CN115010725B - Amphiphilic small molecule prodrug as well as preparation method and application thereof - Google Patents

Amphiphilic small molecule prodrug as well as preparation method and application thereof Download PDF

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CN115010725B
CN115010725B CN202210628156.9A CN202210628156A CN115010725B CN 115010725 B CN115010725 B CN 115010725B CN 202210628156 A CN202210628156 A CN 202210628156A CN 115010725 B CN115010725 B CN 115010725B
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small molecule
amphiphilic small
prodrug
molecule prodrug
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CN115010725A (en
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王耀
麦智健
曾志雯
周国富
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South China Normal University
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Abstract

The invention discloses an amphiphilic small molecule prodrug, a preparation method and application thereof, wherein the amphiphilic small molecule prodrug is prepared from a connecting group which is easy to acidolysis
Figure DDA0003678670420000011
The hydrophilic anticancer drug and the hydrophobic fluorescent probe are connected, and the hydrophilic anticancer drug and the hydrophobic fluorescent probe can be self-assembled in water to form nano particles which are taken up by cells; due to the carbon nitrogen isomerization effect of the connecting groups, the amphiphilic small molecule prodrug has no fluorescence phenomenon, and after being taken up by cancer cells, the connecting groups are broken down in the low pH environment of the cancer cells to release fluorescent probes and anticancer drugs, so that the amphiphilic small molecule prodrug can be selectively and slowly decomposed in the cancer cells, and the purpose of cancer cell specific imaging is realized while the drugs are released from specific sites, thereby achieving the effect of cancer treatment and diagnosis; the small molecular prodrug with self-luminous property is a small molecular self-assembly body, and a high molecular drug delivery carrier does not exist, so that the defect that the high molecular is difficult to degrade in a human body is avoided.

Description

Amphiphilic small molecule prodrug as well as preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to an amphiphilic small molecule prodrug, and a preparation method and application thereof.
Background
The cancer medicine can reach target site to reach pathological treatment and has diagnosis and treatment effect. Cancer drug molecules have been attracting more and more attention in recent years, and therapeutic diagnostics is a new discipline for this purpose. Typical drug delivery systems with diagnostic effects employ, for example: the liposome, polymer, micelle, solid nano-particle, antibody and other modes are used for simultaneously wrapping the medicine and the contrast agent so as to achieve the aim of treatment and diagnosis. However, these nanocarriers often have no therapeutic effect and are not easily degraded, and are extremely prone to side effects on kidneys or other organs.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides an amphiphilic small molecule prodrug, and a preparation method and application thereof.
In a first aspect of the present invention, an amphiphilic small molecule prodrug is provided, which has a structure as shown in general formula (i):
Figure BDA0003678670400000011
wherein L is 1 To L 4 Each independently selected from the group consisting of hydrogen atoms H,
Figure BDA0003678670400000012
And R is a hydrophilic anticancer drug; and L is 1 To L 4 Not all H. That is, L 1 To L 4 None of which may be H, or 1,2 or 3 of which may be H; in addition, L 1 、L 2 、L 3 And L 4 May be the same or different.
According to the amphiphilic small molecule prodrug disclosed by the embodiment of the invention, the amphiphilic small molecule prodrug has at least the following beneficial effects: the amphiphilic small molecule prodrug is a conjugated compound of an anticancer drug and a fluorescent probe, and specifically passes through a connecting group easy to acidolysis
Figure BDA0003678670400000013
Is composed of a hydrophilic anticancer drug and a hydrophobic fluorescent probe, and is provided with a hydrophobic material (fluorescent probe) -connecting group +.>
Figure BDA0003678670400000014
Figure BDA0003678670400000015
Hydrophilic material (anticancer drug) "structure, which has both hydrophilic and hydrophobic ends, can self-assemble in water to form nanoparticles and be taken up by cells (including normal cells and cancer cells). In addition, due to the carbon nitrogen isomerization of the connecting group, the small molecular prodrug has no obvious fluorescence phenomenon, and after the small molecular prodrug is ingested by cancer cells, the connecting group can be broken down in the low pH environment in the cancer cells due to the low pH value of lysosomes (generally 3.8-4.7) in the cancer cells, and fluorescent probes and anticancer drugs are released, so that the small molecular prodrug can be selectively and slowly decomposed in the cancer cells, and the specific of the cancer cells can be realized while the drugs are released at specific sitesImaging and drug release visualization, and achieves the effect of cancer treatment diagnosis and treatment. In addition, the small molecular prodrug with self-luminous property is a small molecular self-assembly body, and a drug delivery carrier of a polymer does not exist, so that the defect that the polymer is difficult to degrade in a human body can be avoided. />
In some embodiments of the invention, L 1 To L 4 At least one of them is H, i.e. L 1 To L 4 May have 1,2 or 3 of them as H.
