CN115212314B - Albumin combined anti-tumor medicine and nano-composite thereof, preparation method and application - Google Patents

Albumin combined anti-tumor medicine and nano-composite thereof, preparation method and application Download PDF

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CN115212314B
CN115212314B CN202210664403.0A CN202210664403A CN115212314B CN 115212314 B CN115212314 B CN 115212314B CN 202210664403 A CN202210664403 A CN 202210664403A CN 115212314 B CN115212314 B CN 115212314B
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CN115212314A (en
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刘洪卓
王昭蒙
叶剑英
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Shenyang Pharmaceutical University
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    • 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
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    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract

An albumin combined anti-tumor drug, a nano-composite thereof, a preparation method and application thereof, belongs to the technical field of medicines, and in particular relates to synthesis of a series of albumin combined anti-tumor drug polyphenol derivatives, construction of the anti-tumor drug polyphenol derivative albumin nano-composite and application thereof in drug delivery. According to the invention, through polyphenol derivatization modification of the antitumor drug, the affinity of the antitumor drug to albumin is improved, some drugs which cannot be prepared into albumin nanoparticles by simple microfluidic mixing are converted into polyphenol derivatives which can be prepared into albumin-binding nanoparticles by simple mixing, a new thought and opportunity are provided for developing albumin nanoparticles of some drugs with poor protein binding rate, and a new strategy and selection are provided for enriching and developing albumin-binding nano preparations of different types of drugs so as to meet urgent clinical demands for different types of high-end chemotherapeutic preparations.

Description

Albumin combined anti-tumor medicine and nano-composite thereof, preparation method and application
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to synthesis of an albumin-binding type antitumor drug polyphenol derivative, construction of an antitumor drug polyphenol derivative albumin nano-composite and application of the albumin-binding type antitumor drug polyphenol derivative albumin nano-composite in a drug delivery system.
Background
Cancer is a major disease threatening human health, the number of cancer patients worldwide increases year by year, and mortality rates remain high. Chemotherapy remains the primary means of cancer treatment, especially for cancers that cannot be resected and metastasized by surgery. Most of the chemotherapeutics are cytotoxic drugs, and have the defects of low solubility, poor stability, narrow therapeutic window, poor pharmacokinetic properties and the like. For example, the star anticancer drug-taxol has wide antitumor spectrum, is used as a first-line chemotherapeutic drug and is widely applied to various cancer treatments including ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer and the like clinically. However, the Taxol injection (Taxol) which is clinically used at present uses polyoxyethylene castor oil and ethanol as organic solvents, and the allergens can stimulate organisms to release histamine, so that serious anaphylactic reaction and peripheral neuropathy are caused, and the Taxol injection needs to be pretreated by glucocorticoid and antihistamine medicines before use, so that the Taxol injection is extremely inconvenient to use clinically. Of course, the clinical defect of the preparation also leaves a wide room for improvement of the paclitaxel preparation. Albumin-bound paclitaxel nanoparticles of great interestBy virtue of the wide indication and low adverse reaction, taxol is further refulgent, and is approved by FDA for treating breast cancer in 2005, and then the indication is expanded to non-small cell lung cancer, pancreatic cancer and the like. Currently,/>Annual global sales of more than 10 billion dollars. Although/>The technology platform for preparing the nanoparticle has a certain limitation, although the technology platform has great success: (1) The technology is mainly suitable for hydrophobic drugs with high albumin binding rate, and some drugs with low albumin binding rate cannot realize efficient entrapment; (2) The method needs to mix oil and water to prepare the colostrum, and has the advantages of multiple operation steps and time consuming and complicated; (3) The method has high requirements on instruments and equipment, high-pressure homogenizing equipment is usually required, and the method needs to be continuously operated for a plurality of hours under a high-pressure state, and the homogenizing process is easy to cause large equipment loss, such as abrasion of pipelines and cavities, so that the production cost is increased; (4) The problem that the freeze-dried product is difficult to disperse due to albumin aggregation in the homogenizing process can have adverse effects on the product yield. Based on the problems, how to find and develop a technical platform with wide applicability, mild preparation conditions, simple and easy operation and high flux and repeatability to realize the preparation of albumin nanoparticles of different kinds of drugs is a difficult problem and a challenge faced by the next-generation drug delivery technology.
Polyphenols widely exist in nature, are secondary metabolites of plants, and have various biological activities such as antioxidation, anti-inflammatory, antibacterial, antiviral, antitumor, cardiovascular and cerebrovascular disease prevention and the like. Polyphenols are classified into three classes according to their molecular structural features: phenolic, flavonoid and non-flavonoid compounds. The molecular structure of phenolic acid compounds comprises a carboxyl group and a benzene ring, and each benzene ring is provided with one or more hydroxyl groups and/or methoxy groups. The natural plant polyphenol structure contains a large amount of catechol or pyrogallol groups, and the polyphenol hydroxyl groups endow the natural plant polyphenol structure with unique physical and chemical properties, such as combination with proteins through hydrogen bonds, hydrophobic interactions or electrostatic interactions, and the like, and can also be subjected to complexation with metal ions. The biological phenomenon of the naturally evolving polyphenol-protein interaction also exists widely in life, for example, when people eat fruits and beverages, the oral cavity can generate a astringency feeling, and the astringency is the manifestation of the interaction of polyphenol substances and salivary proteins in the oral cavity. Thus, the natural interaction between polyphenols and proteins also provides a new idea for the design of albumin-binding formulations. With the development of nanotechnology and material science, several studies have demonstrated the great potential for polyphenols to be used in the field of drug delivery. However, studies on the preparation of albumin-binding nano-formulations by polyphenol derivatization of chemically active drugs have not been reported.
Disclosure of Invention
In order to overcome the limitation and the defect that the existing Nab TM technology is only suitable for the preparation of albumin binding type nano particles of hydrophobic drugs with high protein binding rate, the invention designs and synthesizes the anti-tumor drug polyphenol derivative with high protein affinity, and the polyphenol derivative and human serum albumin are mixed by simple microfluid to prepare the albumin binding type anti-tumor drug polyphenol derivative nano compound with high drug loading and good stability, and the invention provides the application of the albumin binding type anti-tumor drug polyphenol derivative nano compound in a drug delivery system.
The invention is realized by the following technical scheme:
the invention provides an albumin-binding anti-tumor drug, which is an anti-tumor drug polyphenol derivative with affinity with albumin, and has the following structural general formula:
Wherein, drug is an antitumor Drug containing hydroxyl, carboxyl, carbonyl, mercaptan or amino and selected from taxane, anthracycline, nucleoside, camptothecine, platinum, catharanthine, poisoside, artemisinin compound, macrolide and terpenoid; the antitumor drug is connected with a Spacer through a Linker; wherein Linker is ester, amide, imine, oxime, hydrazone, carbonate, carbamate, borate, oxalate oxide, monosulfide bond, monoselene bond, disulfide bond, diselenide bond or ketal bond; the Spacer is an alkyl chain containing or not containing a heteroatom, an alkyl chain containing or not containing a double bond, and the heteroatom is O, S or N; n is an integer of 1 to 3.
