CN111285856A - Organic small molecule compound with excellent photothermal effect - Google Patents

Organic small molecule compound with excellent photothermal effect Download PDF

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CN111285856A
CN111285856A CN201811399004.6A CN201811399004A CN111285856A CN 111285856 A CN111285856 A CN 111285856A CN 201811399004 A CN201811399004 A CN 201811399004A CN 111285856 A CN111285856 A CN 111285856A
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CN111285856B (en
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周现锋
李志波
牟雪璐儿
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Qingdao Boyuan Polymer Materials Research Institute Co Ltd
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Abstract

The invention provides a compound with a structure shown in a formula (III), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compound can be self-assembled in an aqueous solution to form a micro-nano structure, the micro-nano structure has the advantages of high photothermal conversion efficiency, good photothermal stability, good photothermal effect and photodynamic effect, easiness in degradation and high safety, can passively target tumor parts, and has a wide prospect in the aspects of diagnosis and treatment of cancers and skin diseases.

Description

Organic small molecule compound with excellent photothermal effect
Technical Field
The invention relates to a novel organic small-molecule fluorescent compound, in particular to a fluorescent compound which emits heat when emitting light under laser irradiation and kills tumor cells to achieve a healing effect after the temperature rises, and belongs to the field of chemical pharmacy.
Background
In recent years, the incidence of cancer is on the rise, and the life health of people is seriously threatened. The existing treatment technologies such as surgical treatment and chemotherapy have certain limitations. Therefore, the laser photothermal therapy gradually enters the visual field of people, which is a cancer treatment method with clinical application prospect, has the advantages of no wound/micro wound and greatly reduces the pain of patients. The method uses a beam of near infrared light to radiate tumor tissue, the fluorescent compound can emit heat while emitting light, and the cancer cells can be killed by heating up to achieve the treatment effect. The method has less side reaction and high selectivity.
Since conventional organic small-molecule fluorescent compounds generally have the disadvantage of poor photo-thermal stability in photo-thermal treatment, many researchers have studied inorganic nanomaterials as photo-thermal agents for the photo-thermal treatment of cancer in recent years. Although inorganic nanomaterials can have high photothermal conversion efficiency, they are generally not easily degraded in vivo, and have potential toxicity problems, thereby limiting their clinical development and application. In addition, the grafting of macromolecular groups such as PEG on organic small-molecule fluorescent compounds to increase the photothermal conversion efficiency and photothermal stability of the compounds has also been reported in the prior art, but the fluorescent compounds still face the problems of difficult metabolism and potential toxicity.
Therefore, the research on the application of the organic small-molecule fluorescent compound with excellent photo-thermal stability to laser photo-thermal treatment of cancers is of great significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel uncharged organic small molecular fluorescent compound and application thereof in phototherapy. The compound can be self-assembled into a micro-nano structure in water, has the advantages of high photothermal conversion efficiency, excellent photothermal stability and high degradation safety, and can be used for in vivo cancer phototherapy.
Accordingly, the invention provides a micro-nano structure formed by self-assembling a compound with a structure shown in a formula (I), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof in an aqueous solution,
Figure BDA0001875886960000021
in formula (I):
a is a substituted or unsubstituted heterocyclic ring, preferably said heterocyclic ring is uncharged, more preferably said heterocyclic ring comprises one or more heteroatoms of N, O and S;
l is a substituted or unsubstituted conjugated carbon chain, preferably, the conjugated carbon chain comprises 2 to 5 double bonds, more preferably, the number of double bonds in the conjugated carbon chain is 2, 3, 4 or 5;
X1is O, N or-CR4R4' -, preferably, X1Is O;
n is 0 or 1, preferably, n is 0;
R1、R1’、R2each independently selected from the group consisting ofAn electron-withdrawing atom or group, preferably said R1、R1’、R2Each independently selected from-CN, -CF3、-F、-SO2CF3、-NO2、-COOEt、-SO2ph、
Figure BDA0001875886960000022
Figure BDA0001875886960000023
More preferably, said R1、R1' are both-CN; r2is-CN or
Figure BDA0001875886960000024
R3And R3' are each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group; preferably, said R is3、R3' each is independently selected from H, - (CH)2)qCH3、-(CH2)qCF3、-(CH2)qCH＝CH2、-(CH2)qC≡CH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCHO、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)q’CH3、
Figure BDA0001875886960000025
Figure BDA0001875886960000026
Wherein q, q' are each independently selected from integers of 0 to 12;
R4and R4' are each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group;
when the group is substituted, the substituent is mono-or polysubstituted.
