CN110840879B - Preparation method and application of rhamnose carbon glycoside drugs - Google Patents
Preparation method and application of rhamnose carbon glycoside drugs Download PDFInfo
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- CN110840879B CN110840879B CN201911096157.8A CN201911096157A CN110840879B CN 110840879 B CN110840879 B CN 110840879B CN 201911096157 A CN201911096157 A CN 201911096157A CN 110840879 B CN110840879 B CN 110840879B
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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Abstract
The invention provides a rhamnose carbon glycoside drug, a compoundStructure is as
Said R 1 Including phenyl, substituted phenyl, various alkyl of C1-C10; r 2 Including phenyl, substituted phenyl; r is 1 、R 2 The substituted phenyl group in (1) includes alkyl group, halogen atom, alkoxy group, alkylthio group substituted phenyl group. The preparation method comprises the steps of acetylating rhamnose and then carrying out bromination reaction on the rhamnose to obtain the rhamnose. The invention can be used for preparing the medicine for resisting gastric cancer, breast cancer and liver cancer.
Description
Technical Field
The invention relates to a synthesis method, structure identification and anticancer activity of a rhamnose carbon glycoside drug, and the compounds show selective antiproliferative action on tumor cells and can provide a substitute drug for tumor chemotherapy.
Background
Sugar, which is an organic compound existing most and widely distributed in nature, is a very important class of living matter other than proteins and nucleic acids, not only participating in processes such as cell growth, information transmission, apoptosis and canceration, but also being a main substance for supplying body energy, and plays an important role in life science and pharmaceutical research. Glycosides are molecules made up of a sugar or a derivative of a sugar when the terminal carbon atom is attached to a non-sugar material, and are called carboglycosides because the non-sugar material is attached to the sugar ring by a carbon bond.
Scientists find that the glucoside not only can utilize the specific immune response mechanism of the sugar to develop vaccines, but also can be used for synthesizing drug molecules for treating viruses, and the glucoside has wide application in the field of biological molecules due to the bioactivity of the glucoside. In view of the current state of research, the research on the application of sugar chemistry has become one of the hot spots for the research of chemists and biologists. According to the reports of the literature and the patent, the carbon glycoside is stable under the acidic condition, has better stability in enzyme, is an important glycosidase inhibitor, and is a molecular template for researching the sugar recognition process in organisms.
In view of the anti-inflammatory activity, anti-tumor activity, anti-viral activity, etc. of the glycoside, the research on the synthesis method of the glycoside is increasingly focused. Review studies have shown that the conversion of sugars into intermediates such as sugar radicals, sugar carbenium ions, and sugar carbanions can be used for the synthesis of sugar glycosides. In recent years, due to the abundant chiral centers in sugar structures, the synthesis reaction of sugar carbon glycosides through transition metal catalysis is widely regarded by synthetic chemists, and for example, Heck reaction of glycal and halogenated hydrocarbon, Suzuki reaction of halogenated glycal and organic boron reagent, Stille reaction of halogenated glycal and organic tin reagent, Negishi reaction of halogenated sugar ring and organic zinc reagent, and the like can be used for the synthesis of sugar carbon glycosides. Although the method is multiple, the method also faces the limitations, such as low selectivity of glycosyl anomeric effect, no water and oxygen harsh reaction conditions, poor functional group tolerance and the like, and further application of the method is also restricted.
Disclosure of Invention
Aiming at the technical problems, the patent provides a method for synthesizing beta-type rhamnose carbon glycoside by catalyzing rhamnose and alkyne ester compounds with scandium trifluoromethanesulfonate at high selectivity, which has the advantages of good functional group compatibility, mild reaction conditions, quick and efficient reaction and enrichment of a synthesis method of carbon glycoside compounds.
The rhamnose carbon glycoside drug has a structural formula shown in the specification
R is as described 1 Including phenyl, various substituted phenyl (such as alkyl, halogen, alkoxy, alkylthio, etc.), CVarious alkyl groups of 1 to C10, and the like, R 2 Comprises phenyl, various substituted phenyl (such as alkyl, halogen atom, alkoxy, alkylthio, etc.), adopts alkyne ester intermediate and rhamnose as raw materials in Sc (OTf) 3 The high-efficiency synthesis of the compound can be realized under catalysis.
