WO2015180424A1 - 水溶性α-萘黄酮醇衍生物及其制备方法、用途 - Google Patents

水溶性α-萘黄酮醇衍生物及其制备方法、用途 Download PDF

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WO2015180424A1
WO2015180424A1 PCT/CN2014/091234 CN2014091234W WO2015180424A1 WO 2015180424 A1 WO2015180424 A1 WO 2015180424A1 CN 2014091234 W CN2014091234 W CN 2014091234W WO 2015180424 A1 WO2015180424 A1 WO 2015180424A1
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naphthoflavone
soluble
water
trimethoxy
alcohol derivative
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French (fr)
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李绍顺
崔家华
孟青青
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上海交通大学
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a water-soluble ⁇ -naphthoflavone alcohol derivative, a preparation method thereof and use thereof.
  • the CYP1B1 enzyme is a subtype of the CYP1 family and is expressed primarily outside the liver. It metabolizes estradiol to 4-hydroxyestradiol, a metabolite that plays a key role in the development of estradiol-induced breast cancer (Cavalieri et al, Proc. Natl. Acad. Sci. USA, 1997) , 94: 10937-10942).
  • the CYP1B1 enzyme is involved in the metabolic activation of polycyclic aromatic hydrocarbon procarcinogens such as benzopyrazole, which is a factor in inducing tumors.
  • CYP1B1 enzyme is highly expressed in tumor tissues such as breast cancer, ovarian cancer, prostate cancer, liver cancer, lung cancer and kidney cancer, but it is rarely expressed in the corresponding normal cells, its specific distribution and development in tumorigenesis. Its important position makes it a new target in drug research.
  • CYP1B1 enzyme is also a metabolic enzyme of some anti-tumor drugs. It can metabolize multiple anti-tumor drugs such as docetaxel, paclitaxel, mitoxantrone, doxorubicin and tamoxifen. It is a cause of drug resistance in tumor cells. (McFadyen et al, Future Oncol., 2005, 1:259-263).
  • ⁇ -naphthoflavone is a strong inhibitor of CYP1B1 enzyme, which can significantly inhibit the metabolic activation of polycyclic aromatic hydrocarbons such as benzopyrene and play a role in tumor prevention (Koley et al, J. Biol. Chem., 1997). , 272: 3149-3152). Studies have shown that ⁇ -naphthoflavone can eliminate the resistance of tumor cells to docetaxel caused by high expression of CYP1B1 in tumor cell lines with high expression of CYP1B1 (McFadyen et al, Biochem. Pharmacol., 2001, 62: 207-212).
  • ⁇ -naphthoflavone as a lead to synthesize an inhibitor having strong inhibitory activity against CYP1B1 enzyme and high selectivity (Invention Patent Application Publication No.: CN 102993157 A); however, these compounds are similar to ⁇ -naphthoflavone, Poor solubility in water limits their use as a drug.
  • the object of the present invention is to provide a water-soluble ⁇ -naphthoflavone alcohol derivative, a preparation method thereof and use thereof, in view of the defects in the prior art.
  • the water-soluble ⁇ -naphthoflavone alcohol derivative according to the invention is capable of inhibiting human CYP1B1
  • the activity of the enzyme can overcome the resistance of tumor cells to antitumor drugs caused by CYP1B1 enzyme, and can be used for preparing drugs for preventing tumor growth and overcoming drug resistance of malignant tumors.
  • the present invention analyzes the crystal structure of ⁇ -naphthoflavone and CYP1B1 enzyme (Wang et al, J. Biol. Chem., 2011, 286: 5736-5743), the naphthalene ring portion of the ⁇ -naphthoflavone molecule and the enzyme
  • the phenylalanine residues (Phe231) of the active center are parallel to each other, and there is a ⁇ - ⁇ interaction; the molecular side chain benzene ring is close to the catalytic center of the enzyme, heme.
  • the 3 position on the pyranone ring of the ⁇ -naphthoflavone molecule is close to the B'-C Loop region where the active center of the CYP1B1 enzyme is active (Fig. 3), so the introduction of a water-soluble group at the 3-position of the pyrone ring may Extending the B'-C Loop region, which is distributed in the solvent region on the surface of the enzyme, does not have a large effect on the binding of the compound to the active site of the enzyme while solving the water solubility of the enzyme inhibitor.
  • the invention selects a hydroxyl group and a hydroxyalkyl alcohol amino acid ester as a water-soluble group, and is linked to the 3-position of the pyranone ring of the ⁇ -naphthoflavone molecule, and solves the lead ⁇ -naphthyl flavonoid and has been published in the patent CN 102993157 A.
  • - Water solubility of the naphthoflavone derivative The invention designs and synthesizes water-soluble ⁇ -naphthoflavone alcohol and derivatives thereof, has good water solubility, can be applied to experiments at the cellular level, and is advantageous for preparing drugs and compositions thereof for tumor prevention and overcoming tumor resistance.
  • the present patent relates to a water-soluble ⁇ -naphthoflavone alcohol derivative; the structure of the water-soluble ⁇ -naphthoflavone alcohol derivative is as shown in the formula (I):
  • R is an aminocarboxylic acid ester of hydrogen or a fatty alcohol and a physiologically acceptable salt thereof; and R 1 , R 2 and R 3 are each hydrogen or halogen.
  • the water-soluble ⁇ -naphthoflavone alcohol derivative is a 6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol derivative, and its structural formula is as shown in formula (III):
  • the water-soluble ⁇ -naphthoflavol derivative is 6,7,10-trimethoxy- ⁇ -naphthoflavone hydroxyalkyl
  • An ether aminocarboxylate derivative having the structural formula shown in formula (IV):
  • the present invention relates to a process for the preparation of the aforementioned water-soluble ⁇ -naphthoflavone alcohol derivative, the method being specifically (as shown in Figure 1): 6,7,10-trimethoxy- ⁇ - the dihydronaphthyl flavonol derivative is suspended in methanol and oxidized with hydrogen peroxide in the presence of sodium hydroxide or potassium hydroxide to obtain the 6,7,10-dimethoxy- ⁇ -naphthoflavone Alcohol derivatives.
  • the present invention relates to a process for the preparation of the aforementioned water-soluble alpha-naphthoflavone alcohol derivative, the process comprising the following steps (as shown in Figure 2):
  • the 6,7,10-trimethoxy- ⁇ -naphthoflavolol hydroxyalkyl ether (N-tert-butoxycarbonyl) amino acid ester derivative is removed in the presence of hydrochloric acid using ethyl acetate as a solvent.
  • the 6,7,10-trimethoxy- ⁇ -naphthoflavolol hydroxyalkyl ether amino acid ester derivative (IV) is obtained in addition to N-tert-butoxycarbonyl.
  • the present invention relates to the use of the aforementioned water-soluble ⁇ -naphthoflavone alcohol derivative for the preparation of an active agent for inhibiting human CYP1B1 enzyme.
  • the present invention relates to the use of the aforementioned water-soluble ⁇ -naphthoflavone alcohol derivative for the preparation of a medicament for preventing tumorigenesis.
  • the present invention relates to the use of the aforementioned water-soluble ⁇ -naphthoflavone alcohol derivative for the preparation of a medicament for overcoming anti-tumor drug resistance caused by a CYP1B1 enzyme, the water-soluble ⁇ -naphthoflavone alcohol derivative Combined with anti-tumor drugs.
  • the present invention relates to a compound drug for overcoming anti-tumor drug resistance caused by a CYP1B1 enzyme, which is composed of a water-soluble ⁇ -naphthoflavinol derivative as described above and an antitumor drug. .
  • the present invention has the following beneficial effects: the water-soluble ⁇ -naphthoflavone alcohol derivative of the present invention can inhibit the activity of the human CYP1B1 enzyme, has good water solubility, and can be used for the prevention of malignant tumors.