The micro-nano structure formed by self-assembling the compound of the formula (I) in an aqueous solution has the advantages of high photothermal conversion efficiency, excellent photothermal stability, easiness in degradation and high safety.
In some preferred embodiments, a is selected from the group consisting of a substituted or unsubstituted pyrrole or hydrogenated pyrrole ring, a substituted or unsubstituted furan or hydrogenated furan ring, a substituted or unsubstituted thiophene or hydrogenated thiophene ring, a substituted or unsubstituted pyrazole or hydrogenated pyrazole ring, a substituted or unsubstituted imidazole or hydrogenated imidazole ring, a substituted or unsubstituted oxazole or hydrogenated oxazole ring, a substituted or unsubstituted isoxazole or hydrogenated isoxazole ring, a substituted or unsubstituted thiazole or hydrogenated thiazole ring, a substituted or unsubstituted indole or hydrogenated indole ring, a substituted or unsubstituted benzofuran or hydrogenated benzofuran ring, a substituted or unsubstituted benzimidazole or hydrogenated benzimidazole ring, a substituted or unsubstituted carbazole or hydrogenated carbazole ring, a substituted or unsubstituted pyridine or hydrogenated pyridine ring, a substituted or unsubstituted pyran or hydrogenated pyran ring, a substituted or unsubstituted pyran ring, a substituted or hydrogenated furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole or hydrogenated pyrazole ring, a substituted or thiophene ring, a substituted or unsubstituted, A substituted or unsubstituted thiopyran or hydrothiopyran ring, a substituted or unsubstituted benzopyran or hydrobenzopyrazole ring, a substituted or unsubstituted pyridazine or hydropyridazine ring, a substituted or unsubstituted pyrimidazine or hydropyrimidine ring, a substituted or unsubstituted pyrazine or hydropyrazine ring, a substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine ring, a substituted or unsubstituted thiomorpholine ring, and a substituted or unsubstituted triazole ring;
more preferably, A is
Figure BDA0001875886960000031
Figure BDA0001875886960000032
Wherein R is5、R6、R6' are each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group.
In other preferred embodiments, L is
Figure BDA0001875886960000041
Wherein
Y1Is a halogen atom, a substituted or unsubstituted amino group or a hydrocarbyloxy group;
m is an integer of 0 to 5, preferably, m is 3;
R7each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group.
In a particularly preferred embodiment, m is 3 and Y1Is Cl, Br, -NR8R8' OR-OR8(ii) a And, R7Is H, -CH3、
Figure BDA0001875886960000042
R8And R8' are each independently selected from the group consisting of H, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted alcohol group, substituted or unsubstituted ether group, substituted or unsubstituted aldehyde group, substituted or unsubstituted carboxyl group, substituted or unsubstituted amido group, substituted or unsubstituted ester group and substituted or unsubstituted amino group.