Specifically, the amphiphilic small molecule prodrug can be abbreviated as TPE- (n) imine-d, and n represents L 1 To L 4 In (a)
Figure BDA0003678670400000021
Figure BDA0003678670400000022
Is a number of (3). In some embodiments of the invention, L 1 To L 4 One of them is selected from
Figure BDA0003678670400000023
Figure BDA0003678670400000024
The rest is selected from H, namely the amphiphilic small molecule prodrug is TPE- (1) imine-d, and the structural formula can be as follows:
Figure BDA0003678670400000025
wherein R is 1 Is a hydrophilic anticancer drug.
In some embodiments of the invention, L 1 To L 4 Two of which are selected from
Figure BDA0003678670400000026
The rest is selected from H, and the structural formula of the amphiphilic small molecule prodrug TPE- (2) imine-d can be any one of the following formulas:
Figure BDA0003678670400000027
Figure BDA0003678670400000031
wherein R is 1 、R 2 Is hydrophilic anticancer medicine, R 1 、R 2 May be the same or different.
In some embodiments of the invention, L 1 To L 4 Three of which are selected from
Figure BDA0003678670400000032
The rest is selected from H, and the structural formula of the amphiphilic small molecule prodrug TPE- (3) imine-d can be any one of the following formulas: />
Figure BDA0003678670400000033
Figure BDA0003678670400000034
Wherein R is 1 、R 2 、R 3 Is hydrophilic anticancer medicine, R 1 、R 2 、R 3 May be the same or different.
In some embodiments of the invention, L 1 To L 4 Are all selected from
Figure BDA0003678670400000035
The structural formula of the amphiphilic small molecule prodrug TPE- (4) imine-d can be any one of the following formulas:
Figure BDA0003678670400000036
Figure BDA0003678670400000041
wherein R is 1 、R 2 、R 3 、R 4 Is hydrophilic anticancer medicine, R 1 、R 2 、R 3 、R 4 May be the same or different.
In some embodiments of the invention, the hydrophilic anticancer drug is selected from any one of lenalidomide, cidamine, doxorubicin, gemcitabine, vincristine.
In a second aspect of the present invention, a method for preparing any one of the amphiphilic small molecule prodrugs according to the first aspect of the present invention is provided, comprising the steps of:
the compound A and the hydrophilic anticancer drug are prepared through condensation reaction;
the structural formula of the compound A is as follows:
Figure BDA0003678670400000042
wherein M is 1 、M 2 、M 3 And M 4 Each independently selected from H, -NH 2 or-CHO, and M 1 、M 2 、M 3 And M 4 Not all H.
Specifically, the compound A and the hydrophilic anticancer drug are mixed with a solvent to prepare the amphiphilic small molecule prodrug of the product through condensation reaction, wherein the solvent can adopt ethanol, dichloromethane, ethyl acetate and the like. The condensation reaction principle of the compound A and the hydrophilic anticancer drug is mainly that the carbon-nitrogen double bond is formed by condensing amine and active carbonyl, so that the hydrophilic anticancer drug is connected into the compound A. Thus, when compound A contains-NH 2 or-CHO as active group, hydrophilic anticancer drug correspondingly contains-CHO or-NH 2 。
In some embodiments of the invention, compound a is compound a 1 And Compound A 2 Prepared by a maxmery coupling reaction;
the compound A 1 Is of the structure of
Figure BDA0003678670400000043
The compound A 2 Is of the structure of
Figure BDA0003678670400000044
Wherein M is 1 、M 2 、M 3 And M 4 As defined above.
Wherein, after the completion of the Maxmery coupling reaction, the purification treatment is also included. The purification treatment can be specifically carried out by extracting and filtering the filtrate, then extracting, spin-drying, and then carrying out column chromatography separation; the extraction can be carried out by adopting ethyl acetate as an extractant, and the column chromatography separation can be carried out by adopting a mixed solution of dichloromethane and methanol with the mass ratio of 10:1 as an eluent.
In some embodiments of the invention, the temperature of the condensation reaction is controlled between 80 and 100 ℃, further between 80 and 90 ℃, for example, 85 ℃.
In some embodiments of the invention, the condensation reaction is performed under an inert atmosphere. The inert atmosphere may be nitrogen, helium, neon, or the like.
In some embodiments of the invention, the condensation reaction is carried out under the action of a catalyst selected from at least one of formic acid, acetic acid, p-toluenesulfonic acid, piperidine.