In the preferred scheme, the structural formula of the rhamnose carbon glycoside drug is shown as
The preparation method of the rhamnose carbon glycoside medicine comprises the following steps:
acetylation of rhamnose
Dissolving L-rhamnose in acetic anhydride, adding pyridine, reacting in water bath, and monitoring by TLC to obtain total acetyl rhamnose;
bromination of peracetyl rhamnose
Under the protection of nitrogen, adding a solution of the total acetyl rhamnose dissolved by dichloromethane, stirring, dropwise adding a mixed solution of HBr/AcOH by using a constant-pressure dropping funnel under ice bath, gradually changing the color of the colorless solution into yellow, and after the dropwise adding is finished, stopping the monitoring reaction by a point plate to obtain a bromo-acetyl rhamnose intermediate;
preparation of rhamnose intermediate
Sequentially adding NaH into a container bottle 2 PO 4 Adding bromo-rhamnosyl sugar into Zn powder and ethyl acetate, stirring, dropwise adding phosphoric acid, heating in a water bath at 55-65 ℃ for 0.5-1.5 hours, and reacting completely to obtain a rhamnose intermediate;
preparation of rhamnose carbon glycoside medicine
In a dichloromethane solvent, reacting the glycal intermediate with the alkyne ester intermediate for 2-3 hours at room temperature under the action of a catalyst to obtain the rhamnose carbon glycoside drug with high yield, wherein the reaction formula is as follows:
R 1 including phenyl, various substituted phenyl (such as alkyl, halogen atom, alkoxy, alkylthio, etc.), various alkyl groups of C1-C10, etc., R 2 Comprises phenyl, various substituted phenyl (such as alkyl, halogen atom, alkoxy, alkylthio, etc.), adopts alkyne ester intermediate and rhamnose as raw materials in Sc (OTf) 3 The high-efficiency synthesis of the compound can be realized under catalysis.
The solvent in the step (iv) comprises dichloromethane, trichloromethane or toluene.
The catalyst in the step (IV) comprises AuCl 3 、AgSbF 6 、Ph 3 PAuCl、AgOTf、Cu(OTf) 2 、Sc(OTf) 3 Any one of them. Preferred catalysts are Sc (OTf) 3 。
In the above synthetic process, the 18 The mechanism for obtaining the rhamnose carbon glycoside compound by marking isotope O is as follows: firstly carrying out intramolecular cyclization on Sc (III) and activated alkyne bonds to obtain an intermediate (A), and then carrying out 1, 3-sigma migration on ester groups to obtain a allene intermediate (B); on the other hand, allyl acetate is removed from the glycal under the action of Sc (III) to obtain allyl carbocation (C), and finally the allyl carbocation is subjected to nucleophilic attack of the allene intermediate (B) to obtain the rhamnose carbon glycoside compound (shown in the following).
The other technical scheme of the invention is the application of the rhamnose carbon glycoside drug in preparing anti-gastric cancer drugs.
The other technical scheme of the invention is the application of the rhamnose carbon glycoside medicine in preparing the medicine for treating breast cancer.
The other technical scheme of the invention is the application of the rhamnose carbon glycoside drug in preparing drugs for treating liver cancer.
Drawings
FIG. 1 is a NMR spectrum of Compound 3 r.
FIG. 2 is a NMR carbon spectrum of Compound 3 r.
Detailed Description
Preparation of rhamnose carbon glycoside compound
Synthesis of rhamnose intermediate
Acetylation of rhamnose
L-Rhamnose (18.0g,109.8mmol) was dissolved in acetic anhydride (64mL), pyridine (47mL) was added to dissolve completely, and the reaction was carried out in a water bath. TLC monitoring was done until the reaction was complete. And (3) post-treatment: equivalent dichloromethane was added, poured into water, the aqueous phase was extracted twice with ethyl acetate (2 × 25mL) and the organic phases combined, washed several times with 1M HCl until pyridine free (dot panel uv free), saturated sodium carbonate solution until PH 7, washed 2 times with water, the organic phases combined, dried over sodium sulfate and concentrated to give total acetyl rhamnose as a colorless oil 35.28g with a yield of 96%.