The invention also provides a micro-nano structure formed by self-assembling a compound with a structure shown in a formula (II), an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution,
Figure BDA0001875886960000043
in the formula (II), the compound is shown in the specification,
Y2is Cl, Br,
Figure BDA0001875886960000044
Wherein q, q' are each independently selected from integers of 0 to 12;
R9is-CN or
Figure BDA0001875886960000045
R10Is- (CH)2)m-、
Figure BDA0001875886960000051
m is an integer of 0 to 5, preferably R10is-CH2-、-(CH2)2-、-(CH2)3-or- (CH)2)4-, more preferably, R10Is- (CH)2)3-；
R11Is composed of
Figure BDA0001875886960000052
R12Is composed of
Figure BDA0001875886960000053
Figure BDA0001875886960000054
Q, q' are each independently selected from integers of 0-12;
more preferably, the micro-nano structure is formed by self-assembling compounds II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14 or II-15 in an aqueous solution.
Due to the abundant blood vessels of tumor (especially solid tumor) tissues and the lack of a lymphatic reflux system, the micro-nano structure disclosed by the invention has high passive permeability and retentivity at the tumor position. The high permeability effect and retention effect of such micro-nano structures in solid tumor tissues are called EPR effect (enhanced permeability and retention effect). The ability of passively targeting tumors enables the micromolecular compounds which can be assembled into micro-nano structures by supermolecules to have obvious advantages compared with other reported micromolecular photothermal conversion reagents.
In a preferred embodiment of the present invention, the micro-nano structure has a particle size of 1nm to 500nm, preferably 10nm to 200 nm. More preferably, it is from 30nm to 150 nm.
In another preferred embodiment of the present invention, the micro-nano structure is a vesicle structure formed by self-assembling a compound having a structure shown in formula (I) or formula (II), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof in an aqueous solution. The inner aqueous phase and the hydrophobic layer of the vesicular structure may encapsulate or be loaded with a variety of bioactive agents. The vesicle has the drug transport capacity as a vesicle, and provides possibility for the combined treatment of tumors.
The invention also provides a preparation method of the micro-nano structure, which comprises the following steps:
1) dissolving a compound having a structure represented by formula (I) or formula (II), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof with an organic solvent; preferably, the organic solvent is one or more of alkane, alkene, aromatic hydrocarbon, alcohol, ketone, aldehyde, carboxylic acid, ester or ether; more preferably, the organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, methanol, ethanol, ethylene glycol, N-propanol, isopropanol, propylene glycol, glycerol, N-butanol, isobutanol, butanediol or polyethylene glycol, acetone, dichloromethane or acetonitrile; in a preferred embodiment, the organic solvent is ethanol;
2) adding the solution obtained in the step 1) into an aqueous solution, preferably, in the system formed in the step 2), the final concentration of the compound is 1 nM-1M; more preferably 10nM to 1 mM; more preferably 100 nM-500. mu.M; most preferably 0.46. mu.M-300. mu.M;
3) and the compound is self-assembled in an aqueous solution to form the micro-nano structure.
The preparation method is simple, convenient and fast, and is suitable for large-scale production.
In another aspect of the present invention, there is provided a pharmaceutical composition comprising:
1) a therapeutically effective amount of said micro-nano structure, and
2) a pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable carrier includes a diluent, a disintegrant, an excipient, a binder, a stabilizer, or a combination thereof.
The pharmaceutical composition can be preferably prepared into an injection, and the injection comprises a therapeutically effective dose of the micro-nano structure and an injection solvent or additive or a combination thereof; preferably, the injection solvent is one or a mixed solvent of two or more of water for injection, ethanol, propylene glycol, glycerol and polyethylene glycol.
In some preferred embodiments, the micro-nano structure is a vesicular structure, and the pharmaceutical composition further comprises an active agent, preferably a therapeutic or diagnostic agent, more preferably a chemotherapeutic or radiotherapeutic agent, such as a small molecule chemotherapeutic drug, targeted therapeutic drug, chemotherapeutic drug, antibody drug, or the like, encapsulated in the micro-nano structure. More preferably, the micro-nano structure further comprises a targeting molecule, preferably an antibody, a peptide, an aptamer, folic acid or the like.
