavity, and the compound is deduced to be a STAT3 signaling inhibitor acting on the STAT3 phosphorylation site.
FIG. 5 is a graph showing that the compound SMBAA002 (2 a) induces apoptosis MTT assay of breast cancer and lung cancer cells, wherein the results of the MTT assay are characterized by IC50 (mu mol/L) value.
FIG. 6 is an illustration of the apoptotic MTT assay of the compound SMBAA007 (1 a) for breast, leukemia, colon and lung cancer cells, wherein the results of the MTT assay are characterized by IC50 (. Mu.mol/L) values.
FIG. 7 is the result of Western blotting of compound SMBAA002 (2 a). And (3) transferring the total cell proteins separated by electrophoresis from the gel to a solid support membrane according to the result of a western blotting experiment, and detecting the corresponding protein expression levels through STAT3, p-STAT3 and beta-Actin antibodies according to the antigen-antibody specificity principle. As a result, it can be seen that HCC827 expresses STAT3 and β -Actin protein in an unchanged amount and p-STAT3 expresses in a decreasing amount with increasing concentration of the drug, and that compound SMBAA002 (2 a) significantly inhibits the expression of p-STAT 3.
FIG. 8 is the result of Western blotting of compound SMBAA007 (1 a). And (3) transferring the total cell proteins separated by electrophoresis from the gel to a solid support membrane according to the result of a western blotting experiment, and detecting the corresponding protein expression levels through STAT3, p-STAT3 and beta-Actin antibodies according to the antigen-antibody specificity principle. As a result, it can be seen that HCC827 expresses STAT3 and β -Actin protein in an unchanged amount with increasing concentration of the drug under the action of the drug, while the expression level of p-STAT3 is decreased, and the compound SMBAA007 (1 a) significantly inhibits the expression of p-STAT 3.
FIG. 9 shows the results of a reverse transcription Polymerase Chain Reaction (PCR) assay for compound SMBAA007 (1 a). Measuring the expression condition of related anti-apoptosis genes by using semi-quantitative RT-PCR, and verifying the physiological condition of HCC827 under the action of different drug concentrations; HCC827 under the action of different concentrations is respectively expressed by extracting RNA samples, measuring the content of the RNA, reversely transcribing cDNA of the samples and amplifying beta-Actin, survivin by PCR; the expression of the anti-apoptosis gene under different medicines is compared, and the compound SMBAA007 (1 a) can be seen to have obvious inhibition effect on Survivin expression.
The partial information for the compounds described above is given in the following table:
Detailed Description
The invention is further described below by means of specific preparation examples and simulation and biological test examples, but it should be understood that these examples and test examples are only for the purpose of more detailed description and should not be construed as limiting the invention in any way.
The present invention generally and/or specifically describes the materials used in the test as well as the test methods. Although many materials and methods of operation are known in the art for accomplishing the objectives of the present invention, the present invention will nevertheless be described in as much detail as possible. It will be clear to those skilled in the art that hereinafter, unless otherwise indicated, the materials and methods of operation used in the present invention are well known in the art.
In the present invention, unless otherwise specified, wherein: (i) The temperature is expressed in degrees centigrade (DEG C), and the operation is performed in a room temperature environment; more specifically, the room temperature is 20-30 ℃; (ii) Drying the organic solvent by a common drying method, evaporating the solvent by a rotary evaporator under reduced pressure, wherein the bath temperature is not higher than 50 ℃; (iii) the reaction process is followed by Thin Layer Chromatography (TLC); (iv) The final product had satisfactory proton nuclear magnetic resonance (1H-NMR) and Mass Spectrometry (MS) data.