  • the water-soluble ⁇ -naphthoflavone alcohol derivative and the antitumor drug can overcome the anti-tumor drug resistance caused by the CYP1B1 enzyme.
  • the preparation method of the invention has easy availability of raw materials, simple operation and high reaction yield.
  • FIG. 2 is a schematic diagram of the preparation of a 6,10,10-trimethoxy- ⁇ -naphthoflavolol hydroxyalkyl ether aminocarboxylate derivative of the formula (IV) according to the present invention.
  • Figure 3 is a crystal structure diagram of a complex of ⁇ -naphthoflavone and CYP1B1 enzyme.
  • the present embodiment relates to a method for preparing 6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol (III-1) having the formula (III), as shown in FIG. 1, comprising the following steps:
  • 2-acetyl-4,5,8-trimethoxy-1-naphthol is dissolved in anhydrous N,N'-dimethylformamide, and the ice water bath is cooled to 5 ° C under nitrogen protection. 1.2 equivalents of sodium hydride were added in portions. After stirring for 5 minutes, 1.2 equivalents of re-distilled chloromethyl methyl ether was added dropwise to the reaction liquid. The reaction solution was stirred at room temperature for 3 h and poured into a pre-cooled saturated sodium bicarbonate solution.
  • the mixture was suction filtered, and the filter cake was washed with a small amount of cold water, and the filter cake was dried to obtain a large amount of yellow powder, 4,5,8-trimethoxy-2-acetyl-1-naphthol methoxymethyl ether, yield 96 %.
  • Step two 4,5,8-trimethoxy-2-acetyl-1-naphthol methoxymethyl ether is dissolved in an appropriate amount of 10% potassium hydroxide-anhydrous ethanol solution (W/V), The reaction solution was cooled to 5 ° C under nitrogen. 2.0 times equivalent of benzaldehyde was slowly added dropwise to the reaction liquid, and the reaction solution was stirred at a low temperature overnight, and the reaction was quenched by a saturated ammonium chloride solution, and the organic layer was combined.
  • W/V potassium hydroxide-anhydrous ethanol solution
  • Step 3 (E)-1-(1'-methoxymethoxy-4',5',8'-trimethoxynaphthalene-2')-3-phenylpropenyl-1-one in methanol
  • the suspension was suspended, and the ice water bath was cooled to 5 ° C; 16% sodium hydroxide solution (10 equivalents) and 30% hydrogen peroxide (8 equivalents) were added dropwise to the reaction solution, and the reaction solution was stirred at a low temperature overnight.
  • Step four 1-(1'-methoxymethoxy-4',5',8'-trimethoxynaphthalene-2')-2,3-epoxy-3-phenylpropyl-1-
  • the ketone was suspended in methanol, concentrated hydrochloric acid (10-fold equivalent) was added, and the mixture was heated to 50 ° C to react, and the reaction was stopped after the disappearance of the starting material.
  • the reaction mixture was suction filtered, and the cake was crystallized from ethyl acetate, and then purified from ethyl acetate to give 6,7,10-trimethoxy- ⁇ -dihydronaphthalenol.
  • the product exhibited pale yellow crystals with a yield of 42%.
  • Step 5 6,7,10-trimethoxy- ⁇ -dihydronaphthyl flavonol was suspended in methanol, adding 16% sodium hydroxide solution (8 equivalents) and 30% hydrogen peroxide (12 equivalents) The reaction was carried out at 30 ° C for 36 h. The reaction solution was acidified with 3N hydrochloric acid and filtered. The filter cake was washed with methanol and water and dried to give 6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol as a yellow powder, yield 87%.
  • the present embodiment relates to a method for preparing 2'-fluoro-6,7,10-trimethoxy- ⁇ -naphthyl flavonol (III-2) having the formula (III), as shown in FIG. 1, comprising the following steps :
  • the present embodiment relates to a method for preparing 3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol (III-3) having the formula (III), as shown in FIG. 1, comprising the following steps :
  • the present embodiment relates to a method for preparing 4'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol (III-4) having the formula (III), as shown in FIG. 1, comprising the following steps :
  • the present embodiment relates to a method for preparing 2'-chloro-6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol (III-5) having the formula (III), as shown in FIG. 1, comprising the following steps :
  • the present embodiment relates to a method for preparing 3'-chloro-6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol (III-6) having the formula (III), as shown in FIG. 1, comprising the following steps :
  • the present embodiment relates to a method for preparing 4'-chloro-6,7,10-trimethoxy- ⁇ -naphthoflavone alcohol (III-7) having the formula (III), as shown in FIG. 1, comprising the following steps :
  • This example relates to 2-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-ethanol glycinate hydrochloride (IV) having the formula (IV).
  • the preparation method of -1 as shown in FIG. 2, comprises the following steps:
  • the product was a yellow powder with a yield of 81% (two steps).
  • Step three 2-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-ethanol is dissolved in anhydrous dichloromethane, and an equal amount of N is added.
  • the product was a bright yellow powder with a yield of 92%.
  • Step 4 the step 3 product is dissolved in ethyl acetate, and the N-tert-butoxycarbonyl protecting group is removed in the presence of hydrochloric acid to obtain the final product 2-(3'-fluoro-6,7,10-trimethoxy Base- ⁇ -naphthoflavone-3-oxo-1-ethanol glycinate ester hydrochloride.
  • the product was a reddish brown powder with a yield of 74%.
  • This example relates to a 2-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-ethanol alaninate hydrochloride having the formula (IV)
  • the preparation method of (IV-2), as shown in FIG. 2, includes the following steps:
  • the procedure of this example is the same as the first step, the second step, the third step and the fourth step of the embodiment 8.
  • the N-tert-butoxycarbonyl-glycine is replaced by N-tert-butoxycarbonyl-L-alanine.
  • the product was a brown powder with a total yield of 17%.
  • This example relates to a 2-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-ethanol valine ester hydrochloride having the formula (IV)
  • the preparation method of (IV-3), as shown in FIG. 2 includes the following steps:
  • the procedure of this example is the same as the first step, the second step, the third step and the fourth step of the embodiment 8.
  • N-tert-butoxycarbonyl-L-proline is substituted for N-tert-butoxycarbonyl-glycine.
  • the product was a brown-red powder with a total yield of 17%.
  • This example relates to a 2-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-ethanol lysine hydrochloride salt of the formula (IV).
  • the preparation method of (IV-4), as shown in FIG. 2, includes the following steps:
  • the procedure of this example is the same as the first step, the second step, the third step and the fourth step of the embodiment 8.
  • N-tert-butoxycarbonyl-L-lysine is substituted for N-tert-butoxycarbonyl-glycine.
  • the product was a dark red powder with a total yield of 25%.
  • This embodiment relates to 4-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-butanyl glycinate hydrochloride having the formula (IV) (
  • the preparation method of IV-5), as shown in FIG. 2 includes the following steps:
  • the procedure of this example is the same as the first step, the second step, the third step and the fourth step of the first embodiment.
  • the 4-bromo-1-butanol is substituted for the 2-bromoethanol.
  • the product was a brown powder with a total yield of 15%.
  • This embodiment relates to a 6-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavin-3-oxo)-hexanol glycinate hydrochloride having the formula (IV) (
  • the preparation method of IV-6), as shown in FIG. 2 includes the following steps:
  • the procedure of this example is the same as the first step, the second step, the third step and the fourth step of the embodiment 8.
  • the 2-bromoethanol is replaced by 6-bromo-1-hexanol.
  • the product was an orange powder with a total yield of 17%.
  • This example relates to 8-(3'-fluoro-6,7,10-trimethoxy- ⁇ -naphthoflavone-3-oxo)-1-octanyl glycinate hydrochloride having the formula (IV) (
  • the preparation method of IV-7), as shown in FIG. 2 includes the following steps:
  • the procedure of this example is the same as the first step, the second step, the third step and the fourth step of the embodiment 8.