In some preferred embodiments, the pharmaceutical composition is an injection solution,
the invention also provides application of the micro-nano structure or the pharmaceutical composition in preparation of a photo-therapeutic drug, preferably, the photo-therapeutic drug is a photo-thermal therapeutic drug, a photodynamic therapeutic drug or a photo-acoustic therapeutic drug.
The invention also provides application of the micro-nano structure or the pharmaceutical composition as a photosensitizer, and preferably, the photosensitizer is used for preparing a photo-thermal treatment medicament, a photodynamic treatment medicament or a photo-acoustic treatment medicament.
The invention also provides application of the micro-nano structure or the pharmaceutical composition in preparing a medicine for diagnosing and/or treating cancer, preferably, the cancer is esophagus cancer, non-small cell lung cancer, biliary tract cancer, head and neck cancer, barrett's esophagitis, bladder cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain tumor, breast cancer or skin cancer; the skin cancer includes melanoma.
The invention also provides application of the micro-nano structure or the pharmaceutical composition in preparing a medicine for treating skin diseases, preferably, the skin diseases are actinic keratosis, basal cell carcinoma, skin T cell lymphoma, Bowen's disease, squamous cell carcinoma, intraepithelial neoplasia of vulva and anus or Paget's disease.
In another aspect, the invention provides a method of phototherapy of a target area in a subject, comprising:
1) providing the micro-nano structure;
2) administering the micro-nano structure to a subject;
3) waiting for the micro-nano structure to be enriched in the target area;
3) irradiating a target region of the subject with light of the micro-nano structure excitation band, preferably with light of 808 nm.
In another aspect, the invention provides a compound having a structure shown in formula (III), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof,
Figure BDA0001875886960000071
in the formula (III):
X2selected from O, S or-CR20R20’-；
Y3、Y4、Y5Each independently selected from H, hydroxyl, halogen atom, substituted or unsubstituted amino and alkoxy;
t1、t2、t3each independently selected from an integer of 0 to 5, preferably said t1And t2Are all 1, t3Is 0;
R13、R13’、R14each independently selected from-CN, -CF3，F，-SO2CF3，-NO2，-COOEt，-SO2ph，
Figure BDA0001875886960000072
Figure BDA0001875886960000073
Preferably, R13、R13' are all-CN, R14is-CN
R15Is- (CH)2)m-、
Figure BDA0001875886960000074
m is an integer from 0 to 5, preferably m is 3;
R16and R17Together forming a connection that is one of:
Figure BDA0001875886960000081
or R16、R17And X2Together form the following connection
Figure BDA0001875886960000082
Wherein R isa、Rb、Rc、Rd、Re、Rf、RgEach independently selected from H, halogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carboxyl, substituted or unsubstituted hydroxyl and substituted or unsubstituted amino;
R18、R18’、R20and R20' are each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group; preferably, R18、R18' each is independently selected from H, - (CH)2)qCH3、-(CH2)qCF3、-(CH2)qCHCH2、-(CH2)qCCH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCHO、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)r’CH3、
Figure BDA0001875886960000083
Figure BDA0001875886960000084
Wherein q, q' are each independently selected from integers from 0 to 12;
when the group is substituted, the substituent is mono-or polysubstituted.
In a preferred embodiment of the present invention,
said Y is3And Y5Are all H;
Y4is Cl, Br or-NR21R21’-；
t1、t2Are all 1, t3Is 0;
R21、R21' are each independently selected from the group consisting of H, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted alcohol group, substituted or unsubstituted ether group, substituted or unsubstituted aldehyde group, substituted or unsubstituted carboxyl group, substituted or unsubstituted amido group, substituted or unsubstituted ester group and substituted or unsubstituted amino group.
More preferably, the compound of formula (III) is a compound II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14 or II-15.
In another aspect of the present invention, a pharmaceutical composition comprises
3) A therapeutically effective amount of a compound of formula (III), its isomer, pharmaceutically acceptable salt, hydrate or solvate thereof, and
4) a pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable carrier includes a diluent, a disintegrant, an excipient, a binder, a stabilizer, or a combination thereof.