Example 1: synthesis of Compounds 1a-1f
1a：X＝-CO-，Y＝-CH 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1b：X＝-CO-，Y＝-CH 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1c：X＝-CO-，Y＝-CH 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1d：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1e：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
1f：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
Specific synthetic methods are exemplified by compound 1 a:
n- (4-hydroxynaphthyl) -4- [2- (N-piperidine) -ethoxy ] benzamide
Step 1.4- [2- (N-piperidine) -ethoxy ] -benzoic acid methyl ester (3)
N-hydroxyethyl piperidine (6.45 g,50 mmol) is added with 80mL of anhydrous tetrahydrofuran, methyl benzoate (7.60 g,50 mmol) and triphenylphosphine (14.41 g,55 mmol) are sequentially added, ice salt bath is cooled to 0 ℃ after the triphenylphosphine is protected by nitrogen, diisopropyl azodicarboxylate (11.12 g,55 mmol) is added dropwise, the temperature is obviously increased, the system is gradually light yellow and transparent, the temperature is controlled to be not higher than 30 ℃, the reaction is stirred for 4h, after TLC detection reaction is completed, 2N hydrochloric acid is added to adjust the pH to 4, the mixture is extracted with 50mL of acetic acid, a water layer is taken after separation, the aqueous layer is adjusted to pH to 10 with sodium bicarbonate aqueous solution, 50mL of ethyl acetate is added for extraction, and the organic layer is dried and concentrated to obtain 10.1g (yield 76%) of a light yellow oily compound.
1 H NMR：(300MHz，CDCl 3 )δ7.90(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，4.08(t，J＝6.0Hz，2H)，3.81(s，3H)，2.71(t，J＝6.0Hz，2H)，2.53-2.36(m，4H)，1.61-1.46(m，4H)，1.38(dd，J＝10.7，5.5Hz，2H)。
Step 2.4- [2- (N-piperidine) -ethoxy ] -benzoic acid (4)
Methyl 4- [2- (N-piperidine) -ethoxy ] -benzoate (3) (10 g,38 mmol) was added with 12mL of 50% aqueous sodium hydroxide solution, 50mL of tetrahydrofuran was added, the reaction was warmed to 50℃for 10h, after completion of the TLC detection, tetrahydrofuran was concentrated by rotary evaporation at 50℃and cooled to room temperature, the pH was adjusted with 1N hydrochloric acid until a large amount of white solid appeared, pH was monitored to about 4 to 5, white firmware powder was obtained by filtration, and 8.1g of a white solid compound was obtained by drying in a vacuum oven (yield 85.6%).
Step 3.4- [2- (N-piperidine) -ethoxy ] -benzoyl chloride (5)
4- [2- (N-piperidine) -ethoxy ] -benzoic acid (4) (8 g,32 mmol) was added with 50mL of methylene dichloride, 20mL of thionyl chloride was added dropwise to the suspension, the temperature was controlled to be not higher than 40 ℃, the temperature was raised to 40 ℃ after the dropwise addition, and the reflux reaction was carried out for 12h, and the system was gradually changed into pale yellow transparent solution. The system was concentrated at 50 ℃ with a vacuum water pump until no liquid drips out, yielding 9g (hydrochloride form, yield 100%) of a white firmware powder.
N- (4-hydroxynaphthyl) -4- [2- (N-piperidine) -ethoxy ] benzamide (1 a)
4-amino-1-naphthol hydrochloride (6 g,30 mmol) was added with 60mL of pyridine and stirred at room temperature (25 ℃) for 30min, the system turned into a purple black solution, 4- [2- (N-piperidine) -ethoxy ] -benzoyl chloride (5) (obtained in step 3, 32 mmol) was added dropwise to the system under nitrogen protection, the dropwise addition was completed and the reaction was carried out overnight at room temperature, TLC detection reaction was completed, pyridine was concentrated, 80mL of water was added and stirred until the system firmware was dispersed, brown firmware powder was obtained by filtration, after 30mL of ethyl acetate was slurried for 30min, the brown firmware powder was obtained by filtration and dried (8.9 g of hydrochloride of 1a, yield 69.5%).
1 H NMR：(300MHz，DMSO-d 6 )δ10.71(s，1H)，10.27(s，1H)，10.09(s，1H)，8.17(dd，J＝6.7，2.6Hz，1H)，8.09(d，J＝8.5Hz，2H)，7.84-7.75(m，1H)，7.53-7.43(m，2H)，7.29(d，J＝8.0Hz，1H)，7.14(d，J＝8.7Hz，2H)，6.92(d，J＝8.0Hz，1H)，4.53(t，J＝4.8Hz，2H)，3.61-3.43(m，4H)，3.01(s，2H)，1.81(d，J＝4.9Hz，4H)，1.70(d，J＝8.8Hz，1H)，1.40(t，J＝18.4Hz，1H)。
Example 2: synthesis of Compounds 2a-2f
2a：X＝-CO-，Y＝-CH 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2b：X＝-CO-，Y＝-CH 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2c：X＝-CO-，Y＝-CH 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2d：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-CH 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2e：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-O-，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
2f：X＝-CO-，Y＝-(CH 2 ) 2 -，E＝-(CH 2 ) 2 -，R 1 ＝H，R 2 ＝H，R 3 ＝H，R 4 ＝H
Specific synthetic methods are exemplified by compound 2 a:
n- (3, 4-dihydroxynaphthyl) -4- [2- (N-piperidine) -ethoxy ] benzamide
Step 1.