Bromination of peracetyl rhamnose
Under nitrogen, a solution of rhamnose (36.6g, 110.5mmol) dissolved in dichloromethane (180mL) was added and stirred for 30 min. 33% HBr/AcOH (19.1mL) was added slowly (3s/D) dropwise from an isopiestic dropping funnel under ice-bath. The colorless solution gradually turns yellow, and the plate is monitored after the dripping is finished. And (3) post-treatment: slowly dropwise into ice water sodium bicarbonate mixture (100mL), the aqueous phase was washed twice with dichloromethane (2X 25mL), and the organic phase was saturated NaHCO 3 Washing to neutrality, washing with water once, combining organic phases, drying with anhydrous sodium sulfate, performing flash column chromatography twice, concentrating under reduced pressure to obtain white oil, adding petroleum ether, and recrystallizing to obtain bromoacetyl rhamnose solid 22.54 g. The calculated pure yield was 58%.
Elimination of bromoacetyl rhamnose
Sequentially adding NaH into a 500mL three-neck bottle 2 PO 4 (203.7g), Zn powder (64.3g) and ethyl acetate (550mL), and acetyl bromide rhamnose is addedSugar (22.5g), mechanically stirred for 10min, then added dropwise with phosphoric acid (43.0mL), heated in a water bath at 60 ℃ and reacted completely after 1 hour. And (3) post-treatment: equivalent DCM was added for dilution, Zn powder was removed by suction filtration, washed twice (2 × 20mL), the organic phase was dried over anhydrous sodium sulfate, concentrated and spin dried. 13.13g of crude product (colorless oil) are obtained. Column chromatography (P: E ═ 7:1) afforded 9.88g of rhamnose intermediate, yield 72%. 1 H NMR(CDCl 3 ,400MHz)δ(ppm):7.29-7.25(m,1H),7.20-7.06(m,1H),6.04-5.97(m,1H),5.07-5.01(m,1H),3.07-2.78(m,1H),2.29-2.05(m,2H),1.58(s,1H),1.00(t,J＝4.0Hz,1H). 13 C NMR(CDCl 3 ,100MHz)δ(ppm):141.6,141.1,138.2,132.1,128.4,126.0,124.8,77.3,76.7,72.6,64.3,63.3,44.3,29.6,22.8,21.1,14.0.
To find a suitable catalyst for the glycosidation reaction, part of the metal catalysts were screened for their catalytic effect, and found to be Sc (OTf) 3 The catalyst has better catalysis effect on the reaction. The catalyst is used as Lewis acid, and the anion of the catalyst has strong electron-withdrawing capability, so that the metal ion of the catalyst has stronger electropositivity and forms a cyclic intermediate with a heteroatom, thereby being beneficial to the reaction. Subsequent screening of the laboratory solvent, determination of Sc (OTf) in methylene chloride 3 The catalytic effect of (2) is best, and the yield reaches 92% (the screening results of the catalyst and the solvent are shown in the following table).
Model reaction-based catalyst screening experimental table
Under optimized reaction conditions, the substrate development of the C1-glycosylation reaction was performed. With electron-donating groups bound to propargyl groupsOn the phenyl radical of (R) 2 ) Resulting in lower yields at the anomeric carbon (52% to 73%), L-murinoside derivatives (compounds 3f-3 n); while electron withdrawing groups generally lead to better stereoselectivity and yields (82% to 92%, compounds 3o to 3 r). Further exploration of the substrate range focuses on aliphatic substituents or heterocycles (R) 1 ) The yield of 3s-3w of the alkyne ester compound was moderate (65% to 81%). It is noteworthy that when the steric hindrance of the alkyne ester increases, it results in lower yields of 65% to 78% at the anomeric carbon, compounds 3a-3 e.