  • 8-bromo-1-octanol is used instead of 2-bromoethanol.
  • the product was a brownish yellow powder with a total yield of 19%.
  • the inhibitory activity of the compound on CYP1A1, CYP1B1 and CYP1A2 enzymes was determined by 7-ethoxy-3H-phenoxazin-3-one deethoxylation (EROD) method (Yamaori et al, Biochem. Pharmacol., 2010, 79: 1691-1698).
  • the reaction system (200 ⁇ L) contains 10fmol CYP1A1 or 20fmol CYP1B1 or 50fmol CYP1A2 enzyme, different concentrations of test compound, NADPH regeneration system (1.3mM NADP + , 3.3mM glucose-6-phosphate, 0.5U/ml glucose-6-phosphate Hydrogenase), 3.3 mM MgCl 2 and 150 nmol of 7-ethoxy-3H-phenoxazin-3-one.
  • the reaction buffer was a 50 mM Tris-HCl (pH 7.4) buffer containing 1% BSA. After the reaction system was preheated at 37 ° C for 5 min, the reaction was started by adding a NADPH regeneration system.
  • Enzyme activity inhibition rate (control group value - experimental group value) / control group value ⁇ 100%;
  • Biostatistics The IC 50 values were calculated using nonlinear statistical least squares error regression analysis using the statistical software Origin.
  • This example was carried out according to the conventional tetrazolium bromide (MTT) method, and the change in IC 50 of docetaxel before and after the addition of ⁇ -naphthoflavone or compound IV-1 was measured.
  • the succinate dehydrogenase in the mitochondria of living cells can reduce exogenous tetrazolium bromide to poorly soluble blue-violet crystals and deposit in cells, whereas dead cells do not.
  • Dimethyl sulfoxide can dissolve purple crystals in cells, and its light absorption value can be measured by an enzyme-linked immunosorbent at a wavelength of 570 nm, which can indirectly reflect the number of living cells.
  • This method has been widely used for the detection of activity of some biologically active factors, large-scale anti-tumor drug screening, cytotoxicity test and tumor radiosensitivity determination.
  • Tumor cell line MCF-7 human breast cancer cell line resistant to docetaxel due to high expression of CYP1B1 (using the method of patent WO 03/028713 A2, page 72, from MCF-7 cell line at a concentration of 10 nM) 2,3,7,8-tetrachlorodibenzodioxin induced induction).
  • Inhibition rate (average OD value of the control group - average OD value of the administration group) / average OD value of the control group
  • Dosage setting When docetaxel acts on cells, five concentrations are set, mainly in the range of 0.1-180 ⁇ /ml; ⁇ -naphthoflavone and compound IV-1 are used in five concentrations of 5, 10, 25, 40, 50, 100 ⁇ . Gradient, reversal of drug resistance experiments, simultaneous addition with docetaxel; determination of ⁇ -naphthoflavone and compound IV-1 against drug-resistant MCF-7 human mammary gland at 5, 10, 25, 50, 100 ⁇ five concentration gradients Cancer cell strain growth inhibition rate.
  • Biometric using SPSS software, according to the suppression rate of the test drug at various concentrations on cell growth, Probit Analysis method to calculate the 50 value IC.
  • the results of MTT assay are shown in Table 2.
  • the IC 50 value of docetaxel is 139.82 ⁇ M; docetaxel combined with 5, 10, 25, 40, 50, 100 ⁇ of ⁇ -naphthoflavone
  • the IC 50 values of the drug-resistant cells were 110.59, 98.15, 87.13, 42.22, 35.60 and 51.79 ⁇ , respectively, and the sensitivity of the cells to paclitaxel was increased by 1.26, 1.42, 1.60, 3.31, 3.93, 2.70 times, respectively;
  • the IC 50 values of the resistant cells were 55.93, 25.52, 10.81, 7.62, 8.46 and 4.63 ⁇ , respectively.
  • the sensitivity of paclitaxel increased by 2.50, 5.48, 12.93, 18.35, 16.35, and 30.20 times, respectively.
  • Example 22 Using the same experimental method as in Example 22, the MCF-7 human breast cancer cell line resistant to docetaxel by high expression of CYP1B1 as described in Example 16 was selected and tested by the MTT method.
  • Dosage setting When docetaxel acts on cells, five concentrations are set, mainly in the range of 0.1-180 ⁇ /mL; ⁇ -naphthoflavone, compound III-3 and compound IV-7 are both concentration gradients of 5 ⁇ and 10 ⁇ . When reversing the drug resistance experiment, it was added simultaneously with docetaxel; ⁇ -naphthoflavone, compound III-3 and compound IV-7 were tested for drug-resistant MCF-7 human breast cancer cell lines under the concentration gradient of 5 ⁇ and 10 ⁇ . Growth inhibition rate.
  • Biometric using SPSS software, according to the suppression rate of the test drug at various concentrations on cell growth, Probit Analysis method to calculate the 50 value IC.
  • the results of MTT assay are shown in Table 4.
  • the IC 50 value of docetaxel was 139.82 ⁇ M; after docetaxel combined with 5 ⁇ and 10 ⁇ of ⁇ -naphthoflavone, the drug-resistant cells were used.
  • the IC 50 values were 110.59 ⁇ and 98.15 ⁇ , respectively, which increased the sensitivity of cells to paclitaxel by 1.26 times and 1.42 times, respectively.
  • the IC of the drug-resistant cells was obtained.
  • the 50 values were 83.73 ⁇ and 67.22 ⁇ , respectively, which increased the sensitivity of cells to paclitaxel by 1.67 and 2.08 times, respectively;
  • the water-soluble ⁇ -naphthoflavone alcohol derivative of the present invention can inhibit the activity of human CYP1B1 enzyme and has good water solubility, and can alleviate the metabolic activation of polycyclic aromatic hydrocarbon procarcinogens; and antitumor drugs;
  • the drug resistance of the tumor cell strain induced by CYP1B1 can be reversed, and the drug can be used for preparing a drug for preventing tumorigenesis and overcoming malignant tumor resistance; the preparation method of the invention has easy availability of raw materials, simple operation and high reaction yield .

