CN112321625A - Folic acid-based MIDA boric acid ester-naphthalimide compound and preparation and application thereof - Google Patents
Folic acid-based MIDA boric acid ester-naphthalimide compound and preparation and application thereof Download PDFInfo
- Publication number
- CN112321625A CN112321625A CN202011367834.8A CN202011367834A CN112321625A CN 112321625 A CN112321625 A CN 112321625A CN 202011367834 A CN202011367834 A CN 202011367834A CN 112321625 A CN112321625 A CN 112321625A
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- CN
- China
- Prior art keywords
- folic acid
- naphthalimide
- lhx
- compound
- mida
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims abstract description 131
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 74
- 239000011724 folic acid Substances 0.000 title claims abstract description 74
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 229960000304 folic acid Drugs 0.000 title claims abstract description 57
- 239000004327 boric acid Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 241001139947 Mida Species 0.000 title claims abstract 17
- -1 boric acid ester Chemical class 0.000 claims abstract description 28
- 238000001514 detection method Methods 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- 229940014144 folate Drugs 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 14
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- 239000007850 fluorescent dye Substances 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 60
- 229940127093 camptothecin Drugs 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 17
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 17
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 17
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 14
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
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- 239000004312 hexamethylene tetramine Substances 0.000 claims description 7
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- APBIDAXJCGEEIS-UHFFFAOYSA-N 6-bromobenzo[de]isoquinoline-1,3-dione Chemical class O=C1NC(=O)C2=CC=CC3=C2C1=CC=C3Br APBIDAXJCGEEIS-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- DTUOTSLAFJCQHN-UHFFFAOYSA-N 4-bromo-1,8-naphthalic anhydride Chemical compound O=C1OC(=O)C2=CC=CC3=C2C1=CC=C3Br DTUOTSLAFJCQHN-UHFFFAOYSA-N 0.000 claims description 5
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 5
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 5
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- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 4
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- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
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- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
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- ZEFNYUUKDPUZPG-UHFFFAOYSA-N B(O)(O)O.CN(CC(=O)O)CC(=O)O Chemical compound B(O)(O)O.CN(CC(=O)O)CC(=O)O ZEFNYUUKDPUZPG-UHFFFAOYSA-N 0.000 claims 1
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- XWSGEVNYFYKXCP-UHFFFAOYSA-N 2-[carboxymethyl(methyl)amino]acetic acid Chemical compound OC(=O)CN(C)CC(O)=O XWSGEVNYFYKXCP-UHFFFAOYSA-N 0.000 description 30
- 230000004044 response Effects 0.000 description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
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- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical class C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 3
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
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- 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
- A61K47/545—Heterocyclic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention provides a folic acid-based MIDA boric acid ester-naphthalimide compound, and a preparation method and application thereof. The folate-based MIDA boric acid ester-naphthalimide compound can respond to H through the special space structure of the MIDA boric acid ester regulation group2O2Can realize the H pair2O2Detection of (3). The compound has the function of being used as a drug carrier, and the drug CPT is loaded on the CPT baseLHX-CPT is obtained from the MIDA boric acid ester-naphthalimide compound of folic acid, and a drug delivery system with stable neutral condition (blood circulation) and acid sensitivity can be realized by means of the MIDA boric acid ester regulation mechanism. At H2O2In the enriched environment, the drug and the fluorescent compound with anticancer activity are released, and the purpose of monitoring the transmission and release of the drug is achieved through fluorescence signal transduction. Meanwhile, the compound has high-efficiency targeting property by introducing a folic acid ligand, and can be used for endogenous H in living cells and living bodies2O2Detection and diagnosis and treatment of related diseases.
Description
Technical Field
The invention relates to a folic acid-based MIDA borate-naphthalimide compound and a preparation method thereof, and also relates to folic acid-based application of the folic acid-based MIDA borate-naphthalimide compound in hydrogen peroxide detection; the invention also relates to an application of the folate-based MIDA borate-naphthalimide compound as a drug delivery carrier, belonging to the fields of chemical synthesis and biological materials.
