CN111620818B - 8, 9-dimethoxy-kephaline compound and application thereof - Google Patents
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Abstract
The invention relates to an 8, 9-dimethoxy-kephaline compound and application thereof. The 8, 9-dimethoxy-kephalidine compound has a structure shown in a formula (I). The compound can selectively inhibit proliferation of tumor cells such as cervical cancer cells represented by Hela (activity obviously superior to that of cisplatin which is a positive drug), non-small cell lung cancer represented by A549, breast cancer cells represented by MCF-7, leukemia cells represented by MEG-01, glioma cells represented by U251 and the like.
Description
Technical Field
The invention relates to the fields of chemical synthesis and drug development, in particular to an 8, 9-dimethoxy-kephaline compound and application thereof.
Background
Tumors are malignant proliferative diseases, and traditional treatment methods include chemotherapy, radiotherapy, surgery, and the like. In recent decades, targeted therapies have made important breakthroughs, such as ABL inhibitors, EGFR inhibitors and bRAF inhibitors, have been marketed for a long time, and have brought new choices for tumor treatment.
Chemotherapeutic drugs cannot distinguish tumor cells from normal cells, and often have no selectivity in cell proliferation inhibition activity, so that the chemotherapeutic drugs have very large toxic and side effects; the targeted antitumor drug has less side effect because the proliferation of normal cells is not affected while the antitumor effect is ensured. However, there are also problems associated with the clinical use of targeted inhibitors, such as: 1) Only a small number of patients carrying specific gene mutations are sensitive to targeted inhibitors, resulting in limited benefit of the targeted formulation; 2) The eventual inevitable occurrence of acquired drug resistance in sensitive patients; 3) Most of the original targeting preparations at present are patent products of foreign companies, have high price, are not in medical insurance, and have heavy economic burden for patients. Thus, there is an urgent need to find proprietary intellectual property targeted drugs suitable for different tissue sources based on a completely new mechanism for cancer treatment.
Cervical cancer is one of the more common malignant tumors of women, and the prognosis is often poor mainly by treatment means such as chemotherapy, operation and the like at present. Although some targeted inhibitors such as sunitinib and the like are also used for the treatment of cervical cancer, they are poorly targeted and have limited patient benefit. There is an urgent need to find anti-cervical cancer drugs with novel action mechanisms.
The first place of the incidence rate and the mortality rate of the cancers of the non-small cell lung cancer is high, EGFR, ALK and the like are regarded as targets which have been confirmed to be effective treatment targets of the non-small cell lung cancer, and target inhibitors such as gefitinib, erlotinib, octenib, crizotinib and the like developed aiming at the targets can achieve very good clinical treatment effects. However, the patients with non-small cell lung cancer sensitive to EGFR and ALK inhibitors are less than 10%, and a large number of patients with non-small cell lung cancer do not have targeted treatment means.
Breast cancer is the first target of female cancer incidence, and ER, HER2, CDK4/6 and other targets have been demonstrated to be effective breast cancer therapeutic targets. Targeted inhibitors such as lapatinib, afatinib, and the like are effective for breast cancers with high HER2 expression, but most of breast cancers with low HER2 expression, especially triple negative breast cancers, have not been suitable targeted therapeutic drugs for clinical treatment.
Leukemia is complicated in typing, and most leukemias such as megakaryoblastic leukemia and the like do not find suitable therapeutic targets for targeted drug treatment, except that chronic granulocytic leukemia can be treated with BCR/ABL inhibitors such as imatinib and nilotinib, and acute myelogenous leukemia can be treated with FLT3 inhibitors.
Gliomas are a type of tumor with high malignant degree, and due to the reasons of blood brain barrier and the like, the curative effect of drugs is poor, and the current surgical treatment is mainly performed.
Thus, there is an urgent need to find new selective antitumor compound entities.
Disclosure of Invention
Based on the above, the invention provides 8, 9-dimethoxy-kephaline compounds with antitumor activity. Based on cell phenotype screening, the 8, 9-dimethoxy-kephalidine compound has selective anti-tumor effect, and is hopeful to be developed into a novel targeted anti-tumor drug.
The specific technical scheme is as follows:
an 8, 9-dimethoxy-rphine compound with a structure shown in a formula (I) or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof,
wherein each R is independently selected fromSelf-contained: H. halogen, cyano, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, amino, aldehyde, carbomethyl, ethoxycarbomethyl, methoxycarbomethyl or carboxyl;
n is: 1. 2, 3 or 4.
In some embodiments, each R is independently selected from: H. halogen, cyano, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group.