Further, the antitumor drug is paclitaxel, docetaxel, cabazitaxel, podophyllotoxin, triptolide, ralostazol, rapamycin, SN-38, ursolic acid, oleanolic acid and glycyrrhetinic acid, wherein in the antitumor drug polyphenol derivative, hydroxyl of the antitumor drug is connected with phenolic acid compounds through ester bonds, the ester bonds are broken under the action of in vivo esterase to release the antitumor drug, and the phenolic acid compounds have a molecular structure comprising carboxyl and hydroxyl substituted benzene rings, wherein the benzene rings comprise caffeic acid, p-coumaric acid, ferulic acid, sinapic acid, rosmarinic acid, 4-hydroxyphenylacetic acid, 3, 4-dihydroxybenzoic acid, 3,4, 5-trihydroxybenzoic acid and 3, 4-dihydroxyphenylacetic acid.
Still further, the paclitaxel polyphenol derivative having affinity with albumin according to the present invention has any one of the following structures:
the docetaxel polyphenol derivative with affinity with albumin has any one of the following structures:
the cabazitaxel polyphenol derivative with affinity with albumin has any one of the following structures:
the podophyllotoxin polyphenol derivative with affinity with albumin has the following structure:
The triptolide polyphenol derivative with the affinity with albumin has the following structure:
The invention also provides a pharmaceutical composition comprising the albumin binding type antitumor drug or pharmaceutically acceptable salt thereof and an excipient.
The invention also provides a synthesis method of the antitumor drug polyphenol derivative, which comprises the following steps:
Reacting 4-hydroxybenzoic acid, or 3, 4-dihydroxybenzoic acid, or 3,4, 5-trihydroxybenzoic acid, or 3, 4-dihydroxyphenylacetic acid with benzyl bromide under the catalysis of anhydrous potassium carbonate to obtain 4-benzyloxy benzoic acid, or 3, 4-bis (benzyloxy) benzoic acid, or 3,4, 5-tris (benzyloxy) benzoic acid, or 3, 4-bis (benzyloxy) phenylacetic acid; under DMAP, EDCI, HOBT catalysis, 4-benzyloxy benzoic acid, 3, 4-di (benzyloxy) benzoic acid, 3,4, 5-tri (benzyloxy) benzoic acid, or 3, 4-di (benzyloxy) phenylacetic acid reacts with antitumor drugs containing hydroxyl groups, and the intermediate compound is obtained through separation and purification; the intermediate compound is hydrogenated and catalyzed by palladium carbon, the protecting group is removed, and the anti-tumor medicament polyphenol derivative is obtained through separation and purification.
For antitumor drugs containing amino groups: dissolving 4-benzyloxy benzoic acid, 3, 4-di (benzyloxy) benzoic acid, 3,4, 5-tri (benzyloxy) benzoic acid or 3, 4-di (benzyloxy) phenylacetic acid in an organic solvent, adding O-benzotriazole-tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine, carrying out ice bath, adding an antitumor drug containing amino, stirring for 24-48 h at room temperature to obtain an intermediate product, removing protecting groups through palladium-carbon hydrogenation catalysis, and obtaining the antitumor drug polyphenol derivative through preparation, liquid phase separation and purification.
Further, the invention also provides an anti-tumor drug polyphenol derivative albumin nano-composite, which comprises the anti-tumor drug polyphenol derivative and albumin; the weight ratio of the anti-tumor drug polyphenol derivative to the albumin is (1:40) - (10:1), and the dosage of the albumin is conventional in the field. The albumin is human serum albumin, bovine serum albumin or murine serum albumin, preferably human serum albumin and bovine serum albumin.
The preparation method of the antitumor drug polyphenol derivative albumin nano-composite comprises the following steps: dissolving the anti-tumor drug polyphenol derivative into an organic solvent to serve as an organic phase, dissolving albumin into deionized water to serve as a water phase, and after the organic phase and the water phase are rapidly subjected to micro-flow mixing, spontaneously forming a uniform nano-composite by the anti-tumor drug polyphenol derivative and the albumin. The organic solvent is one or more mixed solvents of acetone, ethanol, methanol, acetonitrile or tetrahydrofuran. The weight ratio of the polyphenol derivative of the antitumor drug to the albumin is (1:40) - (10:1).
The invention also provides application of the albumin binding type antitumor drug and the nano-composite thereof or the pharmaceutical composition thereof in preparing a drug delivery system.
The invention also provides application of the albumin binding type antitumor drug and the nano-composite thereof or the pharmaceutical composition thereof in preparing antitumor drugs.
The invention also provides the application of the albumin binding type antitumor drug and the nano-composite thereof or the pharmaceutical composition thereof in preparing injection, oral administration or local administration systems.
The anti-tumor drug polyphenol derivative albumin nano-composite has the advantages that: (1) The micro-fluidic technology is adopted, so that the proportion of an organic phase to a water phase and the total flow rate can be accurately controlled, the preparation process is simple, and the large-scale production is easy; (2) The particle size is small and uniform (about 110 nm), which is beneficial to the accumulation of tumor tissues through the EPR effect; (3) high drug loading and good stability; (4) The freeze-drying and re-dissolving are easy, the re-dispersibility is good, and the long-term storage is convenient; (5) The pharmacokinetic properties are better, in particular the optimal pharmacokinetic properties of the taxol-gallic acid derivative; (6) Compared with a commercially available preparation, the prepared taxol polyphenol derivative albumin nano-composite has obviously improved tolerance dose; (7) Has improved tumor inhibiting effect, obviously reduced toxic and side effects and great clinical application potential.
The Drug in the invention is not limited to anti-tumor drugs, but can also be antimetabolites, anti-inflammatory drugs, antibacterial drugs, hormonal drugs, antimalarial drugs or other insoluble drugs. The antimetabolite is selected from pyrimidine, purine and tabine; the anti-inflammatory drug is selected from nonsteroidal, steroidal, diterpene, triterpene and glycoside and tetraterpene compounds thereof; the antibacterial drugs are selected from beta lactams, macrolides, sulfonamides, aminoglycosides, quinolones, polypeptide polyenes, phosphorus-containing polysaccharides and polyethers; the hormone medicine is selected from adrenocortical hormone, sex hormone and thyroid hormone; the antimalarial drugs are selected from artemisinin drugs, aminoquinolines, quinolinols or other insoluble drugs and derivatives thereof.
The invention has the beneficial effects that:
According to the invention, the polyphenol derivative modification is carried out on the antitumor drug, so that the affinity of the antitumor drug to albumin is improved, some drugs which cannot be prepared into albumin nanoparticles by a simple microfluidic mixing mode are converted into polyphenol derivatives which can be prepared into albumin-binding nanoparticles by simple mixing, a new thought and opportunity are provided for developing albumin nanoparticles of some drugs with poor protein binding rate, and a new strategy and selection are provided for enriching and developing albumin-binding nano preparations of different types of drugs so as to meet urgent clinical demands on different types of high-end chemotherapeutic preparations.
Drawings
FIG. 1 is a high resolution mass spectrum and 1 H-NMR spectrum of a taxol phenyl derivative (PTX-PH) of which phenolic acid moiety is benzoic acid according to example 1 of the present invention.
FIG. 2 is a high resolution mass spectrum and 1 H-NMR spectrum of a taxol polyphenol derivative (PTX-PA) having a phenolic acid moiety of 4-hydroxybenzoic acid according to example 2 of the present invention.
FIG. 3 is a high resolution mass spectrum and 1 H-NMR spectrum of a paclitaxel polyphenol derivative (PTX-CA) having a phenolic acid moiety of 3, 4-dihydroxybenzoic acid in example 3 of the present invention.
FIG. 4 is a high resolution mass spectrum and 1 H-NMR spectrum of a paclitaxel polyphenol derivative (PTX-GA) having a phenolic acid moiety of 3,4, 5-trihydroxybenzoic acid according to example 4 of the present invention.