In some embodiments of the invention, the condensation reaction is completed before further comprising a purification treatment. The purification treatment can be specifically carried out by rotary evaporation to obtain a crude product, further purifying by column chromatography, further carrying out rotary evaporation treatment, and finally carrying out vacuum heating; wherein, ethyl acetate can be used as eluent for column chromatography purification.
In a third aspect, the present invention provides an application of any amphiphilic small molecule prodrug provided in the first aspect in preparing an anticancer drug, or in tumor cell imaging for non-disease diagnosis or treatment purposes, or in visual drug delivery for non-disease diagnosis or treatment purposes.
In the amphiphilic small molecule prodrug of the invention, when the substituent structure appears
Figure BDA0003678670400000051
Indicating that the atom is a bonding atom, e.g.>
Figure BDA0003678670400000052
Represents that the carbon atom in the carbon-nitrogen double bond is a bonding atom. />
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a hydrogen spectrum of the compound A produced in example 1;
FIG. 2 is a hydrogen spectrum of the amphiphilic small molecule prodrug prepared in example 1;
FIG. 3 is a hydrogen spectrum of the compound A produced in example 5;
FIG. 4 is a graph showing the comparison of fluorescence of the amphiphilic small molecule prodrug prepared in example 1 after excitation by irradiation with 365nm ultraviolet lamp at different pH values;
FIG. 5 is a graph showing fluorescence emission spectra of the amphiphilic small molecule prodrug prepared in example 1 at different pH values;
FIG. 6 is a graph showing the particle size measurement of the self-assembled nanoparticles formed in an aqueous environment of the amphiphilic small molecule prodrug prepared in example 1;
FIG. 7 is a graph showing comparison of L929 cells and 4T1 cells viability at different concentrations of amphiphilic small molecule prodrug prepared in example 1;
FIG. 8 is a fluorescence imaging diagram of the amphiphilic small molecule prodrug prepared in example 1 in normal cells and cancer cells;
FIG. 9 is a schematic diagram of the trigger mechanism of the amphiphilic small molecule prodrug prepared in example 1 in cancer cells.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Example 1
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000061
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, preparing the compound 4- (1, 2-triphenylvinyl) benzaldehyde by adopting 4-benzoyl benzaldehyde and benzophenone through a MaxCari coupling reaction. Specifically, zinc powder (3.3 g), 4-benzoyl benzaldehyde (2.7 g) and benzophenone (2.5 g) are added into a fully dried 250mL two-neck round bottom flask, the mixture is circulated for 3 times, vacuumizing and argon filling are carried out, 100mL of ultra-dry Tetrahydrofuran (THF) is injected under argon atmosphere, the mixture is placed into a liquid nitrogen acetone bath for cooling to minus 78 ℃, titanium tetrachloride (2.9 mL) is slowly added dropwise, after the dropwise addition, the reaction mixture is continuously stirred for 15min, the liquid nitrogen acetone bath is removed, the reaction system is gradually restored to room temperature and continuously stirred for half an hour, and finally, the mixture is heated to 80 ℃ for reflux for 12h. Quenching the reaction with 1mol/L hydrochloric acid, filtering, extracting the filtrate with ethyl acetate, spin-drying, and using dichloromethane with the ratio of 10:1: methanol is used as eluent, and is separated by column chromatography to obtain compound A, namely 4- (1, 2-triphenylvinyl) benzaldehyde (4.16 g), which is characterized by Nuclear Magnetic Resonance (NMR) hydrogen (shown in figure 1), 1 H NMR(600MHz,Chloroform-d)δ9.93(s,1H),7.65(s,2H),7.24(s,2H),7.11(d,J＝66.9Hz,15H).
s2, preparing the amphiphilic micromolecule prodrug by adopting a compound 4- (1, 2-triphenylvinyl) benzaldehyde and an anticancer drug lenalidomide through catalytic reaction. Specifically, a mixture of 4- (1, 2-triphenylvinyl) benzaldehyde (0.100 g) and lenalidomide (0.115 g) prepared in step S1 in ethanol (20 mL) was added to a reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 After protection under an atmosphere and heating overnight at 85 ℃, the reaction mixture was evaporated on a rotary evaporator at 40 ℃ and the crude product obtained was further purified by column chromatography (eluent: ethyl acetate). Continuously removing ethyl acetate by using a rotary evaporator, and finally drying the obtained crude product in vacuum at 60 ℃ for 12 hours to finally obtain the product compound I 1 I.e., the amphiphilic small molecule prodrug, was a yellow solid with a yield of 83.6% (0.166 g). The nuclear magnetic resonance hydrogen spectrum is used for characterizing the amphiphilic small molecule prodrug of the product (shown in figure 2), 1 H NMR(600MHz,DMSO-d 6 )δ10.98(s,1H),8.64(s,1H),7.74(s,2H),7.60(s,2H),7.45(s,1H),7.15(s,12H),7.01(s,5H),5.13(s,1H),4.47(s,1H),4.35(s,1H),2.91(s,1H),2.57(s,1H),2.44(s,1H),1.98(s,1H).
example 2
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000071
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, the operation of step S1 in this embodiment is the same as that in embodiment 1.
