CN113667063A - Synthesis method of BX/Nar-g-HPMA/DEAM malate with anticancer activity - Google Patents
Synthesis method of BX/Nar-g-HPMA/DEAM malate with anticancer activity Download PDFInfo
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229940049920 malate Drugs 0.000 title claims abstract description 19
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 229920001221 xylan Polymers 0.000 claims abstract description 40
- 150000004823 xylans Chemical class 0.000 claims abstract description 40
- 241000609240 Ambelania acida Species 0.000 claims abstract description 35
- 239000010905 bagasse Substances 0.000 claims abstract description 35
- SJIXRGNQPBQWMK-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-methylprop-2-enoate Chemical compound CCN(CC)CCOC(=O)C(C)=C SJIXRGNQPBQWMK-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 claims abstract description 26
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 claims abstract description 26
- 229940052490 naringin Drugs 0.000 claims abstract description 26
- 229930019673 naringin Natural products 0.000 claims abstract description 26
- 239000000463 material Substances 0.000 claims abstract description 21
- 239000000178 monomer Substances 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003999 initiator Substances 0.000 claims abstract description 14
- 239000001630 malic acid Substances 0.000 claims abstract description 14
- 235000011090 malic acid Nutrition 0.000 claims abstract description 14
- GNSFRPWPOGYVLO-UHFFFAOYSA-N 3-hydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCO GNSFRPWPOGYVLO-UHFFFAOYSA-N 0.000 claims abstract description 13
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 12
- 229920000578 graft copolymer Polymers 0.000 claims abstract description 12
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002608 ionic liquid Substances 0.000 claims abstract description 9
- RVKZDIDATLDTNR-UHFFFAOYSA-N sulfanylideneeuropium Chemical compound [Eu]=S RVKZDIDATLDTNR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 19
- 238000005303 weighing Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
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- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- SUDJRWYYYIMQTR-UHFFFAOYSA-N 1-(3-prop-2-enoyl-1,3-diazetidin-1-yl)prop-2-en-1-one Chemical compound C=CC(=O)N1CN(C(=O)C=C)C1 SUDJRWYYYIMQTR-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000002131 composite material Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052901 montmorillonite Inorganic materials 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 9
- 102000005962 receptors Human genes 0.000 abstract description 7
- 108020003175 receptors Proteins 0.000 abstract description 7
- 239000002028 Biomass Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 210000001503 joint Anatomy 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 125000000539 amino acid group Chemical group 0.000 abstract description 2
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- 238000007348 radical reaction Methods 0.000 abstract description 2
- 150000003254 radicals Chemical class 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000012086 standard solution Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000032050 esterification Effects 0.000 description 6
- 238000003032 molecular docking Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 4
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 3
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- -1 DEAM malic acid ester Chemical class 0.000 description 2
- 238000002479 acid--base titration Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
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- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
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- 239000012488 sample solution Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XUAXVBUVQVRIIQ-UHFFFAOYSA-N 1-butyl-2,3-dimethylimidazol-3-ium Chemical compound CCCCN1C=C[N+](C)=C1C XUAXVBUVQVRIIQ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 210000003734 kidney Anatomy 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
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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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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/14—Esterification
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Abstract
The invention discloses a synthesis method of anti-cancer activity BX/Nar-g-HPMA/DEAM malate. Bagasse xylan and naringin are used as raw materials, hydroxypropyl methacrylate and diethylaminoethyl methacrylate are used as grafting monomers, ammonium persulfate is used as an initiator, and a bagasse xylan graft copolymer BX/Nar-g-HPMA/DEAM is synthesized in a water solvent through a free radical reaction; the ionic liquid 1-butyl-2, 3-dimethyl imidazolium chloride is used as a solvent, malic acid is used as an esterifying agent, and BX/Nar-g-HPMA/DEAM malate is synthesized through a catalytic esterification reaction. The butt joint object of the active grafting monomer is not a single specific residue or specific residues, the site generating hydrogen bond is wider when the active grafting monomer is in butt joint with receptor protein, the active grafting monomer is effectively combined with various amino acid residues of the receptor protein, the anti-cancer activity of xylan is enhanced, and the product has wide anti-cancer and biomass material development prospects.
Description
Technical Field
The invention relates to the field of biomass materials, in particular to a method for synthesizing anti-cancer activity BX/Nar-g-HPMA/DEAM malate in ionic liquid.