Background
Hydrogen peroxide (H)2O2) Is an important active oxygen molecule and is generated by activating with oxidase. It plays multiple roles in physiological processes, including defense responses, reversible oxidation of proteins, oxidative damage, and cell signaling. It was found that at the level of the organelles, the mitochondria were H2O2Is also the main source of oxygen consumption. H production in mitochondria2O2Influence on organisms, ginseng half: in one aspect, mitochondrial H2O2Can provide beneficial promotion effect for cell survival, growth, differentiation and maintenance; on the other hand, overproduced H2O2Can cause various diseases, such as inflammatory diseases, cardiovascular diseases, Alzheimer's disease, cancer and the like. Thus, in view of intracellular H2O2The steady state of the cells has profound effects on human health and diseases, and a new fluorescence imaging diagnostic method needs to be designed to realize the effect on H in mitochondria of living cells2O2Provides theoretical guidance for detection and quantification of (a).
At present, based on H2O2The targeted drug delivery system as the trigger mainly focuses on the high H activity in vitro or in cells2O2Detection of (3). The problems existing in the method are mainly reflected in that: 1) the detection function is single, and the H can not be detected in a specific body2O2Meanwhile, the controlled release of the medicine is realized; 2) the system is complex, the response speed is slow, the sensitivity is low, the selectivity is low, and the due treatment effect cannot be achieved; 3) the lack of diagnostic components, thereby losing the detection targeting and being prone to false positive signals; 4) there is a lack of an ideal drug delivery system that satisfies the requirement of maintaining zero drug release in the blood circulation and a rapid response at the target site. Therefore, it is imperative to build H-based2O2The regulated diagnosis and treatment integrated platform aims to achieve the purposes of early prediction and diagnosis of related cancers.
As described above, although some hydrogen peroxide detection methods have been reported and applied, the response function is single, and the method can only be used for H in vitro or in cells2O2Qualitative or quantitative detection of (a). In addition, although H is explicitly indicated2O2Is closely related to various diseases, but is based on an acid sensitive system H2O2Stimulated controlled drug release systems have not been reported. More importantly, the lack of anticancer drugs can specifically identify tumor cells. Therefore, it is important to develop a fluorescent probe satisfying both stability and responsiveness.
Disclosure of Invention
The invention aims to provide a folic acid-based MIDA boric acid ester-naphthalimide compound and a preparation method thereof;
another object of the invention is to provide folate based MIDA boronate-naphthalimide compounds in H2O2The use of detection.
It is yet another object of the present invention to provide the use of folate-based MIDA boronate-naphthalimide class compounds as drug delivery vehicles.
Synthesis and preparation of folic acid-based MIDA boric acid ester-naphthalimide compound
The invention provides a folic acid-based MIDA boric acid ester-naphthalimide compound which is marked as LHX-1 and has the following structural formula:
the invention provides a preparation method of an MIDA boric acid ester-naphthalimide compound based on folic acid, which comprises the following steps:
(1) dissolving folic acid and anhydrous trifluoroacetic anhydride in a tetrahydrofuran solution, reacting at room temperature for 10-12 h, adding an ice-water mixture after the reaction is completed, extracting with diethyl ether, combining organic phases, spin-drying the solution, and drying to obtain light yellow powder; finally dissolving it in DMF solution, adding K2CO3Adjusting the pH value to 5.0-7.0, and keeping the temperature constantStirring at room temperature, adding trifluoroacetic acid for acidification, washing, and separating and purifying by column layer to obtain folic acid derivatives. Wherein the mol ratio of the folic acid to the anhydrous trifluoroacetic anhydride is 1: 2.5-1: 5.
(2) Dissolving folic acid derivatives and 4-bromo-1, 8-naphthalic anhydride in an ethanol solution, refluxing for 4-6 h at 78 ℃, cooling to room temperature, washing, and filtering to obtain 4-bromo-1, 8-naphthalimide compounds based on folic acid. Wherein the mol ratio of the folic acid derivative to the 4-bromo-1, 8-naphthalic anhydride is 1: 1-1: 3.