S2, preparing the amphiphilic small molecule prodrug by adopting a catalytic reaction of a compound 4- (1, 2-triphenylvinyl) benzaldehyde and an anticancer drug doxorubicin. Specifically, a mixture of 4- (1, 2-triphenylvinyl) benzaldehyde (0.100 g) and doxorubicin (0.237 g) in ethanol (20 mL) was added to the reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 Protecting under atmosphere and heating at 85deg.C overnight, evaporating the reaction mixture at 40deg.C on rotary evaporator, further purifying the obtained crude product by column chromatography, evaporating ethyl acetate as eluent by rotary evaporator, and vacuum drying the obtained crude product at 60deg.C for 12 hr to obtain the final product compound I 2 Namely, the amphiphilic small molecule prodrug, which is an orange-red solid with a yield of 73.5% (0.289 g). The amphiphilic small molecule prodrug of the product is characterized by nuclear magnetic resonance hydrogen spectrum, 1 H NMR(600MHz,DMSO-d 6 )δ12.04(s,2H)8.61(s,1H),7.90(s,1H),7.82(s,1H),7.78(s,2H),7.66(s,2H),7.45(s,12H),7.38(s,1H),7.31(s,3H),5.73(s,1H),5.39(s,1H),4.67(s,1H),4.58(d,1H),4.08(q,1H),3.94(d,1H),3.91(s,1H),3.75(s,1H),3.60(s,2H),3.55(s,1H),3.39(t,1H),3.23(t,1H),3.05(s,1H),2.81(s,1H),2.15(s,1H),1.99(t,1H),1.93(s,1H),1.70(t,1H),1.11(s,1H).
example 3
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000081
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, the operation of step S1 in this embodiment is the same as that in embodiment 1.
S2, preparing the amphiphilic micromolecular prodrug by adopting a compound 4- (1, 2-triphenylvinyl) benzaldehyde and an anticancer drug of ciladamine through catalytic reaction. Specifically, a mixture of 4- (1, 2-triphenylvinyl) benzaldehyde (0.100 g) and ethanol (20 mL) of cetostelamine (0.173 g) was added to the reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 Protecting under atmosphere and heating at 85deg.C overnight, evaporating the reaction mixture at 40deg.C on rotary evaporator, further purifying the obtained crude product by column chromatography, evaporating ethyl acetate as eluent by rotary evaporator, and vacuum drying the obtained crude product at 60deg.C for 12 hr to obtain the final product compound I 3 I.e., the amphiphilic small molecule prodrug, was a white solid in 79.3% (0.258 g) yield. The amphiphilic small molecule prodrug of the product is characterized by nuclear magnetic resonance hydrogen spectrum, 1 H NMR(600MHz,DMSO-d 6 )δ11.48(s,1H)8.95(t,1H),8.84(s,1H),8.64(s,2H),7.98(s,1H),7.90(s,2H),7.75(s,3H),7.70(s,1H),7.64(s,2H),7.55(s,1H),7.45(s,12H),7.34(s,2H),7.30(s,3H),7.22(s,1H),7.04(s,1H),6.46(s,1H),4.34(s,2H).
example 4
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000082
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, the operation of step S1 in this embodiment is the same as that in embodiment 1.
S2, adopting a compound 4- (1, 2-triphenylethylene)Base) benzaldehyde and anticancer drug gemcitabine are subjected to catalytic reaction to prepare the amphiphilic small molecule prodrug. Specifically, a mixture of 4- (1, 2-triphenylvinyl) benzaldehyde (0.100 g) and gemcitabine (0.117 g) in ethanol (20 mL) was added to the reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 Protecting under atmosphere and heating at 85deg.C overnight, evaporating the reaction mixture at 40deg.C on rotary evaporator, further purifying the obtained crude product by column chromatography, evaporating ethyl acetate as eluent by rotary evaporator, and vacuum drying the obtained crude product at 60deg.C for 12 hr to obtain the final product compound I 4 Namely, the amphiphilic small molecule prodrug, which is a pale yellow solid, has a yield of 80.7% (0.217 g). The amphiphilic small molecule prodrug of the product is characterized by nuclear magnetic resonance hydrogen spectrum, 1 H NMR(600MHz,DMSO-d 6 )δ8.94(s,1H),8.24(s,1H),7.76(s,2H),7.65(s,2H),7.45(s,12H),7.31(s,3H),7.23(s,1H),5.57(s,1H),5.25(d,1H),4.43(m,1H),4.36(d,1H),3.97(t,1H),3.54(t,1H),3.48(s,1H).