Background
The biomass resource is the most abundant green renewable resource on the earth, and has a larger potential development space and application prospect. Xylan is an abundant biomass resource, and researches show that Bagasse Xylan (BX) extracted from sugarcane has a strong inhibiting effect on BRAF mutant melanoma cells, but the activity of the Bagasse Xylan (BX) is a prominent problem troubling the development of medicaments, so that the research on the anti-cancer effect is still in a preliminary exploration stage. Active groups such as monomers, malic acid and the like are introduced into xylan molecules through modification modes such as grafting, esterification and the like, so that insufficient complementation and synergistic interaction can be effectively realized. Meanwhile, the hydrogen bond effect among the xylans can be improved, the stability of the medicine in vivo and the absorption capacity of an organism to the medicine can be improved, the biological activity of the bagasse xylan is further enhanced, and the toxic and side effects of the anticancer medicine to the kidney and BRAF mutant melanoma cells are reduced.
As the molecular chains of the bagasse xylan and the naringin (Nar) have more active hydroxyl groups, the active groups such as hydroxypropyl methacrylate (HPMA), diethylaminoethyl methacrylate (DEAM) and the like can be introduced by grafting, esterification and the like. And then malic acid is used as an esterifying agent to perform esterification reaction with hydroxyl on the BX/Nar graft copolymer, so that the product is beneficial to absorption and diffusion of the medicament in vivo and can also reduce the toxic and side effects of the anticancer medicament on normal cells. The molecular docking simulation shows that the binding constant of the grafted and esterified BX/Nar derivative and the 5CSW protein is as low as 39.74, namely the binding capacity is enhanced, the proliferation of BRAF mutant melanoma cells is inhibited, and the grafted and esterified BX/Nar derivative can be used as an auxiliary drug after cancer chemotherapy.
The Bagasse Xylan (BX) and naringin (Nar) are used as main raw materials, hydroxypropyl methacrylate (HPMA) and diethylaminoethyl methacrylate (DEAM) are used as grafting monomers, ammonium persulfate is used as an initiator, and a bagasse xylan graft copolymer BX/Nar-g-HPMA/DEAM is synthesized in a water solvent through a free radical reaction; then, taking the ionic liquid 1-butyl-2, 3-dimethyl imidazolium as a solvent and malic acid as an esterifying agent, and synthesizing the final product BX/Nar-g-HPMA/DEAM malic acid ester through a catalytic esterification reaction.
Disclosure of Invention
The invention introduces HPMA, DEAM and other bioactive groups by a chemical modification method, and provides a synthesis method of BX/Nar-g-HPMA/DEAM malate with anticancer activity for the research of novel anticancer drugs.
The method comprises the following specific steps:
(1) respectively weighing 5.0-7.0 g of bagasse xylan and 0.3-0.5 g of naringin, and placing in a vacuum constant-temperature drying oven at 60 ℃ for drying for 24 hours to constant weight to obtain dry-based bagasse xylan and dry-based naringin.
(2) Weighing 0.30-0.80 g of ammonium persulfate in a 50mL beaker, adding 10-20 mL of distilled water, stirring at room temperature for 5-10 minutes to dissolve, preparing an initiator solution, and pouring the initiator solution into a 100mL constant-pressure dropping funnel for later use.
(3) 3.6-6.4 mL of analytically pure hydroxypropyl methacrylate and 4.2-6.4 mL of analytically pure diethylaminoethyl methacrylate are measured and placed in a 50mL beaker, and after uniform stirring, a monomer mixed solution is obtained and poured into another 100mL constant-pressure dropping funnel for later use.
(4) Weighing 4.0-6.0 g of the dry bagasse xylan obtained in the step (1) and 0.2-0.4 g of dry naringin, adding the dry bagasse xylan and the dry naringin into a 250mL four-neck flask, adding 0.1-0.2 g of N, N-dimethylene bisacrylamide and 50-70 mL of distilled water, heating to 45-65 ℃, and stirring for dissolving for 30 minutes to obtain the bagasse xylan/naringin activation solution.