FIG. 5 is a high resolution mass spectrum of paclitaxel polyphenol derivative (PTX-EA) with phenolic acid moiety of 3, 4-dihydroxyphenylacetic acid in example 5 of the present invention.
FIG. 6 is a high resolution mass spectrum and 1 H-NMR spectrum of docetaxel polyphenol derivative (DTX-CA) having a phenolic acid moiety of 3, 4-dihydroxybenzoic acid in example 6 of the present invention.
FIG. 7 is a high resolution mass spectrum and 1 H-NMR spectrum of docetaxel polyphenol derivative (DTX-GA) having a phenolic acid moiety of 3,4, 5-trihydroxybenzoic acid according to example 7 of the present invention.
FIG. 8 is a high resolution mass spectrum and 1 H-NMR spectrum of a cabazitaxel polyphenol derivative (CTX-CA) of example 8 in which the phenolic acid moiety is 3, 4-dihydroxybenzoic acid.
FIG. 9 is a high resolution mass spectrum and 1 H-NMR spectrum of a cabazitaxel polyphenol derivative (CTX-GA) of 3,4, 5-trihydroxybenzoic acid as phenolic acid moiety of example 9 of the present invention.
FIG. 10 is a high-resolution mass spectrum and 1 H-NMR spectrum of a podophyllotoxin polyphenol derivative (POD-CA) having a phenolic acid moiety of 3, 4-dihydroxybenzoic acid in example 10 of the present invention.
FIG. 11 is a high resolution mass spectrum and 1 H-NMR spectrum of triptolide polyphenol derivative (TPL-GA) having a phenolic acid moiety of 3,4, 5-trihydroxybenzoic acid in example 11 of the present invention.
FIG. 12 is a graph showing the affinity and kinetic fit of the paclitaxel polyphenol derivative according to example 12 of the present invention to human serum albumin.
FIG. 13 is a graph showing the particle size distribution and appearance of an albumin nanocomposite of docetaxel polyphenol derivative, cabazitaxel polyphenol derivative, podophyllotoxin polyphenol derivative and triptolide polyphenol derivative according to example 13 of the present invention.
FIG. 14 is a diagram showing the appearance of lyophilized powder and reconstituted paclitaxel polyphenol derivative albumin nanocomposite according to example 14 of the present invention.
FIG. 15 is a graph showing the weight change of mice subjected to a tolerance test of the taxol solution, the commercially available albumin-bound taxol nanoparticle and the taxol polyphenol derivative albumin nanocomposite of example 16 of the present invention.
FIG. 16 is a graph showing tumor volume versus time growth of 4T1 tumor-bearing mice in an in vivo efficacy experiment of the paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention.
FIG. 17 is a graph showing the weight-time change of 4T1 tumor-bearing mice in the in vivo efficacy test of the paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention.
FIG. 18 is a graph showing the blood index change of 4T1 tumor-bearing mice in the in vivo efficacy test of the paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention.
FIG. 19 is a graph showing tumor volume versus time growth of MCF-7 tumor-bearing mice in an in vivo efficacy experiment of the paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention.
FIG. 20 is a graph showing weight-time change of MCF-7 tumor-bearing mice in vivo efficacy test of paclitaxel polyphenol derivative albumin nanocomposite according to example 17 of the present invention.
FIG. 21 is a graph showing tumor volume versus time growth of 4T1 tumor-bearing mice tested in vivo as a result of the docetaxel polyphenol derivative albumin nanocomposite of example 18 of the present invention.
FIG. 22 is a graph showing the weight-time change of 4T1 tumor-bearing mice in the in vivo efficacy test of docetaxel polyphenol derivative albumin nanocomposite of example 18 of the present invention.
Detailed Description
The following examples are intended to further illustrate the invention, but not to limit it in any way.
Example 1
Synthesis of paclitaxel-phenyl derivative (PTX-PH)
Benzoic acid (91.5 mg,0.75 mmol), DMAP (91.62 mg,0.75 mmol), EDCI (143.75 mg,0.75 mmol) and HOBT (101.3 mg,0.75 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL anhydrous dichloromethane, and stirred under ice-water bath for 2h. PTX (426.8 mg,0.5 mmol) was then precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction mixture under stirring in an ice bath, and the temperature was raised to 25℃to continue the reaction for 24 hours, followed by monitoring the progress of the reaction by thin layer chromatography. And after the reaction is finished, spin-drying the reaction liquid to obtain a crude product. The crude product was isolated and purified using the preparation (white powder, yield 35.3%). The structure of the target compound is confirmed by high-resolution mass spectrum and 1 H-NMR spectrum, the result is shown in figure 1, and the analysis result of nuclear magnetic resonance spectrum is as follows ：δ9.31(d,J＝8.9Hz,1H,3'-NH),8.03(d,J＝7.4Hz,2H,2'-o-OBz),7.95(d,J＝7.5Hz,2H,2-o-OBz),7.84(d,J＝7.3Hz,2H,3'-o-NHBz),7.72(t,J＝7.4Hz,2H,2-p-OBz,2'-p-OBz),7.61(t,J＝7.7Hz,2H,2'-m-OBz),7.58–7.52(m,5H,3'-p-NHBz,3'-m-NHBz,2-m-OBz),7.48(t,J＝7.1Hz,4H,3'-o-Ph,3'-m-Ph),7.24(t,J＝7.4Hz,1H,3'-p-Ph),6.31(s,1H,,10-H),5.88(t,J＝9.0Hz,1H,13-H),5.80(t,J＝8.7Hz,1H,3'-H),5.55(d,J＝8.6Hz,1H,2'-H),5.43(d,J＝7.2Hz,1H,2-H),4.96–4.91(m,2H,5-H,7-OH),4.68(s,1H,1-OH),4.14(dt,J＝11.0,6.9Hz,1H,7-H),4.05–3.98(m,2H,20-CH2),3.62(d,J＝7.2Hz,1H,3-H),2.37–2.30(m,1H,6α-H),2.28(s,3H,4-OAc),2.10(s,3H,10-OAc),1.90(dd,J＝15.3,9.4Hz,1H,14α-H),1.84(s,3H,18-CH3),1.68–1.59(m,2H,14β-H,6β-H),1.51(s,3H,19-CH3),1.03(s,3H,17-CH3),1.01(s,3H,16-CH3).