example 5
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000091
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, preparing a compound 1- (4-aminophenyl) -1, 2-triphenylethylene by adopting 4-aminobenzophenone and benzophenone through a MaxCari coupling reaction. Specifically, zinc powder (3.3 g), 4-aminobenzophenone (2.5 g) and benzophenone (2.5 g) were put into a sufficiently dried 250mL two-necked round bottom flask, circulated 3 times, and subjected to vacuum pumping and argon filling operation, and 100mL of ultra-dry tetrahydrofuran was injected under argon atmosphere. The mixture was cooled to-78℃in a liquid nitrogen acetone bath, titanium tetrachloride (2.9 mL) was slowly added dropwise, and after the dropwise addition was completed, the reaction mixture was stirred for an additional 15min. The liquid nitrogen acetone bath was removed and the reaction was gradually brought to room temperature and stirred for half an hour. Finally, the mixture was heated to 80℃and refluxed for 12 hours. The reaction is completed,quenching the reaction with 1mol/L hydrochloric acid, filtering, extracting the filtrate with ethyl acetate, spin-drying, and using dichloromethane with the ratio of 10:1: methanol is used as eluent, and is separated by column chromatography to obtain compound A, namely 1- (4-aminophenyl) -1, 2-triphenylethylene (4.16 g), the compound A is characterized by nuclear magnetic resonance hydrogen spectrum (shown in figure 3), 1 H NMR(600MHz,Chloroform-d)δ7.08(d,J＝20.3Hz,15H),6.86(s,2H),6.47(s,2H),3.65(s,2H).
s2, preparing the amphiphilic small molecule prodrug by adopting a catalytic reaction of a compound 1- (4-aminophenyl) -1, 2-triphenylethylene and an anticancer drug vincristine. Specifically, a mixture of 1- (4-aminophenyl) -1, 2-triphenylethylene (0.096 g) and vincristine (0.366 g) prepared in step S1 in ethanol (20 mL) was added to a reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 Protecting under atmosphere and heating at 85deg.C overnight, evaporating the reaction mixture at 40deg.C on rotary evaporator, further purifying the obtained crude product by column chromatography, evaporating ethyl acetate as eluent by rotary evaporator, and vacuum drying the obtained crude product at 60deg.C for 12 hr to obtain the final product compound I 5 I.e., amphiphilic small molecule prodrug, as a white solid in 65.8% (0.341 g) yield. The amphiphilic small molecule prodrug of the product is characterized by nuclear magnetic resonance hydrogen spectrum, 1 H NMR(600MHz,DMSO-d 6 )δ11.67(s,1H),8.54(s,1H),7.84(s,1H),7.53(s,1H),7.45(s,14H),7.40(s,1H),7.31(s,3H),7.22(s,2H),6.93(s,1H),6.85(s,1H),6.23(s,1H),5.81(s,1H),5.73(s,1H),5.23(s,1H),5.17(s,1H),5.03(s,1H),3.77(s,3H),3.63(s,6H),3.48(s,1H),3.38(d,1H),3.26(d,1H),2.63(t,2H),2.56(d,2H),2.53(t,1H),2.40(t,3H),2.33(t,2H),2.25(d,1H),2.15(t,1H),2.03(t,4H),1.93(s,1H),1.75(s,1H),1.66(s,1H),1.58(t,2H),1.40(t,2H),1.24(t,2H),0.91(t,6H).