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Abstract

本发明涉及一种水溶性α-萘黄酮醇衍生物及其制备方法、用途；所述水溶性α-萘黄酮衍生物的结构式如式（I），其中，R代表氢或脂肪醇的氨基羧酸酯及其生理可接受的盐，R1，R2，R3分别为氢或卤素。本发明还涉及前述水溶性α-萘黄酮醇衍生物的制备方法、用途。本发明的水溶性α-萘黄酮醇衍生物能够抑制人体CYP1B1酶的活性、部分化合物的抑制活性远高于α-萘黄酮；可用于恶性肿瘤的预防。本发明的水溶性α-萘黄酮醇衍生物与抗肿瘤药物联合用药，可以克服由CYP1B1酶所引起的抗肿瘤药物耐药。

Description

水溶性α-萘黄酮醇衍生物及其制备方法、用途 技术领域
本发明属于药物化学领域，具体涉及一种水溶性α-萘黄酮醇衍生物及其制备方法、用途。
背景技术
CYP1B1酶是CYP1家族的一个亚型，主要在肝脏外表达。它可以将雌二醇代谢为4-羟基雌二醇，这个代谢物在雌二醇诱导的乳腺癌的发生发展中起关键性作用(Cavalieri et al,Proc.Natl.Acad.Sci.USA,1997,94:10937-10942)。此外,CYP1B1酶参与苯并吡等多环芳香烃类前致癌物的代谢活化，是诱发肿瘤的一个因素。近期大量研究确证，CYP1B1酶在乳腺癌、卵巢癌、前列腺癌、肝癌、肺癌及肾癌等肿瘤组织中高表达，而在相应的正常细胞中表达量很少，其特异性分布及在肿瘤发生发展中的重要地位，使得它成为药物研究中的新靶点。
CYP1B1酶也是部分抗肿瘤药物的代谢酶，它可以代谢多西紫杉醇、紫杉醇、米托蒽醌、多柔比星及它莫昔酚等多种抗肿瘤药物，是肿瘤细胞产生耐药的一个原因(McFadyen et al,Future Oncol.,2005,1:259-263)。
α-萘黄酮是CYP1B1酶的强抑制剂，可显著抑制苯并吡等多环芳香烃类前致癌物的代谢活化，起到了肿瘤预防的作用(Koley et al,J.Biol.Chem.,1997，272:3149-3152)。研究表明，在CYP1B1高表达的肿瘤细胞株中，α-萘黄酮可消除因CYP1B1高表达引起的肿瘤细胞对多西紫杉醇产生的耐药性(McFadyen et al,Biochem.Pharmacol.,2001,62:207-212)。
发明人以α-萘黄酮为先导物，合成了对CYP1B1酶具有强抑制活性及高选择性的抑制剂(发明专利申请公布号：CN 102993157 A)；但这些化合物与α-萘黄酮相似，在水中的溶解度差，限制了它们作为药物的应用。
发明内容
本发明的目的在于针对现有技术中的缺陷，提供一种水溶性α-萘黄酮醇衍生物及其制备方法、用途。本发明涉及的水溶性α-萘黄酮醇衍生物能够抑制人体CYP1B1 酶的活性，能够克服因CYP1B1酶引起的肿瘤细胞对于抗肿瘤药的耐药性，可用于制备预防肿瘤发生和克服恶性肿瘤耐药的药物。
发明原理：本发明对α-萘黄酮与CYP1B1酶的晶体结构(Wang et al,J.Biol.Chem.,2011，286:5736-5743)进行分析，α-萘黄酮分子的萘环部分与酶活性中心的苯丙氨酸残基(Phe231)相互平行，存在π-π相互作用；其分子侧链苯环靠近酶的催化中心—亚铁血红素。α-萘黄酮分子吡喃酮环上的3位靠近CYP1B1酶活性中心可以活动的B’-C Loop区(附图3)，因此在吡喃酮环的3位的引入水溶性基团，可能伸出B’-C Loop区，分布于酶表面的溶剂区域，在解决酶抑制剂水溶性的同时，不会对化合物与酶活性中心的结合产生大的影响。本发明选用羟基及羟基烷基醇氨基酸酯作为水溶性基团，连接于α-萘黄酮分子吡喃酮环的3位，解决了先导物α-萘黄酮及已申请公布专利CN 102993157 A中α-萘黄酮衍生物的水溶性。本发明设计、合成水溶性α-萘黄酮醇及其衍生物，具有良好的水溶性，能够应用于细胞水平的实验，有利于制备用于肿瘤预防和克服肿瘤耐药的药物及其组合物。
本发明的目的是通过以下技术方案来实现的：
第一方面，本专利涉及一种水溶性α-萘黄酮醇衍生物；所述水溶性α-萘黄酮醇衍生物的结构如式(I)所示：
Figure PCTCN2014091234-appb-000001
其中，R为氢或脂肪醇的氨基羧酸酯及其生理可接受的盐；R1，R2，R3分别为氢或卤素。
优选的，所述水溶性α-萘黄酮醇衍生物为6,7,10-三甲氧基-α-萘黄酮醇衍生物，其结构式如式(Ⅲ)所示：
Figure PCTCN2014091234-appb-000002
优选的，所述水溶性α-萘黄酮醇衍生物为为6,7,10-三甲氧基-α-萘黄酮醇羟基烷基 醚氨基羧酸酯衍生物，其结构式如式(Ⅳ)所示：
Figure PCTCN2014091234-appb-000003
其中，R1、R3均为氢，R2为氟，R4为氢或含1至4个碳的直链或含支链的烷基，n＝2～8中任意整数。
第二方面，本发明涉及一种制备前述的水溶性α-萘黄酮醇衍生物的方法，所述方法具体为(如附图1所示)：将6,7,10-三甲氧基-α-二氢萘黄酮醇衍生物于甲醇中混悬，在氢氧化钠或氢氧化钾存在下，与双氧水发生氧化反应，即得所述6,7,10-二甲氧基-α-萘黄酮醇衍生物。
第三方面，本发明涉及一种制备前述的水溶性α-萘黄酮醇衍生物的方法，所述方法包括如下步骤(如附图2所示)：
A、以无水二氯甲烷为溶剂，在对甲苯磺酸或吡啶对甲苯磺酸存在的条件下，溴代脂肪醇与3,4-二氢-2H-吡喃发生加成反应，得2-(溴代烷氧基)-四氢吡喃(Ⅴ)；
B、以无水丙酮为溶剂，在碳酸钾存在的条件下，所述2-(溴代烷氧基)-四氢吡喃与6,7,10-三甲氧基-α-萘黄酮醇衍生物发生亲核取代反应，得6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚衍生物(Ⅵ)；
C、以甲醇为溶剂，在盐酸或硫酸存在的条件下，所述6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚衍生物发生脱除四氢吡喃保护基的反应，得6,7,10-三甲氧基-3-(羟基烷氧基)-α-萘黄酮衍生物(Ⅶ)；
D、以无水二氯甲烷为溶剂，在N,N’-二环己基碳二亚胺及4-二甲氨基吡啶存在的条件下，所述6,7,10-三甲氧基-3-(羟基烷氧基)-α-萘黄酮衍生物与N-叔丁氧羰基氨基酸发生酯化反应，得6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚(N-叔丁氧羰基)氨基酸酯衍生物(Ⅷ)；
E、以乙酸乙酯为溶剂，在盐酸存在的条件下，所述6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚(N-叔丁氧羰基)氨基酸酯衍生物脱除N-叔丁氧羰基，即得所述6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚氨基酸酯衍生物(Ⅳ)。
第四方面，本发明涉及一种前述的水溶性α-萘黄酮醇衍生物在制备抑制人体CYP1B1酶的活性药物中的用途。
第五方面，本发明涉及一种前述的水溶性α-萘黄酮醇衍生物在制备预防肿瘤发生的药物中的用途。
第六方面，本发明涉及一种前述的水溶性α-萘黄酮醇衍生物在制备克服由CYP1B1酶引起的抗肿瘤药物耐药的药物中的用途，所述水溶性α-萘黄酮醇衍生物与抗肿瘤药物联合用药。
第七方面，本发明涉及一种用于克服由CYP1B1酶引起的抗肿瘤药物耐药的复方药物，所述复方药物由如前述的水溶性α-萘黄酮醇衍生物与抗肿瘤药物复合而成。
与现有技术相比，本发明具有如下的有益效果：本发明涉及的水溶性α-萘黄酮醇衍生物能够抑制人体CYP1B1酶的活性，具有良好的水溶性，可用于恶性肿瘤的预防。水溶性α-萘黄酮醇衍生物与抗肿瘤药物联合用药，可以克服由CYP1B1酶引起的抗肿瘤药物耐药。本发明的制备方法原料易得，操作简单，反应收率高。
附图说明
阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为本发明制得结构式(Ⅲ)6,7,10-三甲氧基-α-萘黄酮醇衍生物的制备路线图；
图2为本发明制得结构式(Ⅳ)6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚氨基羧酸酯衍生物的制备路线图。
图3为α-萘黄酮与CYP1B1酶复合物的晶体结构图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
本实施例涉及一种具有结构式(Ⅲ)的6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-1)的制备方法，如图1所示，包括以下步骤：
步骤一，将2-乙酰基-4,5,8-三甲氧基-1-萘酚溶于无水N,N’-二甲基甲酰胺中，氮气保护下冰水浴降温至5℃，分批加入1.2倍当量的氢化钠。搅拌5分钟后，将1.2 倍当量的重蒸过的氯甲基甲基醚滴加至反应液中。反应液于室温下搅拌反应3h后，倒入预先冷却的饱和碳酸氢钠溶液中。混合物抽滤，并用少量冷水洗涤滤饼，滤饼干燥后得大量黄色粉末，即4,5,8-三甲氧基-2-乙酰基-1-萘酚甲氧基甲基醚，收率96％。1H NMR(300MHz,CDCl3)：δ 6.99(s,1H，H-C(2)),6.93(d,J＝8.7Hz,1H),6.88(d,J＝8.7Hz,1H),5.01(s,2H，OCH2O),3.96(s,3H,OCH3),3.93(s,3H,OCH3),3.90(s,3H，OCH3),3.41(s,3H，CH2OCH3),2.78(s,3H，COCH3).