Example 2
Synthesis of paclitaxel-4-hydroxybenzoic acid derivative (PTX-PA)
4-Hydroxybenzoic acid (304.3 mg,2.0 mmol), benzyl bromide (342.6 mg,2.0 mmol), anhydrous potassium carbonate (828.2 mg,6.0 mmol) were weighed precisely, dissolved in 30mL of DMF, stirred at 70℃for 48h, the progress of the reaction was monitored by thin layer chromatography, and after completion of the reaction, 4-benzyloxybenzoic acid was obtained by column chromatography. 4-Benzyloxybenzoic acid (171.6 mg,0.75 mmol), DMAP (91.62 mg,0.75 mmol), EDCI (143.75 mg,0.75 mmol) and HOBT (101.3 mg,0.75 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL anhydrous dichloromethane, and stirred under ice water bath for 2h. PTX (426.8 mg,0.5 mmol) was then precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction mixture under stirring in an ice bath, and the temperature was raised to 25℃to continue the reaction for 24 hours, followed by monitoring the progress of the reaction by thin layer chromatography. And after the reaction is finished, spin-drying the reaction liquid to obtain a crude product. The crude product was isolated and purified with the preparation to give the intermediate (white powder, 15.3% yield). The intermediate (130.1 mg) was added to a 100mL eggplant-type bottle, and dissolved with 15mL of absolute ethanol. Then, 10% by mass of Pd/C (13 mg,10% w/w) was added to the intermediate, and the reaction was carried out under H 2 flow at room temperature for 8 hours, followed by monitoring the reaction by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation liquid phase separation and purification to obtain a target product PTX-PA (white powder, yield 90.5%). The structure of the target compound is confirmed by high-resolution mass spectrum and 1 H-NMR spectrum, the result is shown in figure 2, and the analysis result of nuclear magnetic resonance spectrum is as follows ：δ10.51(s,1H,2'-OBzOH),9.27(d,J＝8.9Hz,1H,3'-NH),7.94(d,J＝7.5Hz,2H,2-o-OBz),7.87(d,J＝8.6Hz,2H,2'-o-OBz),7.84(d,J＝7.4Hz,2H,3'-o-NHBz),7.72(t,J＝7.4Hz,1H,2-p-OBz),7.60(t,J＝7.7Hz,2H,2-m-OBz),7.58–7.44(m,7H,3'-p-NHBz,3'-m-NHBz,3'-o-Ph,3'-m-Ph),7.23(t,J＝7.3Hz,1H,3'-p-Ph),6.86(d,J＝8.6Hz,2H,2'-m-OBz),6.30(s,1H,10-H),5.85(t,J＝8.9Hz,1H,13-H),5.75(t,J＝8.4Hz,1H,3'-H),5.47(d,J＝8.7Hz,1H,2'-H),5.42(d,J＝7.2Hz,1H,2-H),4.95–4.90(m,2H,5-H,7-OH),4.66(s,1H,1-OH),4.13(dt,J＝11.0,6.9Hz,1H,7-H),4.05–3.96(m,2H,20-CH2),3.61(d,J＝7.1Hz,1H,3-H),2.33(td,J＝8.1,3.1Hz,1H,6α-H),2.28(s,3H,4-OAc),2.10(s,3H,10-OAc),1.89(dd,J＝15.2,9.6Hz,1H,14α-H),1.82(s,3H,18-CH3),1.68–1.56(m,2H,14β-H,6β-H),1.50(s,3H,19-CH3),1.02(s,3H,17-CH3),1.00(s,3H,16-CH3).
Example 3
Synthesis of paclitaxel-3, 4-dihydroxybenzoic acid derivative (PTX-CA)
3, 4-Dihydroxybenzoic acid (308.2 mg,2.0 mmol), benzyl bromide (856.5 mg,5.0 mmol), anhydrous potassium carbonate (1104.1 mg,8.0 mmol) were weighed precisely, dissolved in 250mL eggplant type bottle, stirred for 48h at 70℃and monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3 mg,1.0 mmol), DMAP (122.1 mg,1.0 mmol), EDCI (191.67 mg,1.0 mmol) and HOBT (135.1 mg,1.0 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. PTX (571.5 mg,0.67 mmol) was then precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction mixture under stirring in an ice bath, and the mixture was transferred to room temperature to continue the reaction for 24 hours, followed by monitoring the progress of the reaction by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 45.2%) was obtained by separation and purification using a preparative liquid phase. The intermediate (383.8 mg) was added to a 250mL eggplant-type bottle and dissolved in 50mL absolute ethanol. Then 10% Pd/C (38 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparative liquid phase separation and purification to obtain the target product PTX-CA (grey pink solid, yield 91.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 3, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ9.29(d,J＝8.7Hz,1H,3'-NH),7.94(d,J＝7.5Hz,2H,2-o-OBz),7.84(d,J＝7.4Hz,2H,3'-o-NHBz),7.71(t,J＝7.4Hz,1H,2-p-OBz),7.60(t,J＝7.7Hz,2H,2-m-OBz),7.54(t,J＝7.3Hz,1H,3'-p-NHBz,),7.53–7.43(m,6H,3'-m-NHBz,3'-o-Ph,3'-m-Ph),7.38(m,2H,2'-o-OBz),7.22(t,J＝7.3Hz,1H,3'-p-Ph),6.81(d,J＝8.1Hz,1H,2'-m-OBz),6.30(s,1H,10-H),5.83(t,J＝9.2Hz,1H,13-H),5.70(t,J＝8.9Hz,1H,3'-H),5.46(d,J＝9.1Hz,1H,2'-H),5.41(d,J＝7.3Hz,1H,2-H),4.92(d,J＝10.3Hz,1H,5-H),4.13(dd,J＝10.7,6.8Hz,1H,7-H),4.05–3.96(m,2H,20-CH2),3.61(d,J＝7.2Hz,1H,3-H),2.34(td,J＝8.0,3.2Hz,1H,6α-H),2.28(s,3H,4-OAc),2.10(s,3H,10-OAc),1.86(dd,J＝15.2,9.5Hz,1H,14α-H),1.81(s,3H,18-CH3),1.64(t,J＝12.3Hz,1H,6β-H),1.55(dd,J＝15.3,9.0Hz,1H,14β-H),1.50(s,3H,19-CH3),1.02(s,3H,17-CH3),1.00(s,3H,16-CH3).
Example 4
Synthesis of paclitaxel-3, 4, 5-trihydroxybenzoic acid derivative (PTX-GA)
3,4, 5-Trihydroxybenzoic acid (340.2 mg,2.0 mmol), benzyl bromide (1027.8 mg,6.0 mmol), anhydrous potassium carbonate (1380.3 mg,10.0 mmol) were weighed precisely, put into a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70℃for 48h, monitored by thin layer chromatography for reaction progress, and after completion of the reaction, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25 mg,1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. PTX (853.7 mg,1.0 mmol) was then precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction mixture under stirring in an ice bath, and the mixture was transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 45.2%) was obtained by separation and purification using a preparative liquid phase. The intermediate (383.8 mg) was added to a 250mL eggplant-type bottle and dissolved in 50mL absolute ethanol. Then 10% Pd/C (38 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparative liquid phase separation and purification to obtain the target product PTX-GA (grey pink solid, yield 91.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 4, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ9.31(d,J＝8.5Hz,1H,3'-NH),7.93(d,J＝7.5Hz,2H,2-o-OBz),7.84(d,J＝7.3Hz,2H,3'-o-NHBz),7.71(t,J＝7.4Hz,1H,2-p-OBz),7.61(t,J＝7.7Hz,2H,2-m-OBz),7.54(t,J＝7.3Hz,1H,3'-p-NHBz),7.51–7.43(m,6H,3'-m-NHBz,3'-o-Ph,3'-m-Ph),7.20(t,J＝7.1Hz,1H,3'-p-Ph),7.01(s,2H,2'-o-OBz),6.29(s,1H,10-H),5.80(t,J＝9.1Hz,1H,13-H),5.64(t,J＝9.0Hz,1H,3'-H),5.46(d,J＝9.6Hz,1H,2'-H),5.40(d,J＝7.2Hz,1H,2-H),4.93(d,J＝10.5Hz,1H,5-H),4.13(dd,J＝10.7,6.8Hz,1H,7-H),4.05–3.95(m,2H,20-CH2),3.60(d,J＝7.2Hz,1H,3-H),2.34(ddd,J＝15.7,9.5,6.9Hz,1H,6α-H),2.29(s,3H,4-OAc),2.10(s,3H,10-OAc),1.83(dd,J＝15.4,9.7Hz,1H,14α-H),1.79(s,3H,18-CH3),1.64(t,J＝12.3Hz,1H,6β-H),1.50(s,3H,19-CH3),1.48(d,J＝9.1Hz,1H,14β-H),1.02(s,3H,17-CH3),0.99(s,3H,16-CH3).