In some embodiments, each R is independently selected from: H. cl, F, cyano, methyl, trifluoromethyl, methoxy.
In some embodiments, n is: 1 or 2.
In some of these embodiments, the 8, 9-dimethoxyrphidine compound has a structure represented by formula (II) or formula (III):
in some of these embodiments, the 8, 9-dimethoxyrphidine compound is selected from the following compounds:
in some of these embodiments, the 8, 9-dimethoxyrphidine compound is selected from the following compounds:
the invention also provides application of the 8, 9-dimethoxy-kephaline compound.
The specific technical scheme is as follows:
the application of the 8, 9-dimethoxy-kephaline compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof in preparing the medicines for preventing or treating tumors.
In some embodiments, the tumor is cervical cancer, non-small cell lung cancer, breast cancer, leukemia, or glioma.
In some of these embodiments, the tumor is cervical cancer.
The invention also provides a medicine for preventing or treating tumors.
The specific technical scheme is as follows:
the medicine for preventing or treating tumor is prepared with active component and pharmaceutically acceptable supplementary material, and the active component includes the 8, 9-dimethoxy rphine compound, pharmaceutically acceptable salt, stereoisomer or prodrug molecule.
The 8, 9-dimethoxy-kephaline compound and the application thereof have the following advantages:
the inventors have found that 8, 9-dimethoxy-kephaline compounds have excellent selective antitumor activity, and they have been found that these compounds can selectively inhibit proliferation of tumor cells such as cervical cancer cells represented by Hela (activity significantly superior to that of cisplatin, a positive drug), non-small cell lung cancer cells represented by A549, breast cancer cells represented by MCF-7, leukemia cells represented by MEG-01, glioma cells represented by U251, and the like, in half inhibition concentration (IC 50 ) Less than 3 μm; the half-Inhibitory Concentrations (IC) of tumor cells represented by A375, H460, H358, etc 50 ) Greater than 10 μm. The compounds are expected to develop brand new targeted therapeutic drugs for targeting non-small cell lung cancer, breast cancer, leukemia, glioma, especially cervical cancer.
Drawings
Fig. 1 is a graph showing the results of inhibition of tumor cell clone formation by JND3688 compounds at various concentrations.
Detailed Description
In order that the invention may be understood more fully, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended claims. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. These embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Compounds of formula (I)
The compound provided by the invention is an 8, 9-dimethoxy rphine compound with a structure shown in a formula (I),
wherein each R is independently selected from: H. halogen, cyano, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, amino, aldehyde, carbomethyl, ethoxycarbomethyl, methoxycarbomethyl or carboxyl;
n is: 1. 2, 3 or 4.
The term "substituted" in the present invention means that one or more substitutable hydrogen atoms in a given structure are substituted with a particular substituent, and each monosubstituted group may have one substituent substituted at each substitutable position of the group, and when more than one position in a given structural formula may be substituted with one or more substituents of a particular group, then the substituents may be the same or different substituents at each position.
The term "C a -C b Watch (watch)Shows that the compound contains a to b carbon atoms, namely' C a -C b Alkyl "means a straight-chain or branched saturated alkyl group containing a to b carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, … …, e.g." C 1 -C 6 Alkyl "is a straight or branched saturated alkyl group containing 1 to 6 carbon atoms; "C a -C b Alkoxy "means a group containing a to b carbon atoms and one oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, and the like.
In some embodiments, each R in the 8, 9-dimethoxyrphidine-based compound is independently selected from: H. halogen, cyano, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group.
Further preferably, each R is independently selected from: H. cl, F, cyano, methyl, trifluoromethyl, methoxy.
In some embodiments, n in the 8, 9-dimethoxyrphidine-based compound is: 1 or 2.
Further preferably, when n is 1, the 8, 9-dimethoxyrphidine compound has a structure represented by formula (II), and when n is 2, the 8, 9-dimethoxyrphidine compound has a structure represented by formula (III):
the compounds provided herein include the free forms of the compounds of formulas I-III, as well as pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional nontoxic salts include salts prepared from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and also salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.
If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
The compounds provided by the present invention also include stereoisomers of the compounds of formulas I-III. "stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The compounds provided herein also include prodrug molecules of the compounds of formulas I-III. The term "prodrug molecule" as used herein means a compound that is converted in vivo to a compound of formula I-III.
Preparation of the Compounds
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the present invention can be prepared using methods in the following synthetic schemes. The compounds and methods of synthesis described in this invention can be better understood in conjunction with the synthetic schemes described below. The synthetic schemes describe methods that can be used to prepare the compounds described in this invention, which are described for illustrative purposes only and are not limiting on the scope of the invention.