步骤二，将4,5,8-三甲氧基-2-乙酰基-1-萘酚甲氧基甲基醚溶于适量10％的氢氧化钾-无水乙醇溶液(W/V)中，反应液于氮气保护下降温至5℃。将2.0倍当量的苯甲醛缓慢滴加至反应液中，反应液于低温下搅拌过夜，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，合并有机层。有机层经无水硫酸钠干燥、浓缩、硅胶柱层析后得(E)-1-(1’-甲氧甲氧基-4’,5’,8’-三甲氧基萘-2’)-3-苯基丙烯基-1-酮，呈深红色结晶，收率87％。1H NMR(400MHz,CDCl3)：δ 7.72(d,J＝16.0Hz,1H，H-C(3)),7.63(m,2H),7.54(d,J＝16.0Hz,1H，H-C(2)),7.41–7.36(m,3H),7.02(s,1H,H-C(3’)),6.94(d,J＝8.7Hz,1H),6.90(d,J＝8.7Hz,1H),4.98(s,2H，OCH2O),3.97(s,3H，OCH3),3.94(s,3H，OCH3),3.91(s,3H，OCH3),3.39(s,3H，CH2OCH3).
步骤三，将(E)-1-(1’-甲氧甲氧基-4’,5’,8’-三甲氧基萘-2’)-3-苯基丙烯基-1-酮于甲醇中混悬，冰水浴下降温至5℃；将16％的氢氧化钠溶液(10倍当量)及30％的双氧水(8倍当量)滴加至反应液中，反应液于低温下搅拌过夜，抽滤，滤饼经水及少量冷甲醇清洗，得1-(1’-甲氧甲氧基-4’,5’,8’-三甲氧基萘-2’)-2,3-环氧-3-苯基丙基-1-酮，呈黄色粉末，收率90％。1H NMR(400MHz,CDCl3):δ 7.43–7.30(m,5H),7.07(s,1H,H-C(3’)),6.96,6.88(d,J＝8.3Hz,each 1H,H-C(6’),H-C(7’)),4.97,4.89(d,J＝5.2Hz,each 1H,OCH2O),4.60(s,1H,H-C(2)),4.16(s,1H,H-C(3)),3.99(s,3H,OCH3),3.91(s,3H,OCH3),3.88(s,3H,OCH3),3.23(s,3H,CH2OCH3)
步骤四，将1-(1’-甲氧甲氧基-4’,5’,8’-三甲氧基萘-2’)-2,3-环氧-3-苯基丙基-1-酮于甲醇中混悬，加入浓盐酸(10倍当量)，升温至50℃反应，原料消失后停止反应。反应液抽滤，滤饼经少量甲醇清洗用乙酸乙酯重结晶，得6,7,10-三甲氧基-α-二氢萘黄酮醇。产物呈现淡黄色结晶，收率42％。1H NMR(400MHz,d6-DMSO):δ 7.66(d,J＝7.4Hz，2H，H-C(2'),H-C(6')),7.45(t,J＝7.4Hz,2H，H-C(3'),H-C(5')),7.39(m,1H,H-C(4’)),7.16(d,J＝8.8Hz,1H),7.09(s,1H，H-C(5))，7.04 (d,J＝8.8Hz,1H),5.84(d,J＝5.9Hz,1H，OH),5.32(d,J＝12.2Hz，1H，H-C(2)),4.54(dd,J＝12.2,5.9Hz,1H，H-C(3)),3.84(s,3H，OCH3),3.80(s,3H，OCH3),3.70(s,3H，OCH3).
步骤五，将6,7,10-三甲氧基-α-二氢萘黄酮醇于甲醇中混悬，加16％的氢氧化钠溶液(8倍当量)及30％的双氧水(12倍当量)，30℃反应36h。反应液用3N的盐酸酸化，抽滤。滤饼经过甲醇及水清洗后，干燥，得6,7,10-三甲氧基-α-萘黄酮醇，呈黄色粉末，收率87％。1H NMR(400MHz,d6-DMSO):δ 9.80(s,1H,OH),8.52-8.43(m,2H,H-C(2')，H-C(6')),7.69–7.63(m,2H,H-C(3')，H-C(5')),7.59–7.48(m,1H,H-C(4’)),7.33(s,3H，H-C(5)，H-C(8)，H-C(9)),4.09(s,3H，OCH3),3.96(s,3H，OCH3),3.85(s,3H，OCH3).
实施例2
本实施例涉及一种具有结构式(Ⅲ)的2'-氟-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-2)的制备方法，如图1所示，包括以下步骤：
本实施例步骤同实施例1步骤相同，在步骤二中以2-氟苯甲醛代替苯甲醛。产物呈黄色结晶，总收率15％。1H NMR(400MHz,d6-DMSO):δ 9.49(s,1H，OH),7.86(t,J＝6.9Hz,1H),7.63(m,1H),7.43(m,2H),7.33(s，1H，H-C(5)),7.27(d,J＝8.6Hz,1H),7.22(d,J＝8.6Hz,1H),3.96(s,3H，OCH3),3.84(s,6H，OCH3).
实施例3
本实施例涉及一种具有结构式(Ⅲ)的3'-氟-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-3)的制备方法，如图1所示，包括以下步骤：
本实施例步骤同实施例1步骤相同，在步骤二中以3-氟苯甲醛代替苯甲醛。产物呈黄色结晶，总收率13％。1H NMR(400MHz,d6-DMSO):δ 10.03(s,1H，OH),8.33(d,J＝7.9Hz,1H,H-C(2’)),8.23(d,J＝11.4Hz,1H,H-C(6’)),7.68(dd,J＝14.7,7.9Hz,1H,H-C(5’)),7.37(m,1H,H-C(4’)),7.31(s,2H),7.30(s,1H，H-C(5)),4.09(s,3H，OCH3),3.96(s,3H，OCH3),3.85(s,3H，OCH3).
实施例4
本实施例涉及一种具有结构式(Ⅲ)的4'-氟-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-4)的制备方法，如图1所示，包括以下步骤：
本实施例步骤同实施例1步骤相同，在步骤二中以4-氟苯甲醛代替苯甲醛。产物呈黄色结晶，总收率16％。1H NMR(400MHz,d6-DMSO):δ 9.76(s,1H，OH),8.52-8.42 (m,2H,H-C(2')，H-C(6')),7.47(t,J＝8.7Hz,2H,H-C(3')，H-C(5')),7.27(s,1H,H-C(5)),7.26(s,2H,H-C(8)，H-C(9)),4.05(s,3H，OCH3),3.94(s,3H，OCH3),3.84(s,3H，OCH3).
实施例5
本实施例涉及一种具有结构式(Ⅲ)的2'-氯-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-5)的制备方法，如图1所示，包括以下步骤：
本实施例步骤同实施例1步骤相同，在步骤二中以2-氯苯甲醛代替苯甲醛。产物呈黄色结晶，总收率19％。1H NMR(400MHz,d6-DMSO):δ 9.43(s,1H，OH),7.76(dd,J＝7.2,1.3Hz,1H),7.68(d,J＝7.6Hz,1H),7.62–7.51(m,2H),7.34(s,1H，H-C(5)),7.27(d,J＝8.8Hz,1H),7.21(d,J＝8.8Hz,1H),3.97(s,3H，OCH3),3.84(s,3H，OCH3),3.76(s,3H，OCH3).