Structural analysis of rhamnose C-glycoside
An experimental instrument: ultrashied 400MHz Plus nuclear magnetic resonance spectrometer (Bruker, switzerland), API 4000LC-MS/MS mass spectrometer (brueck daltons, germany), 360FT-IR type infrared spectrometer (Nicolet, usa).
Experimental reagent: deuterated chloroform-d (deuterium atom content 99.8%, TMS content 0.03% V/V, 10 x 0.5 mL/box, arm, switzerland); chromatographically pure acetonitrile (content 99.99%, 4L bottles, MILAK, germany); distilled water (4.5L/barrel, Watson Corp.); nuclear magnetic tubes (5mm 100/pk 2ST500-8, Norell, USA); potassium bromide (national chemical group, chemical agents limited).
Test procedure
Accurately weighing 10mg of target compound, dissolving the target compound in 0.5mL of deuterated chloroform in a nuclear magnetic resonance tube, and testing the chemical structure of the target compound by a nuclear magnetic resonance instrument; taking 1.0mg of a sample on an analytical balance, adding 200mg of potassium bromide, uniformly grinding in an agate mortar, drying, pressurizing in a tabletting mold to prepare a salt window, and testing the infrared spectrogram of the compound on an infrared spectrometer; and dissolving a sample to be tested by using chromatographic acetonitrile to prepare a solution with the concentration of 1.0ppm, sampling by using a micro-injector, and testing the mass spectrum of the sample on an electrospray mass spectrometer.
Structural analysis of Compound 3r
The nuclear magnetic resonance hydrogen spectrum analysis shows that the chemical shifts of three aromatic hydrogen protons in the compound 3r are 7.0-7.4ppm, the three protons of the oxygen atoms connected with the rhamnose ring and the three olefinic hydrogen protons are between 3.7 and 6.0ppm, and the proton of the isopropyl substituent and the methyl proton on the rhamnose ring are between 0.9 and 2.2 ppm; the split of all peaks is consistent with the molecular structure. NMR carbon Spectroscopy showed that the signal for the ketone carbonyl carbon was 196.1ppm, the signal for the acetate carbonyl carbon was 170.5ppm, sp 2 The hybridization carbon signal is in the middle of 108.3-142.6 ppm, three aerobic carbon signals on the sugar ring are between 67.1-72.7 ppm, and five aliphatic carbon signals are between 17.3-29.2 ppm. In the high-resolution mass spectrometry of the compound, the ion addition peak of the compound 3r is 365.1567, and the molecular formula of the instrumental test is C 20 H 23 O 4 F 2 This is consistent with the theoretical calculation of [ M + H ].
Evaluation of antitumor Activity of rhamnose C-glycoside in vitro
Experimental reagent: RPMI1640 culture solution (10.4 g dry powder type phenol red-free RPMI640 dissolved in 1000mL distilled water, adding 2.0g sodium bicarbonate, stirring to dissolve completely, then filtering with 0.22 μm sterile positive pressure filter, subpackaging, and adding 10% calf serum, 0.5% penicillin (100U/mL) and streptomycin (100 μ g/mL).
An experimental instrument: an ultra-clean workbench (Beijing Donghong Bihaar instruments manufacturing Co., Ltd.), an ultrasonic cleaning instrument (Lingbaoxinzhi Biotechnology Co., Ltd.), a TDZ4-WS type low-speed centrifuge (Changshan plain instruments Co., Ltd.), a DK-8A type electrothermal constant-temperature water tank (Shanghai Jingjing Macro laboratory instruments Co., Ltd.), an automatic double-steam distiller (Shanghai Yangrong biochemical instruments Co., Ltd.), an HTC-100A type constant-temperature and constant-humidity incubator (Shanghai Sagitang instruments Co., Ltd.), an LDZX-30KBS type vertical pressure steam sterilizer (Shanghai Shenan medical instrument factory), a carbon dioxide incubator (Japan Sanyo Co., Ltd.), and a Stat Fax-2100 type enzyme-linked immunosorbent assay instrument (Awareners, USA).
