CN114656631B - Poly alliin and its preparation method - Google Patents

Poly alliin and its preparation method Download PDF

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CN114656631B
CN114656631B CN202210256255.9A CN202210256255A CN114656631B CN 114656631 B CN114656631 B CN 114656631B CN 202210256255 A CN202210256255 A CN 202210256255A CN 114656631 B CN114656631 B CN 114656631B
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deoxyalliin
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alliin
polydeoxyalliin
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CN114656631A (en
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何晓东
金国首
卢艳枝
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Zhejiang Wedu Medical Devices Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/42—Polyamides containing atoms other than carbon, hydrogen, oxygen, and nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment
    • 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

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Abstract

The invention discloses a method for synthesizing poly (alliin) by selective oxidation of poly (deoxyalliin). The invention synthesizes the homopolymer or the segmented copolymer of the poly (alliin) through selectively oxidizing the homopolymer or the segmented copolymer of the poly (deoxyalliin) and the polyethylene glycol for the first time. The method has mild oxidation conditions, and the polydeoxyalliin can be selectively oxidized into the polydatin in hexafluoroisopropanol. The invention provides a new path for synthesizing the poly-alliin, and has huge application prospect in the field of biological materials.

Description

Poly alliin and its preparation method
Technical Field
The invention belongs to the field of polymers, and particularly relates to poly (alliin) and a method for synthesizing poly (alliin) by polymerization and oxidation of poly (deoxyalliin).
Background
The polyamino acid has a secondary structure similar to that of natural protein, is a polymer with excellent biocompatibility and degradability, and is widely applied to the fields of drug delivery, biological imaging, antibiosis and the like. Amino acid-N-carboxylic anhydrides (NCA) and N-phenoxycarbonyl amino acids (NPC) are two important methods for synthesizing polyamino acids.
Deoxyalliin (also called S-allyl cysteine) and alliin (also called S-allyl cysteine sulfoxide) are sulfur-containing amino acids specific to garlic, and have various effects of resisting tumor, resisting bacteria, killing virus, scavenging free radicals and the like (J.Agr.food chem.,2015,63,10778-10784). In the previous research, the edible and medicinal values of alliin are focused on small molecules, and no report is made about the synthesis and characterization of the polymer. Only in 1955, there is a report on the synthesis of polydeoxyalliin from deoxyalliin-NCA monomers, but there is no detailed structural characterization (Nature, 1955,175,1045-1046). At present, the synthesis report of the poly alliin is not yet seen, and no literature exists on the characteristic characterization aspect of the poly alliin.
The thioether side groups of polyamino acids can be oxidized to sulfoxides or sulfones (chip. Chem. Lett.2020,31,1931-1935;Biomacromolecules 2019,20,3435-3444;Biomacromolecules 2013,14,3610-3614), but the product structure is strongly dependent on the oxidation conditions, too strong an oxidizing agent readily oxidizes part of the sulfoxide side groups further to sulfones. Allyl is also a functional group which is easy to oxidize, and the side group of the polydeoxyalliin has both an allyl and a thioether structure, so that no report of selectively oxidizing thioether to sulfoxide groups and retaining allyl is seen in the range of amino acid and polymer thereof at present.
Disclosure of Invention
The invention aims to provide poly alliin and a method for synthesizing poly alliin and a block copolymer thereof by selectively oxidizing poly-deoxyalliin and a block copolymer thereof. In the oxidation process, the reaction selectivity is strong, the condition is mild, the operation is simple, and the obtained polymer has a definite structure.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a poly alliin, which has a structural formula shown in the following formula (1):
in the formula (1), n is the polymerization degree, and n is more than or equal to 2 and less than or equal to 300.
In the formula (1), R is C1-C10 alkyl or polyethylene glycol chain segment shown in the formula (3), and H on the C1-C10 alkyl is not substituted or is substituted by C6-C10 aryl; preferably R is neopentyl, n-hexyl, benzyl or a polyethylene glycol segment as shown in formula III;
represents a substitution position of the amino acid,
m in the formula (3) represents the polymerization degree, and m is more than or equal to 5 and less than or equal to 227.
A method for synthesizing poly (alliin) by oxidation of poly (deoxyalliin), which comprises the following steps:
the poly-deoxyalliin shown in the formula (2) is synthesized to obtain the poly-alliin shown in the formula (1) through selective oxidation reaction; the oxidant of the selective oxidation reaction is H 2 O 2 。
The structural formula of the polydeoxyalliin is shown as the following formula (2):
in the formula (2), n is the polymerization degree, and n is more than or equal to 2 and less than or equal to 300.