(3) Dissolving 4-bromo-1, 8-naphthalimide compounds based on folic acid into a methanol solution, adding sodium methoxide (NaOMe) to react at 65 ℃ for 30min by taking copper sulfate as a catalyst, adding HI to react at 40-55 ℃ for 3h, evaporating the solvent to obtain a milky yellow solid substance, drying, dissolving the milky yellow solid substance into TFA, adding Hexamethylenetetramine (HMTA) to react at 60-75 ℃ for 3-6 h, adding saturated saline solution, and adding CH2Cl2Extracting, evaporating the organic phase to dryness, and separating the column layer to obtain the naphthalimide compound based on folic acid. The mol ratio of the 4-bromo-1, 8-naphthalimide compound based on folic acid to NaOMe is 1: 1-1: 2; the mol ratio of the 4-bromo-1, 8-naphthalimide compound based on folic acid to copper sulfate is 1: 0.2-1: 0.5; the mol ratio of 4-bromo-1, 8-naphthalimide compounds to HI based on folic acid is 1: 1-1: 2.5; the mol ratio of the 4-bromo-1, 8-naphthalimide compound based on folic acid to hexamethylenetetramine is 1: 0.3-1: 0.6.
(4) Mixing a folic acid-based naphthalimide compound, N-methyliminodiacetic acid (MIDA) borate and K2CO3Dissolving in acetonitrile solution, stirring and reacting for 10-15 h at normal temperature under the protection of nitrogen; after the reaction is completed, filtering and rotary evaporating solvent, adding NaBH4And continuously reacting for 20-24 h at normal temperature, and separating a column layer to obtain the folic acid-based MIDA borate-naphthalimide compound. Wherein, naphthalimide compound based on folic acid, MIDA boric acid ester and K2CO3The molar ratio of (1: 1: 1.5) - (1: 1.5: 2); folic acid based naphthalimide compounds and NaBH4The molar ratio of (A) to (B) is 1:1 to 1: 1.5.
The mass spectrum and hydrogen spectrum of the folate-based MIDA borate-naphthalimide compound are shown in the figure 1 and the figure 2.
II, folate-based MIDA boric acid ester-naphthalimide compound LHX-1 is in H2O2Applications in assays
1. Fluorescent properties of LHX-1 and for H2O2Responsiveness capability
Fluorescence test was performed on a DMSO/PBS solution of LHX-1 (DMSO: PBS =1:9, c =3 μ M). The research shows that LHX-1 has no fluorescence emission performance due to the blocking effect of MIDA boric acid ester, and a fluorescent probe compound is in a quenching state (figure 3). When 45eq H was added2O2At an emission wavelength of 523nm, the fluorescence intensity reached a maximum, indicating LHX-1 vs. H2O2With good responsiveness (fig. 3).
2. LHX-1 to response H2O2Influence of (2)
For different concentrations of LHX-1 in DMSO/PBS (DMSO: PBS =1:9, lambda)ex=470 nm, λem=523 nm), detecting it with H2O2The response procedure of (2). Wherein, the concentration of the probe is selected from 0.2. mu.M, 0.5. mu.M, 1. mu.M, 2. mu.M, 3. mu.M, 5. mu.M, 10. mu.M and 15. mu.M for experimental test. The experimental results showed that the relative fluorescence intensity ratio was maximal when LHX-1 was 3. mu.M (FIG. 4). Therefore, LHX-1 detects H2O2The optimum concentration of (3) is chosen to be at this concentration.
3. Different pH values for LHX-1 response H2O2Influence of (2)
FIG. 5 is a graph showing the fluorescence response of LHX-1 of the present invention at various pH values. As can be seen, there is no H in the pH range of 1.0 to 8.02O2In the presence of the compound, the fluorescence of the compound is in a quenched state, i.e., the fluorescence intensity of the compound is not significantly changed. However, when 45eq H was added to the system2O2Then, as the pH value increases, the fluorescence intensity of LHX-1 also increases. The fluorescence intensity of LHX-1 reaches the maximum value in the range of pH = 5-6. Namely, under the weak acidic condition, LHX-1 has excellent optical properties, which indicates that LHX-1 has biological application potential.