Use of compounds
The invention also provides application of the compound. The compounds of the formulas I-III or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof have anti-tumor activity, and can be prepared into pharmaceutical compositions for preventing or treating tumors with pharmaceutically acceptable auxiliary materials.
Further preferably, the tumor is cervical cancer, non-small cell lung cancer, breast cancer, leukemia, or glioma. Further preferably, the tumor is cervical cancer.
Pharmaceutical composition
The pharmaceutical composition provided by the invention has anti-tumor activity. Further preferably, the tumor is cervical cancer, non-small cell lung cancer, breast cancer, leukemia, or glioma. Further preferably, the tumor is cervical cancer. The pharmaceutical composition is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises 8, 9-dimethoxy rphine compounds shown in formulas I-III or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof. Suitable excipients are well known to those skilled in the pharmaceutical arts and in certain embodiments include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
The present invention will be described in further detail with reference to specific examples, but embodiments of the present invention are not limited thereto.
The reagents used in the examples are commercially available as usual unless otherwise specified.
EXAMPLE 1 preparation of 8, 9-Dimethoxyphenanthridines
Step one: under nitrogen, 1 (5 mmol), 2 (6.5 mmol) and PdCl were combined 2 (PPh 3 ) 2 (0.15 mmol) and potassium carbonate (20 mmol) were added to DME (10 ml). Reflux at 80℃for 10 hours (TLC monitored reaction). After the completion of the reaction, the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated brine, dried and concentrated, and column chromatography gave compound 3 as a white solid.
Step two: compound 3 (2 mmol), hydroxylamine hydrochloride (3 mmol) and pyridine (3.4 mmol) were added to methanol (8 mL) under nitrogen. Reflux at 70 ℃, TLC monitored reaction completion. After the completion of the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed with 1mol/L hydrochloric acid and saturated brine, respectively, and dried and concentrated to give a white solid. A white solid (1 mmol) was dissolved in dichloromethane (6 mL) and triethylamine (1.5 mmol) and p-trifluoromethylbenzoyl chloride (1.1 mmol) were added at 0deg.C. After stirring for 30 minutes, the mixture was warmed to room temperature and stirred for 30 minutes. TLC monitored completion of the reaction and saturated NaHCO was added to the reaction flask 3 The solution was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and concentrated, and re-concentrated with ethyl acetateCrystallization gave compound 4 as a white solid.
Step three: under nitrogen, compound 4 (0.2 mmol) and Ir (ppy) 3 (0.002 mmol) was added to DMF (4 mL) and the reaction was allowed to react for 12 hours with white light. After TLC monitoring the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried and concentrated, and column-chromatographed to give compound 5 as a white solid.
The following 8, 9-dimethoxy rphine compounds are prepared by the method, and the yield and H spectrum data of each compound are as follows.
The yield thereof was found to be 78%. 1 H NMR(400MHz,CDCl 3 )δ9.12(s,1H),8.41(d,J＝8.0Hz,1H),8.15(d,J＝8.0Hz,1H),7.83(s,1H),7.68(t,J＝7.2Hz,1H),7.62(t,J＝7.4Hz,1H),7.31(s,1H),4.11(s,3H),4.05(s,3H).
The yield thereof was found to be 20%. 1 H NMR(400MHz,CDCl 3 )δ＝9.34(s,1H),9.12(s,1H),8.10(d,J＝8.1Hz,1H),7.70(d,J＝7.6Hz,1H),7.56(t,J＝7.9Hz,1H),7.37(s,1H),4.12(s,3H),4.09(s,3H).
The yield thereof was found to be 12%. 1 H NMR(400MHz,CDCl 3 )δ＝9.24(s,1H),9.10(s,1H),7.55(d,J＝2.8Hz,1H),7.39(d,J＝2.8Hz,1H),7.36(s,1H),4.12(s,3H),4.08(s,3H),3.97(s,3H).
The yield thereof was found to be 39%. 1 H NMR(400MHz,CDCl 3 )δ＝9.15(s,1H),8.40(d,J＝3.9Hz,1H),7.98(d,J＝8.1Hz,1H),7.64-7.58(m,J＝8.1,5.7Hz,1H),7.40–7.30(m,2H),4.13(s,7H),4.09(s,3H).
The yield thereof was found to be 18%. 1 H NMR(400MHz,CDCl 3 )δ＝9.21(s,1H),9.20(s,1H),8.40(dd,J＝8.3,1.3Hz,1H),8.06(dd,J＝7.4,1.4Hz,1H),7.73(dd,J＝8.1,7.5Hz,1H),7.42(s,1H),4.18(s,3H),4.11(s,3H).