In the formula (2), R is C1-C10 alkyl or polyethylene glycol chain segment shown in the formula III, and H on the C1-C10 alkyl is not substituted or is substituted by C6-C10 aryl; preferably R is neopentyl, n-hexyl, benzyl or a polyethylene glycol segment as shown in formula III;
represents a substitution position of the amino acid,
m in the formula III represents the polymerization degree, and m is more than or equal to 5 and less than or equal to 227.
Oxidant H of the invention 2 O 2 The amount of the substance (a) is 1 to 20 times, more preferably 2 to 10 times, the amount of the substance (b) of the deoxyalliin repeating unit.
Oxidizing agent H 2 O 2 Is usually added in the form of hydrogen peroxide, H being the radical of the oxidant when the amount of oxidant is calculated 2 O 2 Is metered by the amount of substance.
Further, the reaction temperature of the selective oxidation reaction is 0-37 ℃.
Further, the solvent for the selective oxidation reaction is hexafluoroisopropanol.
Further, the volume amount of hexafluoroisopropanol is 50-200 mL/g based on the mass of the polydeoxyalliin.
Further, the reaction time of the selective oxidation reaction is 0.5 to 24 hours.
The polydeoxyalliin is prepared by polymerization reaction of deoxyalliin-NCA or deoxyalliin-NPC monomer and amine initiator, wherein the chemical formula of the deoxyalliin-NCA is shown in formula A, and the chemical formula of the deoxyalliin-NPC is shown in formula B:
the amine initiator is R-NH 2 R is as defined above.
The ratio of the amounts of the substances of the deoxyalliin-NCA or the deoxyalliin-NPC and the amine initiator is 2-300:1.
Further, the polymerization of deoxyalliin-NPC monomer to prepare polydeoxyalliin may be carried out by the following method:
the deoxidized alliin-NPC and amine initiator are reacted in an organic solvent DMSO in a closed way for 6 to 48 hours at the temperature of 60 to 80 ℃, and the obtained reaction liquid is poured into diethyl ether to be precipitated, centrifuged, and the precipitate is collected and dried to prepare the amino-terminated polydeoxyalliin; the amine initiator is R-NH 2 Wherein R is as defined; preferably, the amine initiator is neopentyl amine, n-hexylamine, benzylamine or aminopolyethylene glycol monomethyl ether; the ratio of the amounts of the substances of the deoxyalliin-NPC and the amine initiator is 2-300:1.
The polymerization of deoxyalliin-NCA monomer to prepare polydeoxyalliin can be carried out by the following method:
the deoxidized alliin-NCA and an amine initiator are subjected to closed reaction in an organic solvent DMF at the temperature of 0-60 ℃ for 6-48 hours, and the obtained reaction liquid is poured into diethyl ether to be precipitated, centrifuged, and the precipitate is collected and dried to prepare the amino-terminated polydeoxyalliin; the amine initiator is R-NH 2 Wherein R is as defined; preferably, the amine initiator is neopentyl amine, n-hexylamine, benzylamine or aminopolyethylene glycol monomethyl ether; the ratio of the amounts of the substances of the deoxyalliin-NCA and the amine initiator is 2-300:1。
Compared with the prior art, the invention has the beneficial effects that: (1) The poly (alliin) is synthesized by selectively oxidizing the poly (deoxyalliin) for the first time, and the poly (alliin) homopolymer or the poly (ethylene glycol) block copolymer is synthesized by selectively oxidizing the poly (deoxyalliin) homopolymer or the poly (ethylene glycol) block copolymer, so that the oxidation condition is mild, the efficiency is high, and the product side groups are all converted into allyl sulfoxide. (2) The poly (alliin) can be subjected to enzyme and thermal degradation to release allicin which can be sterilized, the poly (alliin) -polyethylene glycol polymer can be self-assembled into nano-micelle, and the poly (alliin) has the characteristics of good biocompatibility, biodegradability, post-functionalization and the like, is an excellent biological material, and has a huge application prospect in the field of biological materials.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of polydeoxyalliin and oxidized polydatin in example 1.
FIG. 2 is an infrared spectrum of the polydeoxyalliin and oxidized polydatin of example 1.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the poly (alliin-polyethylene glycol) polymer prepared in example 5.
Detailed Description
The invention will be further described with reference to the following specific examples.
The molecular weight and structure of the polydeoxyalliin and the polydatin are adopted 1 H NMR and FTIR measurements. For molecular weight 1 H NMR end group method calibration, nuclear magnetism is Bruker Avance DMX% 1 H400 MHz) on an instrument, with deuterated dimethyl sulfoxide (DMSO-d 6 ) As solvent, tetramethylsilane (TMS) was used as an internal standard. The structures of the sulfides and sulfoxides before and after oxidation of the polymer were analyzed by FTIR, determined by Bruker VECTOR 22 infrared analyzer, and the potassium bromide tableting method was used.
Example 1