(5) And (3) dropwise adding one third of the initiator solution obtained in the step (2) into the bagasse xylan/naringin activation solution obtained in the step (4), and controlling the dropwise adding time to be 0.5-1.0 hour. Synchronously dropwise adding the monomer mixed solution obtained in the step (3) and the rest two thirds of the initiator solution obtained in the step (2), controlling the system temperature to be 50-70 ℃, and controlling the dropwise adding time to be 2-3 hours; and after the dropwise addition is finished, continuing the reaction for 3-4 hours, and cooling the material to room temperature.
(6) Adding 20-30 mL of analytically pure absolute ethyl alcohol into the material obtained in the step (5), precipitating for 30 minutes, and then carrying out suction filtration; washing and filtering the filter cake with 20-30 mL of analytically pure cyclohexane and 15-20 mL of analytically pure absolute ethyl alcohol for 2-3 times, and drying the obtained filter cake in a constant-temperature drying oven at 60 ℃ for 24 hours to constant weight to obtain the crude BX/Nar-g-HPMA/DEAM.
(7) Placing the material obtained in the step (6) in a Soxhlet extractor, adding 50-70 mL of analytically pure cyclohexane, and extracting for 12 hours; after extraction, the material is taken out and put into a watch glass, and the watch glass is placed in a vacuum constant-temperature drying oven at 60 ℃ for drying for 24 hours until the weight is constant, so that the pure BX/Nar-g-HPMA/DEAM graft copolymer is obtained.
(8) Weighing 45.0-60.0 g of ionic liquid 1-butyl-2, 3-dimethyl imidazolium chloride into a 250mL four-neck flask, placing the flask in a water bath, and heating to 50-70 ℃.
(9) And (3) weighing 1.5-3.0 g of the pure graft copolymer obtained in the step (7), adding the pure graft copolymer into the ionic liquid 1-butyl-2, 3-dimethyl imidazolium chloride obtained in the step (8), and stirring for 2-4 hours. After the reactants are completely dissolved, adding 2.0-4.0 g of malic acid, stirring and dissolving uniformly, then adding 0.2-0.4 g of 4-dimethylaminopyridine and 0.3-0.7 g of montmorillonite composite catalyst, controlling the temperature of a material system at 60-80 ℃, and reacting for 5-8 hours at the temperature. After the reaction is finished, the temperature of the system is reduced to room temperature.
(10) And (4) precipitating the material obtained in the step (9) by using 30-50 mL of analytically pure absolute ethyl alcohol for 30-40 minutes, and filtering after precipitation. Respectively measuring 15-20 mL of distilled water and 20-25 mL of analytically pure absolute ethyl alcohol, sequentially washing and filtering the precipitate, and repeating the operation for 2-3 times. And (3) drying the obtained filter cake in a constant-temperature drying oven at 60 ℃ for 24 hours to constant weight to obtain the final target product BX/Nar-g-HPMA/DEAM malate.
(12) The method for measuring the esterification substitution degree of the product by using an acid-base titration method comprises the following specific steps: accurately weighing about 0.5g of product sample, putting the product sample into a 50mL conical flask, adding 20mL of deionized water into the conical flask, fully shaking the mixture, adding 2-3 drops of phenolphthalein indicator with the mass fraction of 5%, titrating the sample solution to light red by using a 0.5mol/L NaOH standard solution, and keeping the color of the sample solution unchanged for 30 seconds. Adding 2.5mL of 0.5mol/L sodium hydroxide solution, shaking up, sealing, placing in an electric oscillator at room temperature, shaking for saponification for 4 hours, titrating with 0.5mol/L hydrochloric acid standard solution until the solution system is colorless, and recording the volume of the hydrochloric acid standard solution consumed by titration as V1(ii) a Under the same condition, the bagasse xylan/naringin graft copolymer is used for blank titration, and the volume V of the consumed hydrochloric acid standard solution is recorded0. Mass fraction (w) of carboxylic acid acyl groups in the target productc) The calculation formula of the esterification substitution Degree (DS) of BX/Nar-g-HPMA/DEAM malic acid ester is as follows:
in the formula:
wc-the target product contains the mass fraction of carboxylic acid acyl groups,%;
V0-performing a blank titration consuming a volume of hydrochloric acid standard solution in mL;
V1titrating the volume of the hydrochloric acid standard solution consumed by the target product in mL;
CHCl-hydrochloric acid standard solution concentration, in moL/L;
m is the mass of the target product sample in g;
m-the relative molecular mass of the ester groups used;
132-relative molecular mass of bagasse xylan dewatering units;
DS-esterified substitution of BX/Nar-g-HPMA/DEAM malate.