example 6
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000101
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, preparing a compound 1, 1-diphenyl-2, 2-di (4-aldehyde-based styrene) by adopting benzophenone-4, 4' -dicarboxaldehyde and benzophenone through a MaxCari coupling reaction. Specifically, zinc powder (3.3 g), benzophenone-4, 4' -dicarboxaldehyde (2.9 g) and benzophenone (2.5 g) are added into a fully dried 250mL two-neck round bottom flask, the mixture is circulated for 3 times, vacuumizing and argon filling are carried out, 100mL of ultra-dry Tetrahydrofuran (THF) is injected under argon atmosphere, the mixture is placed into a liquid nitrogen acetone bath for cooling to minus 78 ℃, titanium tetrachloride (2.9 mL) is slowly added dropwise, after the dropwise addition, the reaction mixture is continuously stirred for 15min, the liquid nitrogen acetone bath is removed, the reaction system is gradually restored to room temperature and continuously stirred for half an hour, and finally, the mixture is heated to 80 ℃ for reflux for 12h. Quenching the reaction with 1mol/L hydrochloric acid, filtering, extracting the filtrate with ethyl acetate, spin-drying, and using dichloromethane with the ratio of 10:1: methanol is used as an eluent, and the compound A, namely 1, 1-diphenyl-2, 2-di (4-aldehyde-styrene) ethylene (4.19 g) is obtained through column chromatography separation, and the compound A is characterized by nuclear magnetic resonance hydrogen spectrum. 1 H NMR(600MHz,Chloroform-d)δ9.93(s,2H),7.65(s,2H),7.24(s,2H),7.11(d,J＝66.9Hz,14H).
S2, preparing the amphiphilic small molecule prodrug by adopting a catalytic reaction of a compound of 1, 1-diphenyl-2, 2-di (4-aldehyde-based styrene) and an anticancer drug of lenalidomide. Specifically, a mixture of 1, 1-diphenyl-2, 2-bis (4-aldehydylstyrene) ethylene (0.110 g) obtained in step S1 and ethanol (30 mL) of lenalidomide (0.23 g) was added to the reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 Protecting under atmosphere and heating at 85deg.C overnight, evaporating the reaction mixture at 40deg.C on rotary evaporator, further purifying the obtained crude product by column chromatography, evaporating ethyl acetate as eluent by rotary evaporator, and vacuum drying the obtained crude product at 60deg.C for 12 hr to obtain the final product compound I 6 I.e., the amphiphilic small molecule prodrug, was a yellow solid in 67.3% (0.257 g) yield. Characterization of Compound I using Nuclear magnetic resonance Hydrogen Spectroscopy 6 。 1 H NMR(600MHz,DMSO-d6)δ10.98(s,2H),8.64(s,2H),7.74(s,2H),7.60(s,2H),7.45(s,2H),7.15(s,12H),7.01(s,5H),5.13(s,1H),4.47(s,5H),4.35(s,2H),2.91(s,2H),2.57(s,1H),2.44(s,3H),1.98(s,1H).
Example 7
The amphiphilic small molecule prodrug is prepared in the embodiment, and the synthetic route is as follows:
Figure BDA0003678670400000111
the specific synthesis method of the amphiphilic small molecule prodrug comprises the following steps:
s1, preparing a compound tetra-aldehyde tetraphenyl ethylene by adopting benzophenone-4, 4' -dicarboxaldehyde through a MaxMerrily coupling reaction. Specifically, zinc powder (3.3 g) and benzophenone-4, 4' -dicarboxaldehyde (5.6 g) are added into a fully dried 250mL two-neck round bottom flask, the mixture is circulated for 3 times, vacuumizing and argon filling operation are carried out, ultra-dry Tetrahydrofuran (THF) is injected under argon atmosphere, the mixture is placed into a liquid nitrogen acetone bath for cooling to minus 78 ℃, titanium tetrachloride (2.9 mL) is slowly added dropwise, after the dropwise addition, the reaction mixture is continuously stirred for 15min, the liquid nitrogen acetone bath is removed, the reaction system is gradually restored to room temperature and continuously stirred for half an hour, and finally, the mixture is heated to 80 ℃ for reflux for 12h. Quenching the reaction with 1mol/L hydrochloric acid, filtering, extracting the filtrate with ethyl acetate, spin-drying, and using dichloromethane with the ratio of 10:1: methanol was used as an eluent, and the compound a, namely tetra-aldehyde tetrastyrene (4.35 g), was isolated by column chromatography using nuclear magnetic resonance hydrogen spectroscopy. 1 H NMR(600MHz,Chloroform-d)δ9.93(s,4H),7.65(s,2H),7.24(s,2H),7.11(d,J＝66.9Hz,12H).