(1) 2.8130g (10.0 mmol) of deoxyalliin-NPC is added into a reaction bottle, 7.4mL of DMSO is used for dissolving, 2.6mL of a DMSO solution of pivaloyl amine (0.1270 mol/L,0.3303 mmol) is added, the mol ratio of the deoxyalliin-NPC monomer to the pivaloyl amine is 30:1, the mixture is sealed and then placed into an oil bath at 80 ℃ for reaction for 2 days, the original solution is directly poured into diethyl ether for precipitation, centrifugation and supernatant removal after the reaction, and the obtained polymer is dried in vacuum for 1 day, so that the polymer of the polydeoxyalliin capped by the pivaloyl amine is obtained, the yield is 71%, and the number average molecular weight is 3.7kDa.
(2) 0.0603g (containing 0.4195mmol of deoxyalliin repeating units) of polydeoxyalliin (pivalic amine capped, number average molecular weight 3.7 kDa) were dissolved in 6mL hexafluoroisopropanol and 85. Mu.L (30 wt%) of H was added 2 O 2 (0.8485mmol)，H 2 O 2 The molar ratio of the poly (alliin) to the repeated units of the poly (alliin) is 2:1, the mixture is stirred overnight at 25 ℃, the poly (alliin) is precipitated in diethyl ether, and the poly (alliin) is obtained through vacuum oven drying, wherein the yield is 97%.
Example 2
Polydeoxyalliin (n-hexylamine terminated) was prepared according to step (1) of example 1, except that neopentylamine was replaced with n-hexylamine.
Polydeoxyalliin (n-hexylamine capped, number average molecular weight of 4.8 kDa) was used as starting material, other oxidation conditions were the same as in example 1 except for H 2 O 2 The molar ratio of the poly (deoxyalliin) to the poly (deoxyalliin) repeating unit is 5:1, and the reaction time is 3h. The yield of the product poly alliin is 96%.
Example 3
The other conditions were the same as in example 1, except that the polydeoxyalliin had a number average molecular weight of 2.5kDa, H 2 O 2 The ratio of the poly (deoxyalliin) to the repeated units of the poly (deoxyalliin) is 8:1, the reaction temperature is 10 ℃, the reaction time is 3 hours, and the yield of the poly (alliin) is 94%.
Example 4
Polydeoxyalliin (benzylamine end-capped) was prepared following step (1) of example 1, except that neopentylamine was replaced with benzylamine.
Polydeoxyalliin (benzylamine end capped, number average molecular weight 2.5 kDa) was used as starting material, the other oxidation conditions were the same as in example 1 except for H 2 O 2 The molar ratio of the poly (deoxyalliin) to the poly (deoxyalliin) repeating unit is 10:1, the reaction temperature is 37 ℃, and the reaction time is 0.5h. The yield of the product poly alliin is97％。
Example 5
(1) 0.4221g (1.5 mmol) of deoxyalliin-NPC and 0.250g of polyethylene glycol monomethyl ether amine (5 kDa,0.05 mmol) are added into a reaction bottle, the deoxyalliin-NPC monomer and the polyethylene glycol monomethyl ether amine are dissolved by 3mL of DMSO, the mol ratio of the deoxyalliin-NPC monomer to the polyethylene glycol monomethyl ether amine is 30:1, the reaction is carried out in an oil bath at 80 ℃ for 1 day after the sealing, the original solution is directly poured into diethyl ether for precipitation, centrifugation and supernatant removal, and the obtained polymer is dried in vacuum for 1 day, so as to obtain the polyethylene glycol monomethyl ether amine-terminated polydeoxyalliin 71 percent of yield and 6.7kDa of number average molecular weight.
(2) 0.1030g of polydeoxyalliin-polyethylene glycol (5 kDa polyethylene glycol monomethyl ether amine end-capped, number average molecular weight of 6.7 kDa) was dissolved in 10mL hexafluoroisopropanol and added 5.2. Mu. L H 2 O 2 (30％wt，0.0522mmol)，H 2 O 2 The molar ratio of the polymer to the repeated units of the polydeoxyalliin is 2:1, the mixture is stirred overnight at 25 ℃, the mixture is precipitated in diethyl ether, and the polymer is dried in a vacuum oven to obtain the hydrophilic block polydatin-polyethylene glycol polymer with the yield of 94%.
Example 6
The other conditions were the same as in example 5 except that the number average molecular weight of the polydeoxyalliin-polyethylene glycol was 10.1kDa, H 2 O 2 The molar ratio of the poly (deoxyalliin) to the partial repeating units of the poly (deoxyalliin) is 10:1, the reaction temperature is 37 ℃, and the reaction time is 0.5h. The yield of the obtained hydrophilic block poly alliin-polyethylene glycol polymer was 97%.
Example 7
Poly (deoxyalliin) -polyethylene glycol (2 kDa polyethylene glycol monomethyl ether amine end-capped, number average molecular weight of 5.6 kDa) was used as the starting material, other oxidation conditions were the same as in example 5 except for H 2 O 2 The molar ratio of the poly (deoxyalliin) to the partial repeating units of the poly (deoxyalliin) is 8:1, the reaction temperature is 37 ℃, and the reaction time is 0.5h. The yield of the obtained hydrophilic block poly alliin-polyethylene glycol copolymer is 96%.
Comparative example 1
Otherwise, the conditions were the same as in example 1 except that in the oxidation reaction, the solvent was dimethylacetamide, the reaction temperature was 30℃and the reaction time was 10min, the resulting product was complex, the pendant groups contained unreacted and over-oxidized into sulfone, and some of the polymer decomposition products, and the product structure could not be analyzed.
Example 8
30mg of the alliin prepared in example 1 and 60mg of alliinase are mixed and dissolved in 6mL of phosphate buffer solution, incubated for 14 days at 37 ℃, the product is collected and characterized by using a gas chromatography-mass spectrometry technology, and allicin molecules with antibacterial and bactericidal properties are detected in the mixture.