The invention introduces a plurality of active groups on the basis of bagasse xylan/naringin, and synthesizes BX/Nar-g-HPMA/DEAM malate by chemical modification methods such as grafting, esterification, crosslinking and the like. The butt joint object of the active grafting monomer is not a single specific residue or specific residues, the site generating hydrogen bonds is wide when the active grafting monomer is in butt joint with receptor protein, the active grafting monomer is effectively combined with various amino acid residues of the receptor protein, the anti-cancer activity of xylan is enhanced, and the product has wide anti-cancer and biomass material development prospects.
Drawings
FIG. 1 is an SEM photograph of raw bagasse xylan.
FIG. 2 is an SEM photograph of BX/Nar-g-HPMA/DEAM malate prepared in accordance with an embodiment of the present invention.
FIG. 3 is an IR chart of raw bagasse xylan.
FIG. 4 is an IR chart of BX/Nar-g-HPMA/DEAM malate prepared in an example of the present invention.
Figure 5 is an XRD pattern of raw bagasse xylan.
FIG. 6 is an XRD pattern of BX/Nar-g-HPMA/DEAM malate prepared according to an example of the present invention.
FIG. 7 is a diagram of the docking of BX/Nar-g-HPMA/DEAM malate with 5CSW receptor protein prepared in accordance with an embodiment of the present invention.
FIG. 8 is a diagram of the cavity-to-cavity docking of BX/Nar-g-HPMA/DEAM malate with 5CSW receptor activity prepared in accordance with an embodiment of the present invention.
Detailed Description
Example (b):
(1) respectively weighing 5.5g of bagasse xylan and 0.4g of naringin, and placing in a vacuum constant-temperature drying oven at 60 ℃ for drying for 24 hours to constant weight to obtain dry-based bagasse xylan and dry-based naringin.
(2) 0.30g of ammonium persulfate is weighed into a 50mL beaker, 15mL of distilled water is added, the mixture is stirred at room temperature for 10 minutes to be dissolved to prepare an initiator solution, and the initiator solution is poured into a 100mL constant-pressure dropping funnel for later use.
(3) 3.6mL of analytically pure hydroxypropyl methacrylate and 4.4mL of analytically pure diethylaminoethyl methacrylate are weighed and placed in a 50mL beaker, and after uniform stirring, a monomer mixed solution is obtained and poured into another 100mL constant-pressure dropping funnel for later use.
(4) Weighing 45g of the dry bagasse xylan obtained in the step (1) and 0.3g of dry naringin, adding the dry bagasse xylan and the dry naringin into a 250mL four-neck flask, adding 0.15g of N, N-dimethylene bisacrylamide and 60mL of distilled water, heating to 50 ℃, and stirring for dissolving for 30 minutes to obtain the bagasse xylan/naringin activation solution.
(5) And (3) dropwise adding one third of the initiator solution obtained in the step (2) into the bagasse xylan/naringin activation solution obtained in the step (4), and controlling the dropwise adding time to be 0.5 hour. Synchronously dropwise adding the monomer mixed solution obtained in the step (3) and the rest two thirds of the initiator solution obtained in the step (2), controlling the system temperature to be 60 ℃, and controlling the dropwise adding time to be 2 hours; after the addition was completed, the reaction was continued for 3 hours, and the material was cooled to room temperature.
(6) Adding 30mL of analytically pure absolute ethyl alcohol into the material obtained in the step (5), precipitating for 30 minutes, and then carrying out suction filtration; washing the filter cake with 20mL of analytically pure cyclohexane and 15mL of analytically pure absolute ethanol, performing suction filtration for 3 times, and drying the obtained filter cake in a constant-temperature drying oven at 60 ℃ for 24 hours to constant weight to obtain the crude BX/Nar-g-HPMA/DEAM.
(7) Placing the material obtained in the step (6) in a Soxhlet extractor, adding 60mL of analytically pure cyclohexane, and extracting for 12 hours; after extraction, the material is taken out and put into a watch glass, and the watch glass is placed in a vacuum constant-temperature drying oven at 60 ℃ for drying for 24 hours until the weight is constant, so that the pure BX/Nar-g-HPMA/DEAM graft copolymer is obtained.