(E)-N-(4-oxonaphthalen-1(4H)-ylidene)-4-(2-(piperidin-1-yl)ethoxy)benzamide(3)
The compound synthesized in example 1, N- (4-hydroxynaphthyl) -4- [2- (N-piperidine) -ethoxy ] benzamide (1 a) (1 g,2.6 mmol) was added to 30% hydrogen peroxide, stirred at room temperature (25 ℃) and reacted for 48h, the system was changed from brown suspension to reddish brown solution, the color was changed to reddish solution slowly, 10mL X2 of dichloromethane was added and extracted twice, and the organic layer was concentrated to 430mg (yield 43%) of yellow solid.
1 H NMR：(300MHz，DMSO-d 6 )δ8.17(dd，J＝6.7，2.6Hz，1H)，8.09(d，J＝8.5Hz，2H)，7.84-7.75(m，1H)，7.53-7.43(m，2H)，7.29(d，J＝8.0Hz，1H)，7.14(d，J＝8.7Hz，2H)，6.92(d，J＝8.0Hz，1H)，4.08(t，J＝6.0Hz，2H)，2.71(t，J＝6.0Hz，2H)，2.53-2.36(m，4H)，1.61-1.46(m，4H)，1.38(dd，J＝10.7，5.5Hz，2H)。
N- (3, 4-dihydroxynaphthyl) -4- [2- (N-piperidine) -ethoxy ] benzamide (2 a)
(E) -N- (4-oxoaphthalen-1 (4H) -ylethylene) -4- (2- (piperdin-1-yl) ethoxy) benzamide (3) (400 mg,1 mmol) was added to 10% sodium bicarbonate aqueous solution 5mL, the reaction was stirred at room temperature for 72H, TLC detection was performed to give a large polar compound, stirring was stopped, standing overnight, a yellowish solid precipitated, and after filtration, washed with a small amount of dichloromethane and dried to give 137mg (yield 33%) of a yellowish solid.
1 H NMR：(300MHz，DMSO-d 6 )δ10.11(s，1H)，9.79(s，1H)，9.51(s，1H)，8.17(dd，J＝6.7，2.6Hz，1H)，8.09(d，J＝8.5Hz，2H)，7.89-7.82(m，1H)，7.47(d，J＝8.0Hz，1H)，7.31(d，J＝8.0Hz，1H)，7.13(d，J＝8.5Hz，2H)，6.71(s，1H)，4.10(t，J＝6.0Hz，2H)，2.91(t，J＝6.0Hz，2H)，2.55-2.38(m，4H)，1.61-1.46(m，4H)，1.38(dd，J＝10.7，5.5Hz，2H)。
Example 3: molecular docking (docking) experiment
The method comprises the following steps: to verify the interaction mechanism of compound SMBaA002 with STAT3 protein, the inventors used the phosphorylated tyrosine (pY-705) binding region of STAT3 SH2 region as a protein template for computer virtual modeling (docking), with virtual docking regions focused mainly on regions near the phosphorylated tyrosine sites ARG609 and LYS 591. The structure coordinates of STAT3 SH2 were taken from the protein structure database (PDB data bank, ID:1BG 1). Method of molecular docking (docking): all computer coordination modeling (docking) experiments were performed on the sybyl X2.1.1 operating platform using the computer coordination modeling (docking) tool SUEFLEX DOCK. Potential energy plane (potential gradient) was determined and computer coordination modeling (dock) experiments were performed based on calculations performed at selected sites, including predominantly the phosphotyrosine sites ARG609 and LYS 591. Analysis was performed based on the Score (Score) and conformation and interactions of the simulation (dock).