4. LHX-1 to H2O2Single selective detection
In a DMSO/PBS solution of LHX-1 (DMSO: PBS =1:9, c =3 μ M), 45eq (relative to LHX-1) of metal ion K was added, respectively+、Na2+、Ca2+、Mg2+、Zn2+、Cu2+、Hg2+、Fe2+、Fe3+And active oxygen species H2O2、TBHP、HClO、KO2And NO, only H2O2Can make the DMSO/PBS solution of LHX-1 generate strong fluorescence at 523nm, and the metal ion K+、Na2+、Ca2+、Mg2+、Zn2+、Cu2+、Hg2+、Fe2+、Fe3+And active oxygen substances TBHP, HClO, KO2And NO did not cause significant changes in the fluorescence intensity of LHX-1 in DMSO/PBS (FIGS. 6 and 7). LHX-1 can therefore be directed to H2O2A single selective recognition is performed.
Adding 0-80 eq H to a DMSO/PBS solution of LHX-1 (DMSO: PBS =1:9, c =3 μ M)2O2A fluorescence titration experiment was performed (fig. 8). The results show that under acidic conditions (pH = 6.0) the compound LHX-1 fluorescence intensity increases significantly with increasing hydrogen peroxide concentration, up to saturation.
Based on the fluorescence titration experiment, H2O2Linear regression equation (K =20.740, R) with concentration within 0-45 eq2= 0.984), as shown in fig. 9. LHX-1 to H is obtained through equation calculation2O2The minimum detection limit of the LHX-1 is 0.25 mu M, which shows that the LHX-1 has very high sensitivity and the weak acidic condition is more beneficial to the improvement of the sensitivity of the LHX-1, and the LHX-1 serving as a drug carrier provides a powerful guarantee for monitoring the drug delivery and release in the complex intracellular environment.
5. LHX-1 to H2O2Detection mechanism of (2)
In the LHX-1, the naphthalimide compound with the fluorescent group based on folic acid is connected with the quenching group MIDA boric acid ester, and the naphthalimide compound based on folic acid is quenched by the MIDA boric acid esterDue to the fluorescence of the compound, LHX-1 has no fluorescence emission performance. At H2O2Under the stimulation of (3), quenching group MIDA boric acid ester is rapidly cracked to initiate electron transfer, and the cracking of the quenching group MIDA boric acid ester enables the fluorescence of the naphthalimide compound with the fluorescent group based on folic acid to be recovered and enhanced, thereby realizing the aim of H2O2High selectivity and sensitivity.
Preparation of LHX-CPT and medicine release performance
1. Preparation of LHX-CPT
LHX-1 is taken as a drug carrier, and the drug camptothecin CPT is loaded on the LHX-1, and the preparation method comprises the following steps: dissolving LHX-1 into ethanol, adding a medicine camptothecin CPT, and reacting for 5-6 hours at 75-80 ℃; after the reaction, the reaction mixture was cooled to room temperature, and saturated brine was added thereto and then the reaction mixture was reacted with CH2Cl2Carrying out extraction; extracting with anhydrous Na2SO4Drying, suction filtering, vacuum distilling to remove solvent, and separating column layer to obtain LHX-CPT. The molar ratio of LHX-1 to Camptothecin (CPT) is 1: 1.2-1: 2.5. The structure of LHX-CPT is as follows:
2. drug Release Properties
FIG. 10 shows LHX-CPT at H2O2In DMSO/PBS solution (pH = 6) versus CPT. As can be seen from the figure, the drug release rate was slow within the first 10 min; after 25 min, the release rate reaches 61 percent; after 45 min, the drug release rate reaches a stable state, which can reach 96%. From the above results, it is understood that the folate-based MIDA borate-naphthalimide compound sufficiently releases the anticancer drug CPT in a very short time under weakly acidic conditions.
3. Mechanism of controlled drug release
The method is characterized in that the MIDA borate-naphthalimide compound based on folic acid is used as a drug carrier, and the drug camptothecin CPT is loaded on the MIDA borate-naphthalimide compound based on folic acid to prepare LHX-CPT. LHX-CPT in H2O2Under stimulation, MIDA borate esterThe rapid cleavage and the initiation of electron transfer, the cleavage of the boric acid ester of the quenching group MIDA enables the fluorescence of the naphthalimide compound based on folic acid to be recovered and enhanced, and the LHX-CPT is promoted to carry out intramolecular elimination reaction (1, 4-elimination reaction) and rearrangement in the electron transfer process, and CO is accompanied2The molecule generation and the anticancer drug CPT are also released, and the generated fluorescence is gradually enhanced along with the release of the CPT, so that the drug release process can be monitored through the change of the fluorescence intensity.