实施例6
本实施例涉及一种具有结构式(Ⅲ)的3'-氯-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-6)的制备方法，如图1所示，包括以下步骤：
本实施例步骤同实施例1步骤相同，在步骤二中以3-氯苯甲醛代替苯甲醛。产物呈黄色结晶，总收率13％。1H NMR(400MHz,d6-DMSO):δ 10.03(s,1H，OH),8.47(s,1H，H-C(2’)),8.44(d,J＝7.9Hz，1H，H-C(6’)),7.64(t,J＝7.9Hz，1H，H-C(5’)),7.57(d,J＝7.6Hz，1H，H-C(4’)),7.29(s,2H，H-C(8)，H-C(9)),7.28(s,1H，H-C(5)),4.11(s,3H，OCH3),3.95(s,3H，OCH3),3.84(s,3H，OCH3).
实施例7
本实施例涉及一种具有结构式(Ⅲ)的4'-氯-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-7)的制备方法，如图1所示，包括以下步骤：
本实施例步骤同实施例1步骤相同，在步骤二中以4-氯苯甲醛代替苯甲醛。产物呈黄色结晶，总收率12％。1H NMR(400MHz,d6-DMSO):δ 9.97(s,1H，OH),8.46(d,J＝8.6Hz,2H，H-C(2')，H-C(6')),7.73(d,J＝8.6Hz,2H，H-C(3')，H-C(5')),7.31(s,3H，H-C(5)，H-C(8)，H-C(9)),4.09(s,3H，OCH3),3.95(s,3H，OCH3),3.85(s,3H，OCH3)。
实施例8
本实施例涉及一种具有结构式(Ⅳ)的2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇甘氨酸酯盐酸盐(Ⅳ-1)的制备方法，如图2所示，包括以下步骤：
步骤一，将2-溴乙醇溶于无水二氯甲烷中，加入催化量的对甲苯磺酸或吡啶对甲苯磺酸后，滴加1.1倍当量的3，4-二氢-2H-吡喃，室温搅拌5h。加入饱和碳酸氢钠水溶液淬灭反应，CH2Cl2萃取，合并有机层。有机层经饱和碳酸氢钠溶液清洗、无水硫酸钠干燥、浓缩、硅胶柱层析后得，得2-(2-溴乙氧基)-四氢吡喃(Ⅴ，n＝2)。产物呈无色油状物，收率75％。1H NMR(300MHz,CDCl3):δ 4.67(m,1H),4.01(dt,J＝12.3,6.3Hz,1H),3.88(m,1H),3.76(dt,J＝12.3,6.3Hz,1H),3.51(m,3H),1.90–1.50(m,6H).
步骤二，将3’-氟-6,7,10-三甲氧基-α-萘黄酮醇(Ⅲ-3)溶于无水丙酮中，加入10倍当量碳酸钾及3倍当量的2-(2-溴乙氧基)-四氢吡喃，室温反应36h，得6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚衍生物(Ⅵ，n＝2)，呈黄色粉末。将该中间体于甲醇中混悬，加入2倍当量的浓盐酸，室温搅拌12h，抽率，滤饼用少量甲醇清洗，干燥，得2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇(Ⅶ，n＝2)。产物呈黄色粉末，收率81％(两步)。1H NMR(400MHz,CDCl3):δ 8.27(d,J＝8.0Hz,1H),8.20(d,J＝10.5Hz,1H),7.57-7.51(m,1H),7.49(s,1H),7.23(dd,J＝8.0,2.4Hz,1H),7.18(d,J＝8.7Hz,1H),7.10(d,J＝8.7Hz,1H),5.08(s,1H，OH),4.17-4.13(m,2H，OCH2),4.10(s,3H，OCH3),4.07(s,3H，OCH3),3.95(s,3H，OCH3),3.90(m,2H,OCH2).
步骤三，将2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇溶于无水二氯甲烷中，加入等量的N,N’-二环己基碳二亚胺、催化量4-二甲氨基吡啶及1.2倍当量的N-叔丁氧羰基甘氨酸，室温反应24h，反应液加压浓缩至小体积，硅胶柱层析后得2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇-(N-叔丁氧羰基)甘氨酸酯(Ⅷ，n＝2)。产物呈亮黄色粉末，收率92％。1H NMR(400MHz,CDCl3):δ 8.27(d,J＝8.1Hz,1H),8.23(m,1H),7.55–7.49(m,1H),7.48(s,1H),7.23(td,J＝8.1,2.3Hz,1H),7.16(d,J＝8.9Hz,1H),7.09(d,J＝8.9Hz,1H),4.98(br，1H，NH)，4.56-4.50(m,2H，OCH2),4.50-4.45(m,2H，OCH2),4.09(s,3H，OCH3),4.07(s,3H，OCH3),3.95(s,3H，OCH3),3.85(d，J＝5.4Hz,2H，CH2N),1.45(s,9H，OC(CH3)3)。
步骤四，将步骤三产物溶于乙酸乙酯中，在盐酸的存在下，脱除N-叔丁氧羰基保护基，得最终产物2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇甘氨酸酯盐酸盐。产物呈红棕色粉末，收率74％。1H NMR(400MHz,d6-DMSO):δ 8.43(s,br，3H，NH3),8.24(d,J＝8.0Hz,1H),8.17(d,J＝11.2Hz,1H),7.76-7.69(m,1H),7.50-7.44 (m,1H),7.29(s,2H，H-C(8)，H-C(9)),7.28(s,1H，H-C(5)),4.49(m,4H，OCH2),4.04(s,3H，OCH3),3.94(s,3H，OCH3),3.84(s,3H，OCH3),3.76(s,2H，CH2N).