Example 5
Synthesis of paclitaxel-3, 4-dihydroxyphenylacetic acid derivative (PTX-EA)
3, 4-Dihydroxyphenylacetic acid (336.3 mg,2.0 mmol), benzyl bromide (856.5 mg,5.0 mmol), anhydrous potassium carbonate (1104.1 mg,8.0 mmol) were weighed precisely, dissolved in 250mL eggplant type bottle, stirred for 48h at 70℃and monitored by thin layer chromatography, and after completion of the reaction, 3, 4-di (benzyloxy) phenylacetic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) phenylacetic acid (346.1 mg,1.0 mmol), DMAP (122.1 mg,1.0 mmol), EDCI (191.67 mg,1.0 mmol) and HOBT (135.1 mg,1.0 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. PTX (571.5 mg,0.67 mmol) was then precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction mixture under stirring in an ice bath, and the mixture was transferred to room temperature to continue the reaction for 24 hours, followed by monitoring the progress of the reaction by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 43.6%) was obtained by separation and purification using a preparative liquid phase. The intermediate (285.8 mg) was added to a 250mL eggplant-type bottle and dissolved with 50mL absolute ethanol. Then 10% Pd/C (28.5 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction is finished, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation liquid phase separation and purification to obtain a target product PTX-EA (light coffee solid, yield 92.4%). The structure of the target compound was confirmed by high resolution mass spectrometry, and the result is shown in fig. 5.
Example 6
Synthesis of docetaxel-3, 4-dihydroxybenzoic acid derivative (DTX-CA)
3, 4-Dihydroxybenzoic acid (308.2 mg,2.0 mmol), benzyl bromide (856.5 mg,5.0 mmol), anhydrous potassium carbonate (1104.1 mg,8.0 mmol) were weighed precisely, dissolved in 250mL eggplant type bottle, stirred for 48h at 70℃and monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3 mg,1.0 mmol), DMAP (122.1 mg,1.0 mmol), EDCI (191.67 mg,1.0 mmol) and HOBT (135.1 mg,1.0 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. Docetaxel (DTX) (540.6 mg,0.67 mmol) was precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction solution under stirring in an ice bath, transferred to room temperature, and reacted for 24 hours, followed by monitoring the progress of the reaction by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 41.2%) was obtained by separation and purification using a preparative liquid phase. The intermediate (300.8 mg) was added to a 250mL eggplant-type bottle and dissolved with 50mL absolute ethanol. Then 10% Pd/C (30.08 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to separation and purification by a prepared liquid phase to obtain a target product DTX-CA (grey pink solid, yield 91.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 6, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ8.02–7.91(m,3H,3'-NH and 2-o-OBz),7.72(t,J＝6.9Hz,1H,2-p-OBz),7.62(t,J＝7.3Hz,2H,2-m-OBz),7.48(d,J＝8.0Hz,1H,2'-o-OBz),7.43(s,5H,2'-o-OBz,3'-o-Ph,3'-m-Ph),7.18(s,1H,3'-p-Ph),6.81(d,J＝8.1Hz,1H,2'-m-OBz),5.80(t,J＝8.4Hz,1H,13-H),5.40(d,J＝6.8Hz,1H,2-H),5.24–5.16(m,2H,3'-H,2'-H),5.09(s,1H,10-OH),4.92(d,J＝9.2Hz,1H,5-H),4.43(s,1H,1-OH),4.07(t,J＝8.8Hz,1H,7-H),4.01(q,J＝8.2Hz,2H,20-CH2),3.66(d,J＝6.0Hz,1H,3-H),2.27(s,4H,6α-H,4-OAc),1.89–1.82(m,1H,14α-H),1.74(s,3H,18-CH3),1.66(t,J＝12.5Hz,1H,6β-H),1.58–1.48(m,4H,19-CH3,14β-H),1.39(s,9H,3'-NHBoc),0.98(s,6H,17-CH3,16-CH3).
Example 7
Synthesis of docetaxel-3, 4, 5-trihydroxybenzoic acid derivative (DTX-GA)
3,4, 5-Trihydroxybenzoic acid (340.2 mg,2.0 mmol), benzyl bromide (1027.8 mg,6.0 mmol), anhydrous potassium carbonate (1380.3 mg,10.0 mmol) were weighed precisely, put into a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70℃for 48h, monitored by thin layer chromatography for reaction progress, and after completion of the reaction, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25 mg,1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. Subsequently, DTX (807.2 mg,1.0 mmol) was precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction solution under stirring in an ice bath, and the reaction was continued at room temperature for 24 hours, followed by monitoring the progress of the reaction by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 43.7%) was obtained by separation and purification using a preparative liquid phase. The intermediate (283.8 mg) was added to a 250mL eggplant-type bottle, and dissolved with 50mL absolute ethanol. Then 10% Pd/C (28.3 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation liquid phase separation and purification to obtain a target product DTX-GA (grey pink solid, yield 91.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 7, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ7.98(d,J＝9.3Hz,1H,3'-NH),7.96(d,J＝7.5Hz,2H,2-o-OBz),7.72(t,J＝7.4Hz,1H,2-p-OBz),7.63(t,J＝7.7Hz,2H,2-m-OBz),7.46–7.39(m,4H,3'-o-Ph,3'-m-Ph),7.20–7.15(m,1H,3'-p-Ph),7.07(s,2H,2'-o-OBz),5.78(t,J＝8.8Hz,1H,13-H),5.39(d,J＝7.2Hz,1H,2-H),5.23–5.12(m,2H,3'-H,2'-H),5.09(s,1H,10-OH),4.92(d,J＝10.7Hz,1H,5-H),4.41(s,1H,1-OH),4.06(dd,J＝11.0,6.7Hz,1H,7-H),4.05–3.97(m,2H,20-CH2),3.65(d,J＝7.1Hz,1H,3-H),2.32–2.24(m,4H,6α-H,4-OAc),1.83(dd,J＝15.3,9.4Hz,1H,14α-H),1.72(s,3H,18-CH3),1.66(t,J＝12.4Hz,1H,6β-H),1.54–1.47(m,4H,19-CH3,14β-H),1.38(s,9H,3'-NHBoc),0.98(s,6H,17-CH3,16-CH3).