In conclusion, the invention synthesizes the folate-based MIDA borate-naphthalimide compound which can respond to H by fluorescence through the special space structure of the MIDA borate regulation group2O2Can realize the H pair2O2Detection of (3). The folic acid-based MIDA borate-naphthalimide compound has the function of serving as a drug carrier, the drug camptothecin CPT is loaded on the folic acid-based MIDA borate-naphthalimide compound to obtain LHX-CPT, and a stable and acid-sensitive drug delivery system under neutral conditions (blood circulation) can be realized by means of an MIDA borate regulation and control mechanism. At H2O2In the enriched environment, the drug and the fluorescent compound with anticancer activity are released, and the purpose of monitoring the transmission and release of the drug is achieved through fluorescence signal transduction. Meanwhile, the folate-based MIDA boric acid ester-naphthalimide compound has high-efficiency targeting property by introducing the folate ligand, and can be used for endogenous H in living cells and living bodies2O2Detection and diagnosis and treatment of related diseases.
Drawings
FIG. 1 is a mass spectrum of LHX-1 of the present invention;
FIG. 2 is a hydrogen spectrum of LHX-1 of the present invention;
FIG. 3 shows LHX-1 and LHX-1+ H of the present invention2O2A fluorescence spectrum of (a);
FIG. 4 shows LHX-1 of the present invention at different concentrations of H2O2The fluorescence intensity of (1);
FIG. 5 shows LHX-1 and LHX-1+ H of the present invention2O2Fluorescence spectra at different pH values;
FIG. 6 shows the selectivity of LHX-1 of the present invention to different metal ions;
FIG. 7 is a graph of the selectivity of LHX-1 of the present invention to different reactive oxygen species;
FIG. 8 shows LHX-1 of the present invention for different concentrations of H2O2A fluorescence spectrum of (a);
FIG. 9 shows the variation of the concentration H of LHX-1 of the present invention at 523nm excitation wavelength2O2(0-45 eq) varying linear fit relationship;
FIG. 10 is a graph showing the release profile of LHX-CPT of the present invention to CPT under weakly acidic conditions.
Detailed Description
The preparation and use of LHX-1 and LHX-CPT of the present invention are further illustrated by the following specific examples.
EXAMPLE 1 preparation of LHX-1
(1) To a solution of 20 mL Tetrahydrofuran (THF), folic acid (FA, 2.3 mmol, 1.0 g) and 3mL anhydrous trifluoroacetic anhydride (TFAA) were added to completely dissolve the solid material. And then the mixture is placed at room temperature for acting for 10-12 h. After the reaction was completed, a certain amount of an ice-water mixture was added to the system, and extracted with diethyl ether. And (4) after the organic phases are combined, carrying out steaming drying treatment on the solution on a rotary steaming instrument, and drying to obtain yellow powder. Then dissolving it in DMF solution, and slowly adding K dropwise2CO3And stirring the system for 30-50 min at room temperature until the pH is 5.0-7.0. Finally, trifluoroacetic acid is added for acidification, water and ether are respectively used for washing, and the folic acid derivative A is obtained after column layer separation.
(2) Dissolving (1.2 mmol, 0.55 g) folic acid derivative A and 4-bromo-1, 8-naphthalic anhydride (1.0 mmol, 0.28 g) in 30 ml ethanol solution, refluxing at 78 ℃ for 4-6 h, cooling to room temperature, washing with water three times, and filtering to obtain 4-bromo-1, 8-naphthalimide compound B based on folic acid.