实施例9
本实施例涉及一种具有结构式(Ⅳ)的2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇丙氨酸酯盐酸盐(Ⅳ-2)的制备方法，如图2所示，包括以下步骤：
本实施例步骤同实施例8步骤一，步骤二，步骤三及步骤四，在步骤三中以N-叔丁氧羰基-L-丙氨酸代替N-叔丁氧羰基-甘氨酸。产物呈棕色粉末，总收率17％。1H NMR(400MHz,d6-DMSO):δ 8.67(s,br，3H，NH3),8.24(d,J＝8.0Hz,1H),8.16(d,J＝10.9Hz,1H),7.75–7.68(m,1H),7.50–7.44(m,1H),7.29(s,2H,H-C(8'),H-C(9')),7.27(s,1H,H-C(5')),4.56–4.42(m,4H,OCH2),4.04(s,3H,OCH3),3.93(s,4H,OCH3),3.84(s,3H,OCH3),1.37(d,J＝7.2Hz,3H,CCH3)。
实施例10
本实施例涉及一种具有结构式(Ⅳ)的2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇缬氨酸酯盐酸盐(Ⅳ-3)的制备方法，如图2所示，包括以下步骤：
本实施例步骤同实施例8步骤一，步骤二，步骤三及步骤四，在步骤三中以N-叔丁氧羰基-L-缬氨酸代替N-叔丁氧羰基-甘氨酸。产物呈棕红色粉末，总收率17％。1H NMR(400MHz,d6-DMSO):δ 8.60(s,br，3H，NH3),8.24(d,J＝8.0Hz,1H),8.18-8.13(m,1H),7.76-7.69(m,1H),7.48(td,J＝8.5,2.4Hz,1H),7.29(s,2H，H-C(8')，H-C(9')),7.28(s,1H，H-C(5')),4.60–4.52(m,2H,OCH2),4.52–4.42(m,2H，OCH2),4.04(s,3H，OCH3),3.94(s,3H，OCH3),3.84(s,3H，OCH3),3.79(s,1H),3.82-3.67(m,1H,COCHN),2.23-2.03(m，1H,CH)，0.93(d,J＝3.3Hz,3H，CH3),0.91(d,J＝3.3Hz,3H，CH3)。
实施例11
本实施例涉及一种具有结构式(Ⅳ)的2-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-乙醇赖氨酸酯盐酸盐(Ⅳ-4)的制备方法，如图2所示，包括以下步骤：
本实施例步骤同实施例8步骤一，步骤二，步骤三及步骤四，在步骤三中以N-叔丁氧羰基-L-赖氨酸代替N-叔丁氧羰基-甘氨酸。产物呈暗红色粉末，总收率25％。1H NMR(400MHz,d6-DMSO):δ 8.71(s,br,3H,NH3),8.25(d,J＝8.0Hz,1H),8.20–8.15(m,1H),7.75(dd,J＝14.5,8.0Hz),7.54–7.47(m,1H),7.32(s,2H，H-C(8'),H-C(9')),7.31(s,1H,H-C(5')),4.58–4.46(m,4H,OCH2),4.06(s, 3H,OCH3),4.04–4.02(m,1H,COCHN),3.95(s,3H,OCH3),3.85(s,3H,OCH3),2.78–2.72(m,2H,CH2N),1.84–1.76(m,2H),1.58–1.46(m,2H)。
实施例12
本实施例涉及一种具有结构式(Ⅳ)的4-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-丁醇甘氨酸酯盐酸盐(Ⅳ-5)的制备方法，如图2所示，包括以下步骤：
本实施例步骤同实施例8步骤一，步骤二，步骤三及步骤四，在步骤一中以4-溴-1-丁醇代替2-溴乙醇。产物呈棕色粉末，总收率15％。1H NMR(400MHz,d6-DMSO):δ 8.36(s,br，3H，NH3),8.20(d,J＝7.8Hz,1H),8.12(d,J＝11.0Hz,1H),7.72(dd,J＝14.8,7.8Hz,1H),7.50–7.43(m,1H),7.30(s,3H),4.27–4.22(m,2H，OCH2),4.20–4.15(m,2H，OCH2),4.04(s,3H，OCH3),3.94(s,3H，OCH3),3.85(s,3H，OCH3),3.84–3.79(m,2H，CH2N),1.82(s,4H，OCH2)。
实施例13
本实施例涉及一种具有结构式(Ⅳ)的6-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-己醇甘氨酸酯盐酸盐(Ⅳ-6)的制备方法，如图2所示，包括以下步骤：
本实施例步骤同实施例8步骤一，步骤二，步骤三及步骤四，在步骤一中以6-溴-1-己醇代替2-溴乙醇。产物呈橘黄色粉末，总收率17％。1H NMR(400MHz,d6-DMSO)：δ8.39(s,br，3H，NH3),8.19(d,J＝7.8Hz,1H),8.11(d,J＝11.2Hz,1H),7.75–7.66(m,1H),7.45(t,J＝8.3Hz,1H),7.28(s,3H),4.19–4.12(m，4H，OCH2),4.03(s,3H，OCH3),3.94(s,3H，OCH3),3.84(s,3H，OCH3),3.82–3.77(m,2H，CH2N),1.77–1.67(m,2H，CH2),1.65–1.57(m,2H，CH2),1.48–1.31(m,4H，CH2)。
实施例14
本实施例涉及一种具有结构式(Ⅳ)的8-(3’-氟-6,7,10-三甲氧基-α-萘黄酮-3-氧)-1-辛醇甘氨酸酯盐酸盐(Ⅳ-7)的制备方法，如图2所示，包括以下步骤：
本实施例步骤同实施例8步骤一，步骤二，步骤三及步骤四，在步骤一中以8-溴-1-辛醇代替2-溴乙醇。产物呈棕黄色粉末，总收率19％。1H NMR(400MHz,d6-DMSO):δ 8.29(s,br，3H，NH3),8.21(d,J＝7.9Hz，1H),8.13(d,J＝11.0Hz,1H),7.71(dd,J＝14.6,7.9Hz，1H),7.51–7.41(m，1H),7.31(s，3H),4.15(m，4H，OCH2),4.05(s,3H，OCH3),3.95(s,3H，OCH3),3.85(s,3H，OCH3),3.81(s，2H，CH2N),1.75–1.65(m，2H，CH2),1.65–1.55(m，2H，CH2),1.43–1.33(m，2H，CH2), 1.33–1.22(m，6H，CH2)。
实施例15
实施例1-14得到的化合物的酶抑制测试，结果见表1所示：
本实施例采用7-乙氧基-3H-吩恶嗪-3-酮脱乙氧基(EROD)法，测定化合物对CYP1A1、CYP1B1及CYP1A2酶的抑制活性(Yamaori et al,Biochem.Pharmacol.,2010,79:1691-1698)。反应体系(200μL)包含10fmol CYP1A1或20fmol CYP1B1或50fmol CYP1A2酶，不同浓度的待测化合物，NADPH再生系统(1.3mM NADP+，3.3mM葡萄糖-6-磷酸，0.5U/ml葡萄糖-6-磷酸脱氢酶)，3.3mM MgCl2和150nmol的7-乙氧基-3H-吩恶嗪-3-酮。反应缓冲液为含有1％BSA的50mM Tris-HCl(pH 7.4)缓冲液。反应体系37℃预热5min后，加入NADPH再生系统启动反应，待反应结束后加入100μL已预冷的乙腈终止反应。荧光读数选用Thermo Scientific Varioskan Flash多功能酶标仪检测，激发波长和发射波长分别为545nm和590nm。
评价方法：
酶活性抑制率＝(对照组值-实验组值)/对照组值×100％；
生物统计：IC50值利用统计软件Origin，选取非线性最小平方误差回归分析计算得到。
结果：实施例1-14得到的化合物对CYP1A1及CYP1B1两种酶的抑制活性数据见表1。
表1水溶性α-萘黄酮醇衍生物对CYP1A1及CYP1B1酶的抑制活性数据
Figure PCTCN2014091234-appb-000004
Figure PCTCN2014091234-appb-000005
实施例16
α-萘黄酮及化合物Ⅳ-1对因CYP1B1高表达而耐药的肿瘤株的逆转耐药实验。