Example 4: experiment for inducing apoptosis MTT of lung cancer cells
The method comprises the following steps: collecting HCC827 cells in logarithmic growth phase, counting, adjusting cell suspension concentration to 50000 cells/mL, and adding 100ul of cell suspension per well, namely 5000 cells per well; HCC827 cells were treated with compound at final concentrations of 0.1, 0.3, 1, 3, 10, 30, 100, 300 (μmol/L) gradients, respectively, and cultured for 48h; after the treatment of the drugs, 50. Mu.L (1 mg/mL) of thiazole blue reagent is added into each hole, the mixture is incubated for 4 hours at 37 ℃, the liquid in the holes is thrown away, the water is drained, the residual liquid is sucked by filter paper, then 100. Mu.L of dimethyl sulfoxide is added, the reaction is carried out for 7-8 minutes on a horizontal oscillator until the blue-violet crystals are completely dissolved, the value is read by an enzyme-labeled instrument, the OD value at the absorption wavelength of 570nm is measured, and the result is recorded.
Example 5: western immunoblotting (Westernblot) experiment
1. Cell culture and drug addition:
(1) HCC827 cells in logarithmic growth phase were harvested, digested with pancreatin, and single cell suspensions at a density of 300000 cells/mL were prepared in RPMI-1640 medium containing 10% fetal bovine serum, and 2mL of cell suspension was added to each well and inoculated into 6-well cell culture plates.
(2)37℃、5％CO 2 After the cells are attached to the wall, medicines with different concentrations are added into the experimental group, 30 mu L of stimulation cells with the concentration of 1mg/mL interleukin-6 (IL-6) are added after 1h, and the final concentration of interleukin-6 (IL-6) is 30ng/mL.
(3) After a further 0.5h incubation, the cells were lysed with RIPA lysate to collect the protein.
2. Cell collection and lysis
(1) The upper medium was removed and cells in six well plates were washed twice with Phosphate Buffered Saline (PBS). 160. Mu.L of precooled RIPA cell lysate (protease inhibitor and phenylmethylsulfonyl fluoride were added to the lysate at a ratio of 1:100) was added. The cell lysate was scraped off with a pre-washed cell scraper and collected in a clean 1.5mL centrifuge tube.
(2) Placing on ice, and cracking for 30min, and swirling once every certain time (6 min).
(3) Centrifuge at 12000rpm for 12min at 4 ℃.
(4) The cell supernatant was transferred to a clean centrifuge tube. Cell supernatants are divided into two parts: adding 5 mu L of the mixture into a 1.5mL centrifuge tube for BCA protein content measurement, and adding 45 mu L of 1 Xphosphate buffer (PBS) to mix uniformly for later use; the remaining cell supernatant was quantitatively taken at 140. Mu.L, and 35. Mu.L of 5 XSDS Loading Buffer (Loading Buffer) was added thereto, and after mixing, the mixture was boiled in boiling water for 8 minutes, centrifuged and stored in a refrigerator at-20 ℃.
(5) Protein concentration determination:
A. 1 Xphosphate buffer (PBS) diluted protein standard:
B. BCA working solution preparation: the total required amount of A and B mixed working fluid is calculated according to the number of the standard substance and the sample to be tested. Working solution is prepared according to the volume ratio of BCA reagent A to B of 50:1, and vortex oscillation is carried out for uniform mixing for standby.
C. Protein standards and sample supernatants diluted with Phosphate Buffered Saline (PBS) (10-fold dilution) were each added in 25. Mu.L to a new 96-well plate. Then 200. Mu.L of BCA working solution prepared in advance was added respectively and mixed well. The bubbles are not generated by blowing, the cover of the 96-well plate is tightly covered, and the reaction is carried out for 30min in a constant temperature box at 37 ℃.
D. The 96-well plate was removed and returned to room temperature for 3-5min, absorbance at 562nm was measured on an microplate reader, and a standard curve was made to calculate 1. Mu.L/Protein content of each sample for Protein loading.
3. Sodium dodecyl sulfonate-polyacrylamide gel (SDS-PAGE)
(1) The gel plate was fixed and 10% SDS-PAGE separating gel was prepared.
The release gel was prepared according to the following table: 10mL
(2) Adding the mixed separating glue into 2 glue plates, respectively, adding into the position 1.0cm away from the top, filling the glue plates with absolute ethyl alcohol, and standing for 30-45min.
(3) After the gel is separated, the residual absolute ethyl alcohol is poured out, and the residual absolute ethyl alcohol is sucked clean by filter paper.
(4) 5mL of 5% concentrated gel was prepared according to the following Table
(5) Slowly adding the prepared concentrated gel into a gel plate to avoid bubble generation, inserting a sample comb, and standing for 30-45min.