(3) Dissolving 4-bromo-1, 8-naphthalimide compound B (1.0 mmol, 0.70 g) based on folic acid in 20 mL of methanol solution, dropwise adding sodium methoxide (1.5 mmol) solution, adding copper sulfate (0.2-0.5 mmol, 0.03-0.08 g) as a catalyst, reacting at 65 ℃ for 30min,adding 1.5 mLHI, and reacting for 3 hours at 40-55 ℃ until the color becomes dark. And (5) evaporating the solvent to dryness to obtain a milky yellow solid substance. After drying, dissolving the intermediate compound into 10 ml of LTFA, adding 0.5mmol of Hexamethylenetetramine (HMTA), reacting for 3-6 h, adding saturated saline solution, and adding CH2Cl2Extracting, evaporating an organic phase to dryness, and separating a column layer to obtain the naphthalimide compound C based on folic acid.
(4) Folic acid-based naphthalimide compound C (1.0 mmol, 0.68 g) was added to a 20 ml acetonitrile solution and MIDA borate (1.2 mmol, 0.2 g) and K were added2CO3(1.5 mmol, 0.21 g), stirring at normal temperature for 10-15 h under the protection of nitrogen. After the reaction of the system is completed, the solvent is filtered and rotary evaporated. Then NaBH is added4(1.2 mmol, 0.2 g) was allowed to act for a further 24h and finally the folate based MIDA boronate-naphthalimide compound D was isolated via column chromatography. The yield was 62%.
The synthetic route of LHX-1 is as follows:
EXAMPLE 2 Synthesis of LHX-CPT
Dissolving folic acid-based MIDA borate-naphthalimide compound D (0.6 mmol, 0.56 g) in ethanol, adding camptothecin (CPT, 1.5 mmol, 0.52 g), and reacting at 80 deg.C for 5 h; after the reaction, the mixture was cooled to room temperature, poured into saturated brine and added with CH2Cl2Carrying out extraction; extracting with anhydrous Na2SO4Drying, vacuum filtering, distilling under reduced pressure to remove solvent, and separating with mixed eluent of dichloromethane and methanol to obtain LHX-CPT D. The yield was 46.7%.
The synthetic route of LHX-CPT is as follows:
example 3 LHX-1 vs. H2O2Detection of (2)
DMSO/PB in LHX-1To the S solution (DMSO: PBS =1:9, c =3 μ M), 45eq (metal ion K relative to LHX-1) was added, respectively+、Na2+、Ca2+、Mg2+、Zn2+、Cu2+、Hg2+、Fe2+、Fe3+And active oxygen species H2O2、TBHP、HClO、KO2And NO, if a DMSO/PBS solution of LHX-1 produces intense fluorescence at 523nm, then H is added2O2(ii) a If the fluorescence intensity of the DMSO/PBS solution of LHX-1 is not obviously changed, other metal ions and active oxygen substances are added.
Claims (10)
1. A folic acid-based MIDA borate-naphthalimide compound has the following structural formula:
2. the process for the preparation of folate based MIDA boronate-naphthalimide compounds according to claim 1, comprising the steps of:
(1) dissolving folic acid and anhydrous trifluoroacetic anhydride in a tetrahydrofuran solution, reacting at room temperature for 10-12 h, adding an ice-water mixture after the reaction is completed, extracting with diethyl ether, combining organic phases, spin-drying the solution, and drying to obtain light yellow powder; finally dissolving it in DMF solution, adding K2CO3Adjusting the pH value to 5.0-7.0, stirring at room temperature, adding trifluoroacetic acid for acidification, washing, and separating and purifying by a column layer to obtain a folic acid derivative;
(2) dissolving folic acid derivatives and 4-bromo-1, 8-naphthalic anhydride in an ethanol solution, refluxing for 4-6 h at 78 ℃, cooling to room temperature, washing, and filtering to obtain 4-bromo-1, 8-naphthalimide compounds based on folic acid;
(3) dissolving 4-bromo-1, 8-naphthalimide compounds based on folic acid into methanol solution, adding sodium methoxide into the methanol solution to react for 30min at 65 ℃ by taking copper sulfate as a catalyst, adding HI into the methanol solution to react for 3h at 40-55 ℃, and evaporating the solvent to drynessDrying to obtain a milk yellow solid substance, dissolving the milk yellow solid substance into TFA, adding hexamethylenetetramine, reacting at the temperature of 60-75 ℃ for 3-6 h, adding saturated salt water, and adding CH2Cl2Extracting, evaporating an organic phase to dryness, and separating a column layer to obtain a naphthalimide compound based on folic acid;
(4) mixing a folic acid-based naphthalimide compound, N-methyliminodiacetic acid borate and K2CO3Dissolving in acetonitrile solution, stirring and reacting for 10-15 h at normal temperature under the protection of nitrogen; after the reaction is complete, filtration is carried out, and NaBH is subsequently added to the filtrate4And continuously reacting for 20-24 h at normal temperature, and separating column layers to obtain the folate-based MIDA borate-naphthalimide compound LHX-1.