实验方法：本实施例按照常规溴化四氮唑蓝(MTT)法进行，测定加入α-萘黄酮或化合物Ⅳ-1前后多西紫杉醇的IC50变化情况。活细胞线粒体中的琥珀酸脱氢酶能使外源性溴化四氮唑还原为难溶性的蓝紫色结晶物并沉积在细胞中，而死细胞无此功能。二甲基亚砜能溶解细胞中的紫色结晶物，用酶联免疫检测仪在570nm波长处测定其光吸收值，可间接反映活细胞数量。该方法已广泛用于一些生物活性因子的活性检测，大规模的抗肿瘤药物筛选，细胞毒性试验以及肿瘤放射敏感性测定等。
肿瘤细胞株：选用因CYP1B1高表达而对多西紫杉醇耐药的MCF-7人乳腺癌细胞株(采用专利WO 03/028713 A2说明书第72页的方法，由MCF-7细胞株经浓度为10nM的2,3,7,8-四氯二苯并二噁英诱导获得)。
细胞抑制率计算：
抑制率＝(对照组平均OD值－给药组平均OD值)/对照组平均OD值
剂量设置：多西紫杉醇对细胞作用时，设五个浓度，主要在0.1～180μΜ/ml范围内；α-萘黄酮及化合物Ⅳ-1采用5、10、25、40、50、100μΜ六个浓度梯度，逆转耐药实验时，与多西紫杉醇同时加入；在5、10、25、50、100μΜ五个浓度梯度下，测定α-萘黄酮及化合物Ⅳ-1对耐药的MCF-7人乳腺癌细胞株生长抑制率。
生物统计：使用SPSS软件，根据试验药物在不同浓度下对细胞生长的抑制率，以Probit Analysis方法计算IC50值。
MTT法结果如表2所示，对所选用的耐药肿瘤细胞株，多西紫杉醇的IC50值为139.82μM；多西紫杉醇联合5、10、25、40、50、100μΜ的α-萘黄酮作用后，对该耐药细胞的IC50值分别为110.59、98.15、87.13、42.22、35.60及51.79μΜ，使细胞对紫杉醇的敏感性分别增加了1.26、1.42、1.60、3.31、3.93、2.70倍；多西紫杉醇联合5、10、25、40、50、100μΜ的化合物Ⅳ-1作用后，对该耐药细胞的IC50值分别为55.93、25.52、10.81、7.62、8.46及4.63μΜ，使细胞对紫杉醇的敏感性分别增加了2.50、5.48、12.93、18.35、16.35、30.20倍。
表2CYP1B1抑制剂逆转肿瘤细胞株耐药数据
Figure PCTCN2014091234-appb-000006
Figure PCTCN2014091234-appb-000007
表3α-萘黄酮及化合物Ⅳ-1对耐药肿瘤细胞株生长抑制作用数据
Figure PCTCN2014091234-appb-000008
实施例17
化合物Ⅲ-3及化合物Ⅳ-7对因CYP1B1高表达而耐药的肿瘤细胞株的逆转耐药实验。
采用与实施例22相同的实验方法，选用如实施例16所述的因CYP1B1高表达而对多西紫杉醇耐药的MCF-7人乳腺癌细胞株，应用MTT法进行实验。
细胞抑制率计算:
抑制率＝(对照组平均OD值－给药组平均OD值)/对照组平均OD值
剂量设置：多西紫杉醇对细胞作用时，设五个浓度，主要在0.1～180μΜ/mL范围内；α-萘黄酮、化合物Ⅲ-3及化合物Ⅳ-7均采用5μΜ和10μΜ两个浓度梯度，逆转耐药实验时，与多西紫杉醇同时加入；在5μΜ和10μΜ两个浓度梯度下，测定α-萘黄酮、化合物Ⅲ-3及化合物Ⅳ-7对耐药的MCF-7人乳腺癌细胞株生长抑制率。
生物统计：使用SPSS软件，根据试验药物在不同浓度下对细胞生长的抑制率，以Probit Analysis方法计算IC50值。
MTT法结果如表4所示，对所选用的耐药肿瘤细胞株，多西紫杉醇的IC50值为139.82μM；多西紫杉醇联合5μΜ和10μΜ的α-萘黄酮作用后，对该耐药细胞的IC50值分别为110.59μΜ和98.15μΜ，使细胞对紫杉醇的敏感性分别增加了1.26倍及1.42倍；多西紫杉醇联合5μΜ及10μΜ的化合物Ⅲ-3作用后，对该耐药细胞的IC50值分别为 83.73μΜ及67.22μΜ，使细胞对紫杉醇的敏感性分别增加了1.67及2.08倍；多西紫杉醇联合5μΜ及10μΜ的的化合物Ⅳ-7作用后，对该耐药细胞的IC50值分别为54.21μΜ及25.30μΜ，使细胞对紫杉醇的敏感性分别增加了2.50及5.52倍；
表4CYP1B1抑制剂逆转肿瘤细胞株耐药数据
Figure PCTCN2014091234-appb-000009
表5α-萘黄酮及化合物Ⅳ-1对耐药肿瘤细胞株生长抑制作用数据
Figure PCTCN2014091234-appb-000010
综上所述，本发明涉及的水溶性α-萘黄酮醇衍生物能够抑制人体CYP1B1酶的活性且具有良好的水溶性，能够缓解多环芳香烃类前致癌物质的代谢活化；与抗肿瘤药物联用，可逆转引CYP1B1引起的肿瘤细胞株的耐药性，进而能够用于制备预防肿瘤发生以及克服恶性肿瘤耐药的药物；本发明的制备方法原料易得，操作简单，反应收率高。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (9)

  1. 一种水溶性α-萘黄酮醇衍生物，其特征在于，所述水溶性α-萘黄酮醇衍生物的结构如式(I)所示：
    Figure PCTCN2014091234-appb-100001
    其中，R为氢或脂肪醇的氨基羧酸酯及其生理可接受的盐；R1，R2，R3分别为氢或卤素。
  2. 根据权利要求1所述的水溶性α-萘黄酮醇衍生物，其特征在于，所述水溶性α-萘黄酮醇衍生物为6,7,10-三甲氧基-α-萘黄酮醇衍生物，其结构式如式(Ⅲ)所示：
    Figure PCTCN2014091234-appb-100002
  3. 根据权利要求1所述的水溶性α-萘黄酮醇衍生物，其特征在于，所述水溶性α-萘黄酮醇衍生物为为6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚氨基羧酸酯衍生物，其结构式如式(Ⅳ)所示：
    Figure PCTCN2014091234-appb-100003
    其中，R1、R3均为氢，R2为氟，R4为氢或含1至4个碳的直链或支链的烷基，n＝2～8中任意整数。
  4. 一种制备如权利要求2所述的水溶性α-萘黄酮醇衍生物的方法，其特征在于，所述方法具体为：将6,7,10-三甲氧基-α-二氢萘黄酮醇衍生物于甲醇中混悬，在氢氧化钠或氢氧化钾存在下，与双氧水发生氧化反应，即得所述6,7,10-二甲氧基-α-萘黄酮醇衍生物。
  5. 一种制备如权利要求3所述的水溶性α-萘黄酮醇衍生物的方法，其特征在于，所述方法包括如下步骤：
    A、以无水二氯甲烷为溶剂，在对甲苯磺酸或吡啶对甲苯磺酸存在的条件下，溴代脂肪醇与3,4-二氢-2H-吡喃发生加成反应，得2-(溴代烷氧基)-四氢吡喃；
    B、以无水丙酮为溶剂，在碳酸钾存在的条件下，所述2-(溴代烷氧基)-四氢吡喃与6,7,10-三甲氧基-α-萘黄酮醇衍生物发生亲核取代反应，得6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚衍生物；
    C、以甲醇为溶剂，在盐酸或硫酸存在的条件下，所述6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚衍生物发生脱除四氢吡喃保护基的反应，得6,7,10-三甲氧基-3-(羟基烷氧基)-α-萘黄酮衍生物；
    D、以无水二氯甲烷为溶剂，在N,N’-二环己基碳二亚胺及4-二甲氨基吡啶存在的条件下，所述6,7,10-三甲氧基-3-(羟基烷氧基)-α-萘黄酮衍生物与N-叔丁氧羰基氨基酸发生酯化反应，得6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚(N-叔丁氧羰基)氨基酸酯衍生物；
    E、以乙酸乙酯为溶剂，在盐酸存在的条件下，所述6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚(N-叔丁氧羰基)氨基酸酯衍生物脱除N-叔丁氧羰基，即得所述6,7,10-三甲氧基-α-萘黄酮醇羟基烷基醚氨基酸酯衍生物。
  6. 一种如权利要求1～3中任一项所述的水溶性α-萘黄酮醇衍生物在制备抑制人体CYP1B1酶活性的药物中的用途。
  7. 一种如权利要求1～3中任一项所述的水溶性α-萘黄酮醇衍生物在制备预防肿瘤发生的药物中的用途。
  8. 一种如权利要求1～3中任一项所述的水溶性α-萘黄酮醇衍生物在制备克服由CYP1B1酶引起的抗肿瘤药物耐药的药物中的用途，其特征在于，所述水溶性α-萘黄酮醇衍生物与抗肿瘤药物联合用药。
  9. 一种用于克服由CYP1B1酶引起的抗肿瘤药物耐药的复方药物，其特征在于，所述复方药物由如权利要求1～3中任一项所述的水溶性α-萘黄酮醇衍生物与抗肿瘤药物复配而成。
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