(6) Taking out the protein sample, heating in water bath at 100deg.C for 5min, rotating at 10000rpm, and centrifuging for 10min.
(7) The gel plate is fixed in an electrophoresis tank, SDS-PAGE electrophoresis buffer is added, a sample comb is pulled out, and the processed protein samples are added into the sample tank in sequence.
(8) Electrophoresis at 80V for 40min.
(9) Changing the voltage to 120V for electrophoresis for about 1.5 hours until bromophenol blue goes out of the colloid;
4. western-blot transfer film
(1) And (3) placing the SDS-PAGE gel subjected to electrophoresis into TBST buffer solution for rinsing once, and placing the protein gel into transfer buffer solution for soaking.
(2) Soaking a layer of foam cushion in a film transfer buffer solution, clamping the foam cushion onto a film transfer device by using tweezers, and soaking the foam cushion, the three layers of filter paper, the albumin glue, the polyvinylidene fluoride (PVDF) film, the three layers of filter paper and the foam cushion in sequence, aligning the foam cushion, clamping the foam cushion onto the film transfer device, and during operation, soaking the filter paper and the foam cushion in the film transfer buffer solution. If bubbles exist between each two layers, the bubbles are removed by using a glass test tube to gently roll.
(3) The film transfer instrument was turned on, and 300mA was transferred for 75min.
(4) The membrane was removed and placed in TBST buffer and rinsed 3 times with a 60rpm horizontal shaker for 8min each.
(5) Blocking was performed with 20mL of 5% Bovine Serum Albumin (BSA) blocking solution at 60rpm with a horizontal shaker at room temperature for 2h.
(6) Incubation was performed overnight with a 3mL antibody incubation with 3. Mu.L primary antibody (Stat 3 and p-STAT3 1:1000) at 4deg.C with a 60rpm horizontal shaker.
(7) The PVDF membrane was washed three times, 10min each, with 10mL TBST, a 60rpm horizontal shaker at ambient temperature.
(8) PVDF membrane was incubated with 20mL of antibody incubation with 2. Mu.L of secondary antibody at room temperature with a 60rpm horizontal shaker for 2h.
(9) The PVDF membrane was washed three times, 10min each, with 10mL TBST, a 60rpm horizontal shaker at ambient temperature.
(10) 1mL each of chemiluminescent substrate reagent solution A and solution B was taken and developed for 5min at room temperature.
(11) The liquid on the film was blotted dry with filter paper and developed with a developer.
Example 6: reverse transcription polymerase chain reaction assay (RT-PCR)
1. Cell culture and drug addition:
(1) HCC827 cells in logarithmic growth phase were prepared, digested with pancreatin, and single cell suspension having a density of 100000 cells/mL was prepared in RPMI-1640 medium containing 10% fetal bovine serum, and 2mL of the cell suspension was added to each well to inoculate in a 6-well cell culture plate.
(2)37℃、5％CO 2 After the cells are attached to the wall, the fresh culture medium is replaced, 3, 10, 30 and 100 (mu mol/L) medicines with different concentrations are added into an experimental group, 30 mu L of stimulation cells with the concentration of 1mg/mL interleukin-6 (IL-6) are added after 1h, and the final concentration of interleukin-6 (IL-6) is 30ng/mL.
(3) After further culturing for 24 hours, total RNA was extracted from each group of cells according to the RNA extraction kit instructions.
2. Preparation of RNA samples:
(1) When the cell growth density of the 6-hole plate is 90-100%, taking out from the aseptic chamber, discarding the supernatant, adding 1mL of TRIZOL total RNA extraction reagent into each hole, shaking uniformly, digesting for 5min on ice, blowing by using a pipetting gun head, and sucking the liquid of each hole into a 1.5mL centrifuge tube.
(2) 0.2mL of chloroform was added thereto, the mixture was gently shaken for 15s, and the mixture was allowed to stand at room temperature for 3 minutes.
(3) Centrifuge at 12000rpm at 4℃for 15min. After centrifugation, the liquid was divided into three layers, the upper layer was colorless water sample layer RNA, the middle white was DNA, the bottom red was protein, and carefully aspirated the upper layer colorless liquid and transferred to a new centrifuge tube.
(4) About 0.4mL of the supernatant was taken and added with an equal volume of isopropanol and allowed to stand at room temperature for 10min.