Example 8
Synthesis of cabazitaxel-3, 4-dihydroxybenzoic acid derivative (CTX-CA)
3, 4-Dihydroxybenzoic acid (308.2 mg,2.0 mmol), benzyl bromide (856.5 mg,5.0 mmol), anhydrous potassium carbonate (1104.1 mg,8.0 mmol) were weighed precisely, dissolved in 250mL eggplant type bottle, stirred for 48h at 70℃and monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3 mg,1.0 mmol), DMAP (122.1 mg,1.0 mmol), EDCI (191.67 mg,1.0 mmol) and HOBT (135.1 mg,1.0 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. CTX (560.0 mg,0.67 mmol) was weighed precisely, dissolved in 5mL of methylene chloride, and slowly dropped into the reaction mixture under stirring in an ice bath, and the mixture was transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 41.2%) was obtained by separation and purification using a preparative liquid phase. The intermediate (300.8 mg) was added to a 250mL eggplant-type bottle and dissolved with 50mL absolute ethanol. Then 10% Pd/C (30.08 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation, liquid phase separation and purification to obtain the target product CTX-CA (grey pink solid, yield 90.7%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 8, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ8.00(d,J＝9.4Hz,1H,3'-NH),7.96(d,J＝7.5Hz,2H,2-o-OBz),7.73(t,J＝7.4Hz,1H,2-p-OBz),7.64(t,J＝7.7Hz,2H,2-m-OBz),7.48(dd,J＝8.3,2.0Hz,1H,2'-o-OBz),7.45–7.41(m,5H,3'-o-Ph,3'-m-Ph,,2'-o-OBz),7.19(dt,J＝8.7,4.9Hz,1H,3'-p-Ph),6.83(d,J＝8.3Hz,1H,2'-m-OBz),5.83(t,J＝8.9Hz,1H,13-H),5.37(d,J＝7.1Hz,1H,2-H),5.24–5.15(m,2H,3'-H,2'-H),4.97(d,J＝10.4Hz,1H,5-H),4.71(s,1H,10-H),4.50(s,1H,1-OH),4.02(s,2H,20-CH2),3.77(dd,J＝10.4,6.8Hz,1H,7-H),3.61(d,J＝7.1Hz,1H,3-H),3.28(s,3H,10-OCH3),3.23(s,3H,7-OCH3),2.68(ddd,J＝14.1,9.7,6.4Hz,1H,6α-H),2.28(s,3H,4-OAc),1.86–1.78(m,4H,18-CH3,14α-H),1.53–1.49(m,5H,19-CH3,14β-H,6β-H),1.39(s,9H,3'-NHBoc),0.98(s,3H,17-CH3),0.96(s,3H,16-CH3).
Example 9
Synthesis of cabazitaxel-3, 4, 5-trihydroxybenzoic acid derivative (CTX-GA)
3,4, 5-Trihydroxybenzoic acid (340.2 mg,2.0 mmol), benzyl bromide (1027.8 mg,6.0 mmol), anhydrous potassium carbonate (1380.3 mg,10.0 mmol) were weighed precisely, put into a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70℃for 48h, monitored by thin layer chromatography for reaction progress, and after completion of the reaction, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25 mg,1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. CTX (835.9 mg,1.0 mmol) was precisely weighed, dissolved in 5mL of methylene chloride, slowly dropped into the above reaction solution under stirring in an ice bath, transferred to room temperature and reacted for 24 hours, and progress of the reaction was monitored by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 40.6%) was obtained by separation and purification using a preparative liquid phase. The intermediate (283.8 mg) was added to a 250mL eggplant-type bottle, and dissolved with 50mL absolute ethanol. Then 10% Pd/C (28.3 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation, liquid phase separation and purification to obtain a target product CTX-GA (grey pink solid, yield 93.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 9, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ9.25(s,3H,2'-OBzOH),8.00(d,J＝8.7Hz,1H,3'-NH),7.96(d,J＝7.6Hz,2H,2-o-OBz),7.73(t,J＝7.4Hz,1H,2-p-OBz),7.64(t,J＝7.7Hz,2H,2-m-OBz),7.47–7.39(m,4H,3'-o-Ph,3'-m-Ph),7.18(t,J＝6.8Hz,1H,3'-p-Ph),7.07(s,2H,2'-o-OBz),5.81(t,J＝8.9Hz,1H,13-H),5.37(d,J＝7.1Hz,1H,2-H),5.22–5.14(m,2H,3'-H,2'-H),4.97(d,J＝10.2Hz,1H,5-H),4.70(s,1H,10-H),4.48(s,1H,1-OH),4.02(s,2H,20-CH2),3.77(dd,J＝10.3,6.8Hz,1H,7-H),3.60(d,J＝7.1Hz,1H,3-H),3.27(s,3H,10-OCH3),3.23(s,3H,7-OCH3),2.67(td,J＝7.9,3.3Hz,1H,6α-H),2.28(s,3H,4-OAc),1.83–1.81(m,4H,18-CH3,14α-H),1.53–1.49(m,5H,19-CH3,14β-H,6β-H),1.38(s,9H,3'-NHBoc),0.98(s,3H,17-CH3),0.96(s,3H,16-CH3).
Example 10
Synthesis of Podophyllotoxin-3, 4-dihydroxybenzoic acid derivative (POD-CA)
3, 4-Dihydroxybenzoic acid (308.2 mg,2.0 mmol), benzyl bromide (856.5 mg,5.0 mmol), anhydrous potassium carbonate (1104.3 mg,8.0 mmol) were weighed precisely, dissolved in 250mL eggplant type bottle, stirred for 48h at 70℃and monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3 mg,1.0 mmol), DMAP (122.1 mg,1.0 mmol), EDCI (191.67 mg,1.0 mmol) and HOBT (135.1 mg,1.0 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. Then, podophyllotoxin (POD) (277.3 mg,0.67 mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the reaction solution under stirring in an ice bath, transferred to room temperature, and reacted for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 60.2%) was obtained by separation and purification using a preparative liquid phase. The intermediate (100.8 mg) was added to a 100mL eggplant-type bottle, and dissolved with 50mL of absolute ethanol. Then 10% Pd/C (10.08 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation liquid phase separation and purification to obtain the target product POD-CA (grey pink solid, yield 87.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 10, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ7.40(d,J＝2.0Hz,1H,2"-H),7.36(dd,J＝8.3,2.0Hz,1H,6'-H),6.92(s,1H,4-H),6.84(d,J＝8.3Hz,1H,5'-H),6.65(s,1H,10-H),6.39(s,2H,2'-H,6'-H),6.05(d,J＝9.3Hz,1H,5-H),6.03(d,J＝3.3Hz,2H,2α-H,2α-H),4.60(d,J＝4.6Hz,1H,9-H),4.39(t,J＝7.8Hz,1H,6α-H),4.27(t,J＝8.6Hz,1H,6β-H),3.67(s,6H,7'-H),3.62(s,3H,8'-H),3.43(dd,J＝14.6,4.6Hz,1H,8a-H),2.86–2.77(m,1H,5a-H).
Example 11
Synthesis of triptolide-3, 4, 5-trihydroxybenzoic acid derivative (TPL-GA)
3,4, 5-Trihydroxybenzoic acid (340.2 mg,2.0 mmol), benzyl bromide (1027.8 mg,6.0 mmol), anhydrous potassium carbonate (1380.3 mg,10.0 mmol) were weighed precisely, put into a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70℃for 48h, monitored by thin layer chromatography for reaction progress, and after completion of the reaction, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25 mg,1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed precisely, added to a 100mL eggplant-type bottle, dissolved in 25mL dichloromethane, and stirred under ice bath for 2h. Then, triptolide (TPL) (360.5 mg,1.0 mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the reaction solution under stirring in an ice bath, transferred to room temperature, and reacted for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction, the reaction mixture was dried by spin-drying, and the sample was dissolved in acetonitrile, and the intermediate product (white powder, yield 33.7%) was obtained by separation and purification using a preparative liquid phase. The intermediate (93.8 mg) was added to a 250mL eggplant-type bottle, and dissolved with 50mL of absolute ethanol. Then 10% Pd/C (9.3 mg,10% w/w) was added to the intermediate and reacted at room temperature under H 2 flow for 8 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction, pd/C is removed by filtration through a microporous membrane, and the filtrate is subjected to preparation liquid phase separation and purification to obtain the target product TPL-GA (grey pink solid, yield 89.2%). The structure of the target compound was confirmed by high resolution mass spectrometry and 1 H-NMR spectroscopy, and the results are shown in FIG. 11, and the results of the nuclear magnetic resonance spectroscopy are as follows ：δ7.02(s,2H,H-3'),5.12(s,1H,H-14),4.90–4.71(m,2H,H-19),4.01(d,J＝3.3Hz,1H,H-11),3.73(d,J＝3.2Hz,1H,H-12),3.61(d,J＝5.7Hz,1H,H-7),2.68–2.61(m,1H,H-5),2.16–2.09(m,1H,H-2),2.03–1.90(m,2H,H-2,H-6),1.81(dd,J＝15.0,13.2Hz,1H,H-6),1.74(hept,J＝6.9Hz,1H,H-15),1.38–1.28(m,2H,H-1),0.91(s,3H,H-20),0.87(d,J＝7.0Hz,3H,H-16),0.78(d,J＝6.8Hz,3H,H-17).