(8) 45.0g of ionic liquid 1-butyl-2, 3-dimethylimidazolium chloride is weighed into a 250mL four-neck flask, placed in a water bath and heated to 60 ℃.
(9) 3.0g of the pure graft copolymer obtained in step (7) was weighed out and added to the ionic liquid 1-butyl-2, 3-dimethylimidazolium chloride obtained in step (8), and stirred for 2 hours. After the reactants are completely dissolved, 3.0g of malic acid is added, after the reactants are stirred and dissolved evenly, 0.2g of 4-dimethylaminopyridine and 0.5g of montmorillonite composite catalyst are added, the temperature of the system is controlled at 70 ℃, and the reaction is carried out for 6 hours at the temperature. After the reaction is finished, the temperature of the system is reduced to room temperature.
(10) And (4) precipitating the material obtained in the step (9) by using 40mL of analytically pure absolute ethyl alcohol for 30 minutes, and filtering after precipitation. 15mL of distilled water and 20mL of analytically pure absolute ethyl alcohol are respectively measured, and the precipitate is washed, filtered and repeatedly operated for 3 times. And (3) drying the obtained filter cake in a constant-temperature drying oven at 60 ℃ for 24 hours to constant weight to obtain the final target product BX/Nar-g-HPMA/DEAM malate.
(12) The degree of substitution by esterification of the product BX/Nar-g-HPMA/DEAM malate was determined by acid-base titration and found to be 0.79 DS.
As can be seen from SEM analysis, the product particles have irregular shapes and rough and uneven surfaces, and the bagasse xylan and naringin molecules cause the product particles to be enlarged due to the introduction of the HPMA monomer, the DEAM monomer and the malic acid. By IR analysis, the product was 3184.42cm-1Is represented by an O-H stretching vibration absorption peak in malic acid, 1748.22cm-1The peak of C ═ O stretching vibration of HPMA and DEAM and the ester carbonyl of malic acid appeared, 1598.24cm-1The naringin appears with a benzene ring skeleton stretching vibration absorption peak of 1410.19cm-1The O-H in-plane bending vibration absorption peak of malic acid appears, 1209.11cm-1The C-O-C stretching vibration absorption peak of C-N, monomer and malate appears at 1179.48cm-1C-N stretching vibration absorption peaks appear, and the characteristic peaks show characteristic groups of naringin, HPMA, DEAM, malic acid molecules and the like. XRD analysis shows that the bagasse xylan has a strong diffraction peak in the range of 12-20 degrees, and the peak shape is sharp and prominent, which indicates that BX has a certain crystal structure, but except individual peaks, the other peak shapes are relatively weak; and the product after cross-linking and graft modification,the angle change of the diffraction peak is less obvious, but the peak type is slightly changed, which shows that the crystallinity of the bagasse xylan is changed after the multi-step reaction. According to molecular docking, the product is connected with the 5CSW receptor protein in a hydrogen bond form, a strong hydrogen bond network and a hydrophobic effect can be formed, the binding free energy is-7.96 kJ/mol, the product has good affinity and strong inhibition effect on the protein, and the docking effect is ideal.