The invention also provides application of the compound with the structure shown in the formula (IV), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof in preparing a phototherapeutic medicament,
Figure BDA0001875886960000091
in the formula (IV):
X2selected from O, S or-CR20R20’-；
Y3、Y4、Y5Each independently selected from H, hydroxyl, halogen atom, substituted or unsubstituted amino and alkoxy;
t1、t2、t3each independently selected from an integer of 0 to 5, preferably, t1And t2Are all 1, t3Is 0;
R13、R13’、R14each independently selected from-CN, -CF3，F，-SO2CF3，-NO2，-COOEt，-SO2ph，
Figure BDA0001875886960000092
Figure BDA0001875886960000093
Preferably, R13、R13' are all-CN, R14is-CN
Figure BDA0001875886960000094
R15Is- (CH)2)m-、
Figure BDA0001875886960000095
m is an integer from 0 to 5, preferably m is 3;
R16and R17Together forming a connection that is one of:
Figure BDA0001875886960000101
or R16、R17And X2Together form the following connection
Figure BDA0001875886960000102
Wherein R isa、Rb、Rc、Rd、Re、Rf、RgEach independently selected from H, halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted carboxy, substituted or unsubstituted hydroxy and substituted or unsubstituted amino;
R18、R18’、R19、R20and R20' are each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstitutedSubstituted alcohol groups, substituted or unsubstituted ether groups, substituted or unsubstituted aldehyde groups, substituted or unsubstituted carboxyl groups, substituted or unsubstituted amido groups, substituted or unsubstituted ester groups and substituted or unsubstituted amino groups; preferably, R18、R18’、R19Each independently selected from H, - (CH)2)qCH3、-(CH2)qCF3、-(CH2)qCHCH2、-(CH2)qCCH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCHO、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)q’CH3、
Figure BDA0001875886960000103
Figure BDA0001875886960000104
Wherein q, q' are each independently selected from any integer from 0 to 12; preferably, said R is19is-CH2CH3；
When the group is substituted, the substituent is mono-or polysubstituted.
In a preferred embodiment of the present invention,
said Y is3And Y5Are all H;
Y4is Cl, Br or-NR21R21’-；
t1、t2Are all 1, t3Is 0;
R21、R21' are each independently selected from the group consisting of H, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted alcohol group, substituted or unsubstituted ether group, substituted or unsubstituted aldehyde group, substituted or unsubstituted carboxyl group, substituted or unsubstituted amideA substituted or unsubstituted ester group and a substituted or unsubstituted amino group.
More preferably, the compound of formula (IV) is a compound II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14 or II-15.
Preferably, the phototherapeutic agent is a photothermal agent, photodynamic agent or photoacoustic agent.
The invention also provides application of the compound shown as the formula (IV), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as a photosensitizer, and preferably the photosensitizer is used for preparing a photothermal therapy medicament, a photodynamic therapy medicament or a photoacoustic therapy medicament.
The invention also provides application of the compound shown as the formula (IV), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof in preparing a medicament for diagnosing and/or treating cancers, preferably, the cancers are esophagus cancer, non-small cell lung cancer, biliary tract cancer, head and neck cancer, barrett's esophagitis, bladder cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain tumor, breast cancer or skin cancer; the skin cancer includes melanoma.
The invention also provides the use of a compound of formula (iv), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, in the manufacture of a medicament for the treatment of a dermatological condition, preferably actinic keratosis, basal cell carcinoma, cutaneous T-cell lymphoma, bowden's disease, squamous cell carcinoma, intraepithelial neoplasia of the vulva and anus or paget's disease.