Example 12
Determination of affinity of paclitaxel polyphenol derivative to human serum albumin
The affinity of the paclitaxel polyphenol derivative to human serum albumin was determined by a surface plasmon resonance method. Human Serum Albumin (HSA) is fixed on the surface of a CM5 sensing chip through amino coupling, and then samples to be tested (taxol, taxol phenyl derivatives and taxol polyphenol derivatives) pass through the surface at different concentrations to be combined with albumin. The concentration of the immobilized HSA is 80 mug/mL, and the concentration range of the sample to be tested is set between 0.006 mu M and 41.15 mu M. The affinity value of steady state and kinetic data of binding are determined by real-time dynamic analysis of the binding of the sample to be tested to HSA. The smaller the dissociation constant K D value, the higher the affinity. As shown in FIG. 12, the results of ：PTX-GA(KD＝0.812nM)>PTX-PA(KD＝12.5nM)≥PTX-CA(KD＝12.7nM)>PTX-PH(KD＝24.2nM)>PTX(KD＝26.6nM). for paclitaxel and the four paclitaxel derivatives showed that the paclitaxel polyphenol derivatives had significantly higher affinity for human serum albumin than the paclitaxel and paclitaxel phenyl derivatives (PTX-PH).
Example 13
Preparation of paclitaxel polyphenol derivative albumin nano-composite
Paclitaxel and the paclitaxel derivatives (including paclitaxel phenyl derivatives, paclitaxel polyphenol derivatives) prepared in examples 1 to 5 were precisely weighed 5mg and 100mg of human serum albumin, respectively, paclitaxel and paclitaxel derivatives were dissolved with 0.5mL of acetone, human serum albumin was dissolved with 10mL of deionized water, an acetone solution of paclitaxel and paclitaxel derivatives was used as an organic phase, and an aqueous solution of human serum albumin was used as an aqueous phase. The flow rate ratio of the organic phase to the water phase is controlled to be 1:4, the total flow rate is 12mL/min, and the organic solvent in the nano preparation is removed by spin evaporation under the condition of 25 ℃, so that the paclitaxel albumin nano-composite (PTX@HSA NCs), the paclitaxel derivative albumin nano-composite (PTX-PH@HSA NCs, PTX-PA@HSA NCs, PTX-CA@HSA NCs, PTX-GA@HSA NCs and PTX-EA@HSA NCs) are respectively obtained. The particle size and particle size distribution are shown in Table 1.
TABLE 1 particle size and PDI of different paclitaxel and paclitaxel derivative Albumin nanocomposites
In addition, docetaxel (DTX), docetaxel polyphenol derivative (DTX-CA, DTX-GA), cabazitaxel (CTX), cabazitaxel polyphenol derivative (CTX-CA, CTX-GA), podophyllotoxin (POD), podophyllotoxin polyphenol derivative (POD-CA), triptolide (TPL), triptolide polyphenol derivative (TPL-GA) 5.00mg and human serum albumin 220.0mg were precisely weighed, respectively, and a nanocomposite having an external appearance as shown in fig. 13 (particles of multimodal distribution were obtained after mixing the bulk drug and albumin, and particles of unimodal distribution were obtained after mixing the polyphenol derivative and albumin), and the average particle diameters and the particle size distribution were shown in table 2 was prepared according to the above preparation method. The results show that the drug precipitation is observed after the docetaxel, the cabazitaxel, the podophyllotoxin, the triptolide and the human serum albumin are mixed in a micro-flow way, and the nano-composite with uniform particle size can not be directly obtained; in contrast, under the same test conditions, the polyphenol derivative can be effectively combined with albumin to form a nano-composite with uniform particle size, PDI is less than 0.2, the particle size is uniform, and further the fact that some albumin can be successfully prepared into albumin nano-particles through a polyphenol derivatization strategy.
TABLE 2 particle size and PDI of different nanocomposites
Example 14
Freeze-drying preparation of taxol polyphenol derivative albumin nano complex
Concentrating the taxol polyphenol derivative albumin nano-composite to make the concentration of the taxol polyphenol derivative be 10mg/mL, and adding 5% of sucrose as a freeze-drying protective agent for freeze-drying. The state before and after freeze-drying of the taxol polyphenol derivative albumin nano-composite is shown in figure 14, the taxol polyphenol derivative albumin nano-composite has good freeze-dried appearance and smooth surface, and is in a full and loose round cake-shaped structure. Physiological saline was added and gently shaken to redisperse in a short time, and the particle size was not significantly changed as compared with before lyophilization, and the particle size change before and after lyophilization was shown in Table 3.
TABLE 3 particle size and PDI of paclitaxel polyphenol derivative albumin nanocomposite before and after lyophilization
Example 15
Pharmacokinetic study of paclitaxel polyphenol derivative albumin nanocomposite
16 Male healthy rats, 200-250 g in weight, were randomly divided into 4 groups of 4, each, and the commercial formulations Taxol solution (Taxol), albumin-bound Taxol nanoparticle (Abraxane) and Taxol-polyphenol derivative albumin nanocomposite prepared in example 12 were injected into the tail vein, respectively, wherein the equivalent dose of Taxol was 5mg/kg. Blood is taken from the orbit at a specified time, the blood is obtained by centrifugation for 10min at 13000 r, the concentration of the paclitaxel mother drug and the paclitaxel polyphenol derivative in the blood plasma is measured by a high performance liquid chromatography-mass spectrometer, and the main drug dynamics parameters are processed by DAS software and are shown in Table 4. The results show a significant increase in area under the curve (AUC) for the paclitaxel polyphenol derivative albumin nanocomposite as compared to the two commercially available formulations Taxol, abraxane.
TABLE 4 pharmacokinetic parameters of taxol solutions, albumin-bound taxol nanoparticles and taxol-polyphenol-derived albumin nanocomposites
A PTX is from PTX-CA@HSA NCs, and b PTX is from PTX-GA@HSA NCs.