Claims (1)
1. A method for synthesizing anti-cancer active BX/Nar-g-HPMA/DEAM malate is characterized by comprising the following steps:
(1) respectively weighing 5.0-7.0 g of bagasse xylan and 0.3-0.5 g of naringin, and placing in a vacuum constant-temperature drying oven at 60 ℃ for drying for 24 hours to constant weight to obtain dry-based bagasse xylan and dry-based naringin;
(2) weighing 0.30-0.80 g of ammonium persulfate in a 50mL beaker, adding 10-20 mL of distilled water, stirring at room temperature for 5-10 minutes to dissolve, preparing an initiator solution, and pouring the initiator solution into a 100mL constant-pressure dropping funnel for later use;
(3) weighing 3.6-6.4 mL of analytically pure hydroxypropyl methacrylate and 4.2-6.4 mL of analytically pure diethylaminoethyl methacrylate, placing the analytically pure hydroxypropyl methacrylate and the analytically pure diethylaminoethyl methacrylate in a 50mL beaker, uniformly stirring to obtain a monomer mixed solution, and pouring the monomer mixed solution into another 100mL constant-pressure dropping funnel for later use;
(4) weighing 4.0-6.0 g of the dry bagasse xylan obtained in the step (1) and 0.2-0.4 g of dry naringin, adding the dry bagasse xylan and the dry naringin into a 250mL four-neck flask, adding 0.1-0.2 g of N, N-dimethylene bisacrylamide and 50-70 mL of distilled water, heating to 45-65 ℃, and stirring for dissolving for 30 minutes to obtain a bagasse xylan/naringin activation solution;
(5) dropping one third of the initiator solution obtained in the step (2) into the bagasse xylan/naringin activation solution obtained in the step (4), wherein the dropping time is controlled to be 0.5-1.0 hour; synchronously dropwise adding the monomer mixed solution obtained in the step (3) and the rest two thirds of the initiator solution obtained in the step (2), controlling the system temperature to be 50-70 ℃, and controlling the dropwise adding time to be 2-3 hours; after the dropwise addition is finished, continuously reacting for 3-4 hours, and cooling the material to room temperature;
(6) adding 20-30 mL of analytically pure absolute ethyl alcohol into the material obtained in the step (5), precipitating for 30 minutes, and then carrying out suction filtration; washing and filtering the filter cake with 20-30 mL of analytically pure cyclohexane and 15-20 mL of analytically pure absolute ethyl alcohol for 2-3 times, and drying the obtained filter cake in a constant-temperature drying oven at 60 ℃ for 24 hours to constant weight to obtain crude BX/Nar-g-HPMA/DEAM;
(7) placing the material obtained in the step (6) in a Soxhlet extractor, adding 50-70 mL of analytically pure cyclohexane, and extracting for 12 hours; after extraction, taking out the materials, putting the materials into a watch glass, and putting the watch glass in a vacuum constant-temperature drying oven at 60 ℃ for drying for 24 hours until the weight is constant, thus obtaining the pure BX/Nar-g-HPMA/DEAM graft copolymer;
(8) weighing 45.0-60.0 g of ionic liquid 1-butyl-2, 3-dimethyl imidazolium chloride into a 250mL four-neck flask, placing the flask in a water bath, and heating to 50-70 ℃;
(9) weighing 1.5-3.0 g of the pure graft copolymer obtained in the step (7), adding the pure graft copolymer into the ionic liquid 1-butyl-2, 3-dimethyl imidazolium chloride obtained in the step (8), and stirring for 2-4 hours; after the reactants are completely dissolved, adding 2.0-4.0 g of malic acid, stirring and dissolving uniformly, then adding 0.2-0.4 g of 4-dimethylaminopyridine and 0.3-0.7 g of montmorillonite composite catalyst, controlling the temperature of a material system at 60-80 ℃, and reacting for 5-8 hours at the temperature; after the reaction is finished, cooling the system temperature to room temperature;
(10) precipitating the material obtained in the step (9) by using 30-50 mL of analytically pure absolute ethyl alcohol for 30-40 minutes, and filtering after precipitation; respectively measuring 15-20 mL of distilled water and 20-25 mL of analytically pure absolute ethyl alcohol, sequentially washing and filtering the precipitate, and repeating the operation for 2-3 times; and (3) drying the obtained filter cake in a constant-temperature drying oven at 60 ℃ for 24 hours to constant weight to obtain the final target product BX/Nar-g-HPMA/DEAM malate.
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| CN107417857A (en) * | 2017-09-15 | 2017-12-01 | 桂林理工大学 | Active anticancer derivative bagasse xylan cloves acid esters g AM/MMA synthetic method |
| CN109438622A (en) * | 2018-10-21 | 2019-03-08 | 桂林理工大学 | The method of anticancer activity phenylalanine esterification bagasse xylan-g-CHMA is synthesized in ionic liquid |
| US20200188285A1 (en) * | 2016-08-09 | 2020-06-18 | Nof Corporation | Composition for external application and method for producing the same |
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| US20200188285A1 (en) * | 2016-08-09 | 2020-06-18 | Nof Corporation | Composition for external application and method for producing the same |
| CN107417857A (en) * | 2017-09-15 | 2017-12-01 | 桂林理工大学 | Active anticancer derivative bagasse xylan cloves acid esters g AM/MMA synthetic method |
| CN109438622A (en) * | 2018-10-21 | 2019-03-08 | 桂林理工大学 | The method of anticancer activity phenylalanine esterification bagasse xylan-g-CHMA is synthesized in ionic liquid |
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