The yield thereof was found to be 27%. 1 H NMR(400MHz,CDCl 3 )δ＝9.32(s,1H),9.12(s,1H),7.97(s,1H),7.59(d,J＝1.5Hz,1H),7.39(s,1H),4.14(s,3H),4.09(s,3H),2.55(s,3H).
EXAMPLE 2 anti-tumor Activity Studies
Tumor cell lines such as Hela (human cervical cancer cell), A549 (human non-small cell lung cancer cell), MCF-7 (human breast cancer cell), MEG-01 (human megakaryoblastic leukemia cell), U251 (human glioma cell) and the like used in the experiment are all from ATCC or China academy of sciences typical culture Collection Committee cell banks. 3000-10000 of the above cells were inoculated into 96-well plates, and then, different concentrations of JND3688 and other compounds (0-3. Mu.M) were added, respectively, for continuous treatment for 72 hours. CCK8 reagent was then added and incubation was continued for 1-3 hours, followed by measurement of absorbance at 450nm and 650nm with a super microplate reader. Half maximal Inhibitory Concentration (IC) was calculated using grappad5.0 50 )。
The results (Table 1) found: JND3688, JND3873, JND3934 and JND3964 have good inhibitory activity on tumor cells such as Hela, MEG-01, A549, MCF-7, U251, etc., and IC thereof 50 Less than 3. Mu.M, wherein the proliferation inhibition activity on Hela cells is the best, and IC thereof 50 Are less than 0.200 mu M.
TABLE 1 proliferation inhibitory Activity of Compounds against different tumor cells (IC 50 (μM))
Example 3 inhibition of clonogenic Capacity
The cells used in this experiment were all from ATCC or China academy of sciences typical culture Collection Committee cell banks. Spreading 200-2000 cells in a 6-well plate, adding JND3688 compounds with different concentrations after overnight, continuously culturing for 7-14 days, fixing and dyeing with 0.25% crystal violet-methanol solution until the colony grows to a proper size, washing off excessive dye with tap water, airing, photographing, and counting for statistical analysis.
The cloning experiment result is shown in fig. 1, and the result shows that JND3688 can selectively inhibit the cloning of tumor cells such as Hela, a549, MCF7, DU145, U251 and the like in a dose-dependent manner; especially for Hela cells, JND3688 completely inhibited its clonal formation at 33.33 nM.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as 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 (8)
1. An 8, 9-dimethoxy-kephaline compound or a pharmaceutically acceptable salt thereof, wherein the 8, 9-dimethoxy-kephaline compound has a structure shown in formula (II) or formula (III):
each R is independently selected from: cl, F, cyano, trifluoromethyl.
2. An 8, 9-dimethoxyrphine compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:
3. 8, 9-dimethoxyrphine compound or pharmaceutically acceptable salt thereof according to claim 2, selected from the following compounds:
4. use of an 8, 9-dimethoxyrphine compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the prophylaxis or treatment of a tumor.
5. The use according to claim 4, wherein the tumor is cervical cancer, non-small cell lung cancer, breast cancer, leukemia, or glioma.
6. The use according to claim 5, wherein the tumour is cervical cancer.
7. A medicament for preventing or treating tumors, which is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the 8, 9-dimethoxy-rphine compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.
8. The medicament for preventing or treating tumors as claimed in claim 7, wherein the auxiliary materials are selected from the group consisting of starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water or ethanol.
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| WO2018119208A1 (en) * | 2016-12-22 | 2018-06-28 | Global Blood Therapeutics, Inc. | Histone methyltransferase inhibitors |
| CN108727397A (en) * | 2018-05-28 | 2018-11-02 | 潍坊医学院 | phenanthridine derivatives |
| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | A kind of synthetic method and antitumor application thereof of phenanthridines class nitidine derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018119208A1 (en) * | 2016-12-22 | 2018-06-28 | Global Blood Therapeutics, Inc. | Histone methyltransferase inhibitors |
| CN108727397A (en) * | 2018-05-28 | 2018-11-02 | 潍坊医学院 | phenanthridine derivatives |
| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | A kind of synthetic method and antitumor application thereof of phenanthridines class nitidine derivative |
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| Synthesis, Bacteriostatic and Anticancer Activity of Novel Phenanthridines Structurally Similar to Benzo[c]phenanthridine Alkaloids;Pavel Lasák et al.;《Molecules》;20181231;第23卷;第2155-2178页 * |
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