Example 16
Maximum tolerated dose assessment of paclitaxel polyphenol derivative albumin nanocomposite
Safety and tolerability of the different formulations (paclitaxel polyphenol derivative albumin nanocomposite) on healthy BALB/c mice were studied using a multi-dose dosing regimen, the survival status and weight change of each group of mice were observed daily during the dosing period, and the highest dose without toxicity was defined as the maximum tolerating dose when the average weight of mice was reduced by 15% or abnormal behaviors such as humpback posture, rough hair, etc. were defined as toxicity. Mice were randomly divided into 19 groups of 3 animals each, with saline group as control. The tail vein was injected with taxol (taxol equivalent doses 10, 20, 30 mg/kg), albumin-conjugated taxol nanoparticles (taxol equivalent doses 10, 30, 60, 90 and 120 mg/kg), PTX-CA@HSA NCs (taxol equivalent doses 10, 30, 60, 90 and 120 mg/kg) and PTX-GA@HSA NCs (taxol equivalent doses 10, 30, 60, 90 and 120 mg/kg), respectively. Dosing was performed once for 2 days and 5 times altogether, during which time body weight was monitored, recorded and mice behaved.
As shown in FIG. 15, tail vein injection of 30mg/kg of taxol resulted in severe treatment-related death; at a dose of 20mg/kg, it was observed that the mice exhibited abnormal behavior such as drowsiness, coarse fur, humpback, etc., and that although the mice had slightly decreased weight by about 10%, one of the mice died after the fourth administration, indicating that the mice were intolerant and had some cumulative toxicity at this dose level. Thus, the maximum tolerated dose of taxol for healthy BALB/c mice was determined to be 10mg/kg. In contrast, the maximum tolerated dose of the commercially available formulation Abraxane was significantly increased. When the administration dose is more than 60mg/kg, the weight of the mice is reduced by more than 15%, and abnormal behaviors such as rickets, bradykinesia, somnolence and the like occur, so that the maximum tolerated dose of Abraxane is determined to be 30mg/kg here. When the paclitaxel equivalent dose is 120mg/kg, the weight of the mice is slightly reduced, but the mice still fluctuate within a range of less than 10%, and the health state of the mice is not obviously abnormal, which indicates that the paclitaxel polyphenol derivative albumin nano-composite provided by the invention has good safety and greatly improves the maximum tolerance dose.
Example 17
In vivo efficacy experiment of paclitaxel polyphenol derivative albumin nanocomposite
4T1 cells with good growth state are digested by 0.05% pancreatin, then the digestion is stopped by fresh RPMI 1640 cell culture solution, the culture solution containing pancreatin is removed by centrifugation at 1000rpm for 5min, the cells are collected, cold PBS (pH 7.4) is added to uniformly disperse the cells, and the cells are counted, so that the final concentration of the cell suspension is 1 multiplied by 10 7 cells/mL. 100 μl was inoculated subcutaneously into the right back side lumbar dorsal part of female BALB/c mice. When the tumor volume was as long as about 120-150 mm 3 animals were randomly grouped, each group of 5 animals was a normal saline control group, a taxol solution group (taxol equivalent administration doses were 10 and 30mg/kg, respectively), an albumin-bound taxol nanoparticle group (taxol equivalent administration doses were 10 and 30mg/kg, respectively), a PTX-CA@HSA NCs group (taxol equivalent administration doses were 10, 30, 90 and 120mg/kg, respectively) and a PTX-GA@HSA NCs group (taxol equivalent administration doses were 10, 30, 90 and 120mg/kg, respectively). The administration mode is tail vein injection, administration is carried out once every other day, administration is carried out 5 times, and the weight change and the tumor volume of the mice are measured and recorded every day after administration. After the last administration, the mice are subjected to eyeball picking and blood taking, and the whole blood of the mice is collected for blood cell level analysis.
The results are shown in FIG. 16, in which the taxol solutions (10 mg/kg) only slightly inhibited tumor growth at the maximum tolerated dose of each formulation; the albumin-bound taxol nanoparticle (30 mg/kg) has a good effect of inhibiting tumor growth; the tumor of the mice treated by the taxol polyphenol derivative albumin nano-composite (120 mg/kg) is shrunken, so that the tumor is furthest inhibited, and the unique therapeutic advantage is shown.
The safety of the preparation is evaluated by analyzing the weight change and the blood index change of the tumor-bearing mice, and the result is shown in figure 17, the mice treated by albumin-bound paclitaxel nanoparticles (30 mg/kg) show obvious weight reduction, which indicates that the accumulation of drug toxicity occurs and certain toxic and side effects are generated on the organism; the weight of the taxol polyphenol derivative albumin nano-composite is not obviously reduced at the maximum tolerance dose of 120mg/kg, which indicates that the taxol polyphenol derivative albumin nano-composite has good in vivo safety.
The results of the blood cell analysis are shown in FIG. 18, and compared with the normal saline control group, the indexes of the blood leucocytes, lymphocytes, monocytes and neutrophils of the mice are obviously reduced after the treatment by Taxol (10 mg/kg) and Abraxane (30 mg/kg), and the reduction degree of the leucocyte level of the Taxol-polyphenol-derivative-albumin nano-composite is relatively low under the maximum tolerance dose of 120mg/kg, which indicates that the Taxol-polyphenol-derivative-albumin nano-composite has a certain advantage in the aspect of safety. Furthermore, in the tumor-bearing MCF-7 nude mouse model (as in fig. 19-20), similar efficacy results as those of the 4T1 tumor model were observed, again demonstrating the advantages of the paclitaxel polyphenol derivative albumin nanocomposite.
Example 18
In vivo efficacy experiment of docetaxel polyphenol derivative albumin nanocomposite
A physiological saline control group, a docetaxel solution (Taxote) group (docetaxel equivalent administration dose: 6 mg/kg), a DTX-CA@HSA NCs group (docetaxel equivalent administration doses: 6 and 120mg/kg, respectively) and a DTX-GA@HSA NCs group (docetaxel equivalent administration doses: 6 and 120mg/kg, respectively) were set as a model, and administered by a tail vein injection route, and 5 times in each day. The results are shown in fig. 21, in which both docetaxel solution and docetaxel polyphenol derivative albumin nanocomposite had a significant tumor growth inhibitory effect as compared to the physiological saline group, but the weight of the docetaxel solution group mice was reduced by about 20% after treatment (fig. 22). Notably, the therapeutic effect of docetaxel polyphenol derivative albumin nanocomposite exhibited dose-dependent characteristics, and the high-dose treatment group had significant advantages over the low-dose treatment group, exhibited stronger tumor inhibition, and was somewhat superior to docetaxel solution. However, the weight of the mice in the nano-composite group is not obviously reduced, which indicates that the toxicity is reduced, and the mice have better in vivo safety.

Claims (4)

1. An anti-tumor drug polyphenol derivative albumin nanocomposite, characterized in that the nanocomposite comprises an anti-tumor drug polyphenol derivative and albumin; the weight ratio of the anti-tumor drug polyphenol derivative to albumin is 1:40-10:1; the albumin is human serum albumin; the antitumor drug polyphenol derivative is selected from the following compounds:
the preparation method of the antitumor drug polyphenol derivative albumin nano-composite comprises the following steps:
Dissolving an antitumor drug polyphenol derivative into an organic solvent to serve as an organic phase, dissolving albumin into deionized water to serve as a water phase, and spontaneously forming a uniform nano-composite by the antitumor drug polyphenol derivative and the albumin after rapid micro-flow mixing of the organic phase and the water phase; the organic solvent is one or more mixed solvents of acetone, ethanol, methanol, acetonitrile or tetrahydrofuran.
2. Use of the nanocomposite of claim 1 in the preparation of a drug delivery system.
3. Use of the nanocomposite of claim 1 in the preparation of an antitumor drug.
4. Use of a nanocomposite according to claim 1 for the preparation of an injectable, oral or topical delivery system.
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