The invention has the beneficial effects that:
(1) the invention provides a micro-nano structure formed by self-assembling a compound shown as a formula (I) or a formula (II) in an aqueous solution, and a preparation method and application thereof. Experiments prove that the micro-nano structure has the advantages of high photothermal conversion efficiency, good photothermal stability, good photothermal effect and photodynamic effect, easy degradation and high safety, can passively target tumor parts, and has wide prospects in the aspects of diagnosis and treatment of cancers and skin diseases.
(2) The invention provides a compound shown as a formula (I II), which can be self-assembled in an aqueous solution to form a micro-nano structure, and further has the advantages of high photothermal conversion efficiency, good photothermal stability, good photothermal effect and photodynamic effect, easiness in degradation and high safety.
(3) The invention also provides application of the compound shown in the formula (IV) in preparing a medicament for light treatment, a medicament for diagnosing and treating cancers or a medicament for treating skin diseases, and the compound has the advantages of good treatment effect, small wound, great market value and wide economic prospect.
Description of the drawings:
FIG. 1 is a schematic diagram of the structures of the disclosed organic small molecule fluorescent compounds ICG, IR808, IR825 and IR 780;
FIG. 2 shows a synthetic route of the organic small molecule fluorescent compound II-1 of the present invention;
FIG. 3 is a graph of the UV absorption spectrum of compound II-1 in different polar solvents;
FIG. 4 shows fluorescence emission spectra of compound II-1 in different polar solvents;
FIG. 5 is a transmission electron micrograph of vesicles formed by self-assembly of compound II-1 in an aqueous solution;
FIG. 6 shows the particle size test results of the uncharged organic small molecule fluorescent compound in the aqueous solution, which shows that the uncharged organic small molecule fluorescent compound can self-assemble into a micro-nano structure;
FIG. 7 is a graph showing the temperature change of different concentrations of Compound II-1 under 808nm laser irradiation;
FIG. 8 comparison of photothermal stability of Compounds II-1 and ICG;
FIG. 9 is a photomicrograph of vesicles assembled from Compound II-1 taken up by cells, showing that the vesicles assembled from the compound are localized in the lysosomes of the cells.
FIG. 10 is an infrared fluorescence image of the whole body of a mouse at different time points after a vesicle assembled by a compound II-1 is injected into the tumor-bearing mouse intravenously;
FIG. 11 is a graph showing the change in infrared fluorescence intensity at tumor sites at different time points after vesicles assembled with compound II-1 are injected intravenously into tumor-bearing mice;
FIG. 12 photothermal imaging in photothermal therapy in Compound II-1 mice;
FIG. 13 shows the change of tumor volume after intravenous injection of vesicles assembled with Compound II-1 into tumor-bearing mice and photothermal therapy;
FIG. 14 shows the body weight changes of mice after intravenous injection of vesicles assembled with Compound II-1 into tumor-bearing mice and administration of photothermal therapy;
FIG. 15 shows the results of the photodynamic activity test of compound II-1;
FIG. 16 results of photoacoustic imaging test experiment of Compound II-1 in aqueous solution;
FIG. 17 photoacoustic imaging test results of Compound II-1 in tumor-bearing mice.
The specific implementation mode is as follows:
the methods and techniques of the present invention are generally performed according to conventional methods known in the art, unless otherwise indicated. Nomenclature related to biology, pharmacology, and medical and medicinal chemistry described herein, and laboratory procedures and techniques are those well known and commonly used in the art. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and testing or testing.
Unless defined otherwise, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. The following terms have the following definitions:
the term "micro-nano structure" refers to a micro structure with the size below 500nm, namely a new system which is constructed or assembled by taking a compound with a structure of a formula (I) or a formula (II) as a basic unit according to a certain rule. The micro-nano structure comprises a one-dimensional, two-dimensional and three-dimensional system, the specific form of the micro-nano structure can comprise particles, lines, rods, columns, tubes, whiskers, fibers, belts, filaments, vesicles and the like, or the form of the combination of the forms, and preferably, the micro-nano structure is a vesicle structure.