(5) Centrifuge at 12000rpm for 10min at 4 ℃.
(6) The centrifuge tube was discarded and 1mL of 75% ethanol was added.
(7) Centrifugation was performed at 7500rpm at 4℃for 5min, the supernatant carefully discarded, and the mixture was placed in an ultra clean bench and air-dried for 5-10min.
(8) Adding 20-30 μl of diethyl carbonate (DEPC) aqueous solution, packaging, and storing in-70deg.C refrigerator.
(9) 2. Mu.L of total RNA was assayed for concentration and purity using a K5500 ultra-micro spectrophotometer. Total RNA purity was identified based on the OD260/OD280 ratio. OD260/OD280 between 1.8-2.0 indicates a better purity.
(10) mu.L of total RNA was mixed with 1. Mu.L of loading buffer, and the mixture was subjected to electrophoresis at 120V for 30min (1 XTAE) on a 1% agarose gel (containing GleRed), and the quality of the RNA was observed under a gel imaging analysis system. The next experiment was feasible if the RNA was not degraded.
3. cDNA Synthesis
Reverse transcription polymerase chain reaction (Reverse Transcription-Polymerase Chain Reaction, RT-PCR) with experimental principles: first, total RNA in each cell group is extracted, and complementary DNA single strand (complementary DNA) cDNA is synthesized under the catalysis of reverse transcriptase and under the guidance of random primer or poly thymine (Oligo (dT)) or gene specific primer by using mRNA as template. Then, the cDNA is used as a template, and the PCR amplification reaction of the target gene is carried out under the guidance of a specific primer. Since the cDNA is obtained by reverse transcription using mRNA as a template, the target gene sequence to be amplified is a encodable gene sequence containing no intron.
(1) cDNA Synthesis
A. Taking a centrifuge tube without the ribozyme, and sequentially adding the following solutions under an ice bath:
deoxyribonucleoside triphosphate mixture (dNTP Mix) 2.5mM/each 4. Mu.L; primer Mix (Primer Mix) 2uL; 1. Mu.g of RNA Template (RNA Template); RNase-Free Water (RNase-Free Water) was added to 15. Mu.L, and the reaction conditions were: incubation was carried out at 70℃for 10min and ice-bath was rapid for 2min.
B. Sequentially adding the following components into an ice bath, and gently mixing by a pipette:
4. Mu.L of 5-fold First Strand buffer (5 XFirst-Strand buffer); reverse transcriptase (M-MLV) 1. Mu.L, reaction conditions: the reaction was terminated by heating at 85℃for 5min with a bath at 42℃for 50 min.
C. 2-3. Mu.L was used directly for PCR reactions or stored at-20 ℃.
(2) Semi-quantitative PCR amplification of target genes
A. The following reaction systems were added sequentially to the PCR tube on ice:
cDNA 2.5. Mu.L; forward primer (10 mM) 1. Mu.L; reverse primer (10 mM) 1. Mu.L; 2-fold PCR premix enzyme (2×Taq PCR Mix) 12.5uL; double distilled water (ddH) 2 O) was added to 25. Mu.L.
PCR reaction cycle conditions:
the following temperature cycles were followed:
1) Pre-denaturation at 94℃for 5min; 2) Denaturation at 94℃for 30s; 3) Annealing at 61 ℃ for 30s; 4) Extending at 72 ℃ for 1min; 5) Repeating the steps 2-4 for 30 cycles; 6) Extending at 72 ℃ for 5min; 7) Preserving at 4 ℃.
C. And (3) result detection: after the reaction, 5. Mu.L of the reaction product was collected and identified by agarose gel electrophoresis.
Claims (5)
1. Use of naphthol compounds, pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or co-treatment and/or prophylaxis of colon cancer in a mammal。
2. Use of naphthol compounds, pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or co-treatment and/or prophylaxis of breast cancer in a mammalOr (b)。
3. Use of naphthol compounds, pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or co-treatment and/or prophylaxis of leukemia in a mammal。
4. Use of naphthol compounds, pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or co-treatment and/or prophylaxis of lung cancer in a mammalOr (b)。
5. Use of a naphthol compound, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or co-treatment and/or prophylaxis of STAT3 mediated tumors or STAT3 driven tumor cell proliferation and migration in a mammal, characterized in that the compound isOr->。
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