S2, preparing the amphiphilic small molecule prodrug by adopting a compound tetra-aldehyde tetraphenyl ethylene and anticancer drug lenalidomide through catalytic reaction. Specifically, a mixture of step S1 tetra-aldehydetetrastyrene (0.171 g) and ethanol (60 mL) of lenalidomide (0.46 g) was added to the reaction flask, and a trace amount of formic acid was added as a catalyst. At N 2 After protection under an atmosphere and heating overnight at 85 ℃, the reaction mixture was evaporated on a rotary evaporator at 40 ℃ and the crude product obtained was further purified by column chromatography, ethyl acetate as eluent, continued evaporation using rotary evaporator, mostDrying the obtained crude product in vacuum at 60 ℃ for 12 hours to finally obtain the product compound I 7 I.e. amphiphilic small molecule prodrug, as yellow solid in 58.7% yield (0.360 g) as characterized by nuclear magnetic resonance hydrogen spectrum 7 。 1 H NMR(600MHz,DMSO-d6)δ10.98(s,4H),8.64(s,5H),7.74(s,6H),7.60(s,8H),7.45(s,4H),7.15(s,12H),7.01(s,5H),5.13(s,2H),4.47(s,1H),4.35(s,4H),2.91(s,4H),2.57(s,1H),2.44(s,4H),1.98(s,4H).
Experimental example 8
(one) fluorescent Property test
Firstly, the fluorescence property of the amphiphilic small molecule prodrug prepared in the embodiment 1 is tested, and the specific test method comprises the following steps: 0.00602g of the product compound I obtained in example 1 are weighed out 1 Powder, 1X 10 using 1mL volumetric flask -2 The mol/L solvent is a mother solution of dimethyl sulfoxide (DMSO). 50. Mu.L of 1X 10 reagent were added to each of two clean reagent bottles -2 The mother solution of mol/L is added into the reagent bottles respectively with 4.95mL of PBS buffer solution with pH of 7.4 and pH of 5.0, so that the volumes of the solutions in the two reagent bottles are 5mL, the solution is ensured to be fully mixed, and the concentration of the obtained test sample is 1 multiplied by 10 -4 mol/L, buffer solution content of sample (f w ) 99%. The two groups of samples are simultaneously excited by irradiation of an ultraviolet lamp, and the fluorescence conditions of the samples are observed, particularly the fluorescence conditions under the excitation of the 365nm ultraviolet lamp are shown in fig. 4. It was found from the test that the two groups of samples were excited simultaneously using a 365nm uv lamp that the test sample at pH 7.4 did not fluoresce, whereas the test sample at pH 5.0 emitted intense green fluorescence with a maximum emission wavelength of 500nm.
In addition, fluorescence intensities of the two groups of samples were measured, and the obtained fluorescence emission spectra are shown in fig. 5. The fluorescence intensity test result shown in fig. 5 verifies the fluorescence emission property of the amphiphilic small molecule prodrug at the pH of 5.0, and the maximum emission wavelength is 500nm; and at a pH of 7.4, there is substantially no visible fluorescence.
(II) self-Assembly Property test
In order to prove that the amphiphilic small molecule prodrug can self-assemble in water environment,the related self-assembly test is carried out, and the specific test method comprises the following steps: 0.00602g of the compound I obtained in example 1 are weighed out 1 Powder was prepared to a concentration of 1X 10 using a 1mL volumetric flask -2 molar/L dimethyl sulfoxide (DMSO) mother liquor. Subsequently, 30. Mu.L of 1X 10 was added to a clean reagent bottle - 2 The mother solution of mol/L is added with 2.97mL PBS buffer solution with pH of 7.4 to prepare 1 multiplied by 10 -4 An aqueous dispersion of mol/L. The formed nanoparticles were then measured using a nanoparticle size and Zeta potential analyzer, and the results are shown in fig. 6. From the test results, the amphiphilic small molecule prodrug of the embodiment 1 self-assembles in water environment to form particles with the particle size of about 80nm, so that the particles can be conveniently absorbed by cells.
(III) Effect cancer cell Property test
To verify the effect of the amphiphilic small molecule prodrug on the cell level in the present application, first, the aqueous dispersion of the amphiphilic small molecule prodrug prepared in example 1 with different concentrations (1.0, 5.0, 10.0, 20.0, 40.0 μg/mL) was incubated with normal cells (L929) and cancer cells (4T 1) for 24 hours respectively, and the survival rates of the two cells at different concentrations were examined, and the obtained results are shown in fig. 7, wherein (a) in fig. 7 indicates the survival rate of the L929 cells at different amphiphilic small molecule prodrug concentrations, and (b) indicates the survival rate of the 4T1 cells at different amphiphilic small molecule prodrug concentrations. As shown in the results of FIG. 7, when the concentration of the amphiphilic small molecule prodrug solution is as high as 40 mug/mL, the survival rate of L929 cells is still higher than 80%, and the survival rate of the cells in 4T1 cells is obviously reduced along with the increase of the concentration of the amphiphilic small molecule prodrug solution, so that the amphiphilic small molecule prodrug has the effect of selectively killing cancer cells under the concentration, and can be used for treatment and diagnosis of the cancer cells.