The term "isomer" includes conformational isomers, optical isomers (e.g., enantiomers and diastereomers), and geometric isomers (e.g., cis-trans isomers). These isomers or combinations thereof may exist as racemic mixtures (racemates), individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.
The term "aqueous solution" refers to a liquid mixture comprising water in an amount of 0.1% to 100%, preferably 1% to 100%, more preferably 10% to 100% by weight of the aqueous solution. The aqueous solution may be a uniform, stable mixture of components that are miscible with each other, or a non-uniform, unstable mixture of components that are immiscible with each other, such as a suspension or emulsion. Specific examples of the aqueous solution in the present invention may include: physiological saline, plasma, Phosphate Buffered Saline (PBS), glycine-hydrochloric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer, citric acid-sodium citrate buffer, acetic acid-sodium acetate buffer, barbital buffer, Tris buffer, boric acid-borax buffer, and the like.
The term "conjugated carbon chain" refers to a molecular structure containing two or more carbon-carbon double bonds, and the double bonds and the single bonds are arranged alternately with each other.
The term "pharmaceutically acceptable salt" refers to a salt formed by reacting the above compound with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal, or the like. These salts include (but are not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, other salts of benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, tartaric acid, maleic acid, or arginine (3), including salts with alkali or alkaline earth metals (e.g., sodium, potassium, calcium, or magnesium), ammonium or water-soluble amine salts (e.g., N-methylglucamine salts), lower alkanol ammonium salts, and other pharmaceutically acceptable amine salts (e.g., methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, triethanolamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively), or other conventional "prodrug" forms.
The precursor refers to a compound which undergoes a metabolic or chemical reaction in the patient's body to be converted into a compound contained in the general formula of the present invention, and a salt or a solution of the compound, when administered by an appropriate method. Precursors of compounds include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal, and the like forms of the compounds.
The term "halogen atom" means any of the radio-stable atoms in column 7 of the periodic Table of the elements, i.e. fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.
The term "hydrocarbyl" refers to any straight or branched, substituted or unsubstituted, saturated hydrocarbyl group, wherein the hydrocarbyl group has 1 to 10 carbon atoms and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2,4, 4-trimethylpentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, 2-ethylhexyl, cyclooctyl, n-nonyl, cyclononyl, or n-decyl. Other long chain alkyl groups having a greater number of carbon atoms include, but are not limited to, squalene, nonadecanol, and the like.
The terms "aryl", "substituted aryl", "heteroaryl" and "substituted heteroaryl" refer to aromatic hydrocarbon rings, preferably having 5, 6 or 7 atoms, most preferably having 6 atoms making up the ring. "heteroaryl" and "substituted heteroaryl" refer to aromatic hydrocarbon rings having at least one heteroatom (e.g., oxygen, sulfur, or nitrogen atom) and at least one carbon atom in the ring.
The term "substituted" refers to a group in which any at least one hydrogen atom is replaced with a substituent selected from the group consisting of halogen atoms, alkyl groups, substituted alkyl groups, alkoxy groups, substituted alkoxy groups, cycloalkyl groups, substituted cycloalkyl groups, cycloalkenyl groups, substituted cycloalkenyl groups, acyl groups, acylamino groups, acyloxy groups, amino groups, substituted amino groups, aminoacyl groups, aminoacyloxy groups, oxyacylamino groupsA group, cyano, hydroxy, carboxy, carboxyalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl2-alkyl, -SO2-substituted alkyl, -SO2-aryl and-SO2-a heteroaryl group.
The term "particle size" refers to the size of a particle, also known as "particle size" or "diameter". When a certain physical property or physical behavior of the measured particle is most similar to a homogeneous sphere (or combination) with a certain diameter, the diameter (or combination) of the sphere is taken as the equivalent particle diameter of the measured particle. The particle size parameter of the micro-nano structure is measured by the principle of Dynamic Light Scattering (DLS), and is specifically measured by a laser particle sizer.