3. The process for the preparation of folic acid based 4-bromo-1, 8-naphthalimides according to claim 2, characterized in that: in the step (1), the mol ratio of folic acid to anhydrous trifluoroacetic anhydride is 1: 2.5-1: 5; in the step (2), the mol ratio of the folic acid derivative to the 4-bromo-1, 8-naphthalic anhydride is 1: 1-1: 3.
4. The process for preparing a folic-based 3, 4-substituted-1, 8-naphthalimide compound according to claim 2, wherein: in the step (3), the mol ratio of the 4-bromo-1, 8-naphthalimide compound based on folic acid to sodium methoxide is 1: 1-1: 2; the mol ratio of the 4-bromo-1, 8-naphthalimide compound based on folic acid to copper sulfate is 1: 0.2-1: 0.5; the mol ratio of 4-bromo-1, 8-naphthalimide compounds to HI based on folic acid is 1: 1-1: 2.5; the mol ratio of the 4-bromo-1, 8-naphthalimide compound based on folic acid to hexamethylenetetramine is 1: 0.3-1: 0.6.
5. The process for the preparation of folic acid based MIDA boronate-naphthalimide compounds according to claim 2, characterized in that: in the step (4), the naphthalimide compound based on folic acid, N-methyliminodiacetic acid boric acid ester and K2CO3The molar ratio of (1: 1: 1.5) - (1: 1.5: 2); folic acid-based naphthalimide compound and NaBH4The molar ratio of (A) to (B) is 1:1 to 1: 1.5.
6. Folic acid based MIDA boronate-naphthalimide compounds according to claim 1 in H2O2Application in detection.
7. Folic acid based MIDA boronate-naphthalimide compounds according to claim 6 in H2O2Use in detection, characterized by: adding metal ion K into DMSO/PBS solution of LHX-1+、Na2+、Ca2+、Mg2+、Zn2+、Cu2 +、Hg2+、Fe2+、Fe3+And active oxygen species H2O2、TBHP、HClO、KO2And NO, only H2O2The addition of the fluorescent dye can lead the DMSO/PBS solution of the LHX-1 to generate strong fluorescence at 523nm, and other metal ions and active oxygen substances can not lead the fluorescence intensity of the DMSO/PBS solution of the LHX-1 to be obviously changed; in the DMSO/PBS solution, the volume ratio of DMSO to PBS is 1: 6-1: 9.
8. Use of the folate-based MIDA boronate-naphthalimide class compound of claim 1 as a drug delivery vehicle.
9. Use of folate based MIDA boronate-naphthalimide class compounds as drug delivery vehicles according to claim 8, characterized in that: dissolving the MIDA boric acid ester-naphthalimide compound LHX-1 based on folic acid into ethanol, adding a drug camptothecin CPT, and reacting at 75-80 ℃ for 5-6 h; after the reaction, the reaction mixture was cooled to room temperature, and saturated brine was added thereto and then the reaction mixture was reacted with CH2Cl2Carrying out extraction; extracting with anhydrous Na2SO4Drying, suction filtering, reduced pressure distillation to remove solvent, and column layer separation to obtain target product LHX-CPT.
10. Use of folate based MIDA boronate-naphthalimide class compounds as drug delivery vehicles according to claim 9, characterized in that: the mol ratio of the folate-based MIDA borate-naphthalimide compound to the camptothecin CPT is 1: 1.2-1: 2.5.
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