Further, the imaging specificity of the amphiphilic small molecule prodrug is continuously researched, and the specific detection method comprises the following steps: fluorescence imaging detection ability of the amphiphilic small molecule prodrug prepared in example 1 on normal cells and cancer cells was studied using a fluorescence microscope. Taking 4T1 cancer cells and L929 normal cells as model cells, and respectively adding 30 mu L of 1×10 cells in the culture process of the two model cells -4 Two of mol/LAn aqueous dispersion of the affinity small molecule prodrug was incubated for 24 hours and photographed by a fluorescence microscope. The detection results are shown in FIG. 8, wherein (a) is a fluorescence image of the cells, (b) is an imaging image corresponding to the cells in the bright field state, and (c) is an imaging image corresponding to the cells (a) and (b) after overlapping, and the scales of the icons are the same and are 10 μm. The detection result shows that the cell incubated by the amphiphilic small molecular prodrug prepared in the embodiment 1 has weak fluorescent signal in a simulated normal cell environment (pH 7.4), and obvious fluorescent signal in a weak acid microenvironment (pH 5.0) of cancer cells, the fluorescent signal is uniformly dispersed, and the result shown in fig. 8 proves the specificity of the amphiphilic small molecular prodrug in cell imaging in an organism.
From the above, the amphiphilic small molecule prodrug prepared in the above example is a conjugated compound of an anticancer drug and a fluorescent probe, which specifically passes through a connecting group easy to acidolysis
Figure BDA0003678670400000131
Is connected with hydrophilic anticancer drugs and hydrophobic fluorescent probes, and can be regarded as hydrophobic material (fluorescent probes) -connecting group +.>
Figure BDA0003678670400000132
Hydrophilic material (anticancer drug) ", which has both hydrophilic and hydrophobic ends, can self-assemble in water to form nanoparticles and be taken up by cells (normal and cancer cells). In addition, due to the carbon nitrogen isomerization effect of the connecting groups, the small molecular prodrug has no obvious fluorescence phenomenon, and when the small molecular prodrug is taken up by cancer cells, the amphiphilic small molecular prodrug obtained in the embodiment 1 is taken as an example, the action mechanism of the amphiphilic small molecular prodrug is shown in fig. 9, specifically, the connecting groups can be broken down in a low pH environment in the cancer cells due to the low pH value of lysosomes in the cancer cells (generally 3.8-4.7), and fluorescent probes and anticancer drugs are released, so that the small molecular prodrug is selectively and slowly decomposed in the cancer cells, and the purposes of cancer cell specific imaging and drug release visualization can be realized while the drugs are released at specific sites, thereby achieving the effect of cancer treatment and diagnosis. In addition, the small molecule prodrug with self-luminous property is a self-assembly body of small molecules, and is absentThe drug delivery carrier of the macromolecule can avoid the defect that the macromolecule is difficult to degrade in human body.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.

Claims (8)

1. An amphiphilic small molecule prodrug is characterized in that the structure of the amphiphilic small molecule prodrug is shown as a formula (I):
Figure FDA0004150728300000011
2. the method of preparing an amphiphilic small molecule prodrug of claim 1, comprising: the compound A and the hydrophilic anticancer drug are prepared through condensation reaction; the hydrophilic anticancer drug is selected from lenalidomide;
the structural formula of the compound A is as follows:
Figure FDA0004150728300000012
3. the method for preparing an amphiphilic small molecule prodrug according to claim 2, wherein the compound a is a compound a 1 And Compound A 2 Prepared by a maxmery coupling reaction;
the compound A 1 Is of the structure of
Figure FDA0004150728300000013
The compound A 2 Is of the formula->
Figure FDA0004150728300000014
4. The method for preparing an amphiphilic small molecule prodrug according to claim 2, wherein the temperature of the condensation reaction is controlled between 80 ℃ and 100 ℃.
5. The method of preparing an amphiphilic small molecule prodrug of claim 2, wherein the condensation reaction is performed under an inert atmosphere.
6. The method of claim 5, wherein the condensation reaction is performed under the action of a catalyst selected from the group consisting of formic acid.
7. The method of claim 2, wherein the condensation reaction is completed and further comprising a purification process.
8. Use of the amphiphilic small molecule prodrug of claim 1 in the preparation of an anti-breast cancer drug, or in tumor cell imaging for non-disease diagnosis or treatment purposes, or in visual drug delivery for non-disease diagnosis or treatment purposes.
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