The term "therapeutically effective dose" refers to any amount of a drug that, when used alone or in combination with another therapeutic agent, promotes disease regression as manifested by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of a disorder or disability resulting from the disease. The "therapeutically effective dose" of the drug of the present invention also includes a "prophylactically effective dose", which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or suffering from a recurrence of a disease, inhibits the development or recurrence of the disease.
As will be apparent to those skilled in the art, the effective dosage and particular mode of administration in vivo will vary depending upon the species, weight and age of the mammal being treated, the particular compound employed and the particular purpose for which it is employed. Effective dosage levels (i.e., the dosage levels necessary to achieve the desired effect) can be determined by one of skill in the art based on routine pharmacological procedures. Generally, the human clinical application of the product starts with a lower dosage level, followed by increasing dosage levels until the desired effect is achieved. Alternatively, acceptable in vitro studies can be employed to establish useful dosages and routes of administration of the compositions identified by the present methods by available pharmacological methods.
The term "cancer" refers to a broad class of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors or cells that invade adjacent tissues and may also metastasize to distal parts of the body through the lymphatic system or blood stream. Another equivalent description of "treating cancer" in the present invention is "treating tumor" or "anti-cancer" or "anti-tumor".
For example, the diagnostic agent includes an imaging agent such as an imaging agent containing a radioisotope such as indium or technetium, a contrast agent containing iodine or gadolinium, an enzyme such as horseradish peroxidase, GFP, alkaline phosphatase, or β -galactosidase, a fluorescent substance such as a europium derivative, a luminescent substance such as an N-methylacridine derivative, and the like.
The "therapeutic agent" is any chemical substance recognized in the art as being a biologically, physiologically, or pharmacologically active substance. Therapeutic agents, also referred to as "drugs", examples of which are described in known references (e.g., Merck Index, Physicians desk Reference, and The Pharmacological Basis of therapeutics), and include, but are not limited to, drugs, vitamins, mineral supplements, substances for treating, preventing, diagnosing, curing or alleviating a disease or condition, substances that affect The structure or function of The body, or prodrugs that are biologically active or more active when placed in a physiological environment. Various forms of therapeutic agents may be used, wherein upon administration to a subject, the composition is capable of being released from the subject into adjacent tissue or fluid.
The "targeting molecule" is any molecule capable of directing the micro-nano structure to a specific target, e.g. by binding to a receptor or other molecule on the surface of the target cell. The targeting molecule may be a protein, peptide, nucleic acid molecule, sugar or polysaccharide, receptor ligand or other small molecule. The degree of specificity can be adjusted by the choice of targeting molecule. For example, antibodies typically exhibit high specificity. Antibodies can be polyclonal, monoclonal, fragments, recombinant, or single chain, many of which are commercially available or can be readily obtained using standard techniques.
Some examples of compounds of the invention are the following compounds II-1 to II-44:
Figure BDA0001875886960000151
Figure BDA0001875886960000152
Figure BDA0001875886960000161
Figure BDA0001875886960000171
Figure BDA0001875886960000181
Figure BDA0001875886960000191
Figure BDA0001875886960000201
the above compounds can be generally synthesized by the following general reaction formula:
Figure BDA0001875886960000202
the main synthesis steps comprise:
1. separately providing compound A, B, C;
synthesis of Compound A:
Figure BDA0001875886960000203
the compound 1 'and the compound 2' are dissolved in ethanol, and reacted for 24 hours at 60 ℃. The solvent was evaporated under vacuum and the resulting solid was purified by column chromatography to give the title compound A.
Synthesis of Compound B:
Figure BDA0001875886960000204
dichloromethane and compound 4 ' are added into a bottle under ice bath and stirred, compound 5 ' is added under constant pressure and stirred, compound 3 ' is added, and reaction is carried out for 3 hours at 80 ℃. After completion of the reaction, the product