Experimental part
Evaluation of rhamnose-carbon glycosides by MTT methodThe compound has the proliferation inhibiting effect on human gastric cancer cell HGC-27, human cervical cancer Caski cell line and human liver tumor HepG2 cell line (the cell lines are all from Shanghai cell bank of Chinese academy of sciences): adopting RPMI1640 containing 100U/mL streptomycin and 10% newborn fetal calf serum as cell culture solution, placing cells at 37 deg.C and 5% CO 2 The cell culture box of (3). When the cells are passaged, the cell density is adjusted to be 5X 10 4 ～1×10 5 Cells/well were seeded in 96-well plates at 37 ℃ with 5% CO 2 Culturing in an incubator. After 24h, adding drugs with different concentrations, and arranging a blank control group (culture solution), a normal control group (cells + culture solution) and a positive control group (taking the antitumor drug paclitaxel as a positive control) for 48 h. After termination of the experiment, 20. mu.L of MTT (5mg/mL) was added to the wells and incubation was continued at 37 ℃ for 4h, the supernatant was aspirated, 150. mu.L of DMSO was added to each well, shaking was carried out, and the absorbance (OD) at 492nm was measured. After uptake of MTT by living cells, formazan is produced by mitochondrial metabolism, and the more vigorous the mitochondrial activity, the more formazan is produced, the higher the absorbance, and this reflects the survival of cells. The cell inhibition rate was calculated, and whether the drug had an inhibitory effect on the proliferation of cells was judged by the cell inhibition rate (cell inhibition rate T/C ═ 1-cell-administered OD/control cell OD). Median Inhibitory Concentration (IC) 50 ) Often used as a quantitative index reflecting the effect of the drug and widely applied to screening various drugs, therefore, the statistical software SPSS 13.0 is utilized to respectively calculate and compare the IC of the drug acting on different cells 50 Reflecting the action and effect of the drug.
Analysis of structure-activity relationship of rhamnose glycoside compounds
The results of the in vitro antitumor activity of the compounds are shown in the following table.
Analysis of structure-activity relationship: anti-proliferative active compounds of gastric cancer HGC-27 cells include (3a, b,3g、3p、3r、3s、3t、3u)，IC 50 Between 4.25 μ M and 19.4 μ M; the antiproliferative active compounds of human cervical cancer Caski cell line are (3k, 3o, 3p, 3r, 3t, 3u, 3w), IC 50 Between 11.7 μ M and 18.3 μ M; the proliferation inhibiting active compounds of human liver tumor HepG2 cell line include (3o, 3p, 3r, 3s, 3t, 3u, 3v, 3w), IC 50 Between 11.5. mu.M and 19.9. mu.M.
Claims (4)
1. The application of the rhamnose carbon glycoside medicine in preparing the medicine for treating the Caski cell strain resisting human cervical cancer is characterized in that the structural formula of the rhamnose carbon glycoside medicine is shown in the specification
Said R 1 Including phenyl, substituted phenyl, various alkyl of C1-C10; r 2 Is phenyl, substituted phenyl, ethyl, isopropyl; r 1 、R 2 The substituted phenyl group in (1) includes alkyl group, halogen atom, alkoxy group, alkylthio group substituted phenyl group.
2. The application of the rhamnose carbon glycoside medicine in preparing the medicine for treating gastric cancer is characterized in that the structural formula of the rhamnose carbon glycoside medicine is shown as
R is as described 1 Including phenyl, substituted phenyl, various alkyl of C1-C10; r 2 Is phenyl, substituted phenyl, ethyl, isopropyl; r 1 、R 2 The substituted phenyl group in (1) includes alkyl group, halogen atom, alkoxy group, alkylthio group substituted phenyl group.
3. The use of claim 1 or 2, wherein the rhamnose glycosides are of the formula
4. The application of the rhamnose carbon glycoside medicine in preparing the medicine for treating the anti-liver cancer, wherein the liver cancer cell is a human liver tumor HepG2 cell line, and the rhamnose carbon glycoside medicine has the structural formula:
any one of them.
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