Claims (10)

1. The poly alliin is characterized in that the structural formula of the poly alliin is shown as the following formula (1):
in the formula (1), n is the polymerization degree, and n is more than 2 and less than or equal to 300;
in the formula (1), R is C1-C10 alkyl or polyethylene glycol chain segment shown in the formula (3), and H on the C1-C10 alkyl is not substituted or is substituted by C6-C10 aryl;
represents a substitution position, m in the formula (3) represents a polymerization degree, and m is more than or equal to 5 and less than or equal to 227.
2. The poly allied amino acid according to claim 1, wherein R is neopentyl, n-hexyl, benzyl or a polyethylene glycol segment as shown in formula (3).
3. The method for preparing the poly (alliin) according to claim 1, wherein the poly (alliin) is obtained by oxidizing and synthesizing poly (deoxyalliin), and the method comprises the following steps:
the poly-deoxyalliin shown in the formula (2) is synthesized to obtain the poly-alliin shown in the formula (1) through selective oxidation reaction; the oxidant of the selective oxidation reaction is H 2 O 2 ；
The structural formula of the polydeoxyalliin is shown as the following formula (2):
in the formula (2), n and R are defined as in claim 1.
4. A method according to claim 3, characterized in that the oxidizing agent H 2 O 2 The amount of the substance is 1 to 20 times the amount of the substance of the deoxyalliin repeating unit.
5. The method according to claim 4, wherein the oxidizing agent H 2 O 2 The amount of the substance is 2 to 10 times the amount of the substance of the deoxyalliin repeating unit.
6. A process according to claim 3, wherein the solvent for the selective oxidation reaction is hexafluoroisopropanol.
7. A process according to claim 3, wherein the reaction temperature of the selective oxidation reaction is from 0 to 37 ℃.
8. A process according to claim 3, wherein the reaction time of the selective oxidation reaction is from 0.5 hours to 24 hours.
9. The method of claim 3, wherein the polydeoxyalliin is prepared by polymerizing deoxyalliin-NCA or deoxyalliin-NPC monomer with an amine initiator, the deoxyalliin-NCA having the formula a and the deoxyalliin-NPC having the formula B:
the amine initiator is R-NH 2 R is as defined in claim 1.
10. The method according to claim 9, wherein the ratio of the amounts of the substances of the deoxyalliin-NCA or deoxyalliin-NPC and the amine initiator is 2-300:1.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150085543A (en) * 2014-01-15 2015-07-24 한국식품연구원 Composition for Improving, Preventing or Treating Obesity Comprising Allium sativum L. Extracts and Momordica charanti Extract
CN111285788A (en) * 2018-12-07 2020-06-16 武汉远大弘元股份有限公司 Preparation method of alliin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150085543A (en) * 2014-01-15 2015-07-24 한국식품연구원 Composition for Improving, Preventing or Treating Obesity Comprising Allium sativum L. Extracts and Momordica charanti Extract
CN111285788A (en) * 2018-12-07 2020-06-16 武汉远大弘元股份有限公司 Preparation method of alliin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Clickable, Oxidation-Responsive and Enzyme-Degradable Polypeptide Synthesis, Characterization and Side Chain Modification;Yan-Zhi Lu等;《Chinese Journal of POLYMER SCIENCE》(第40期);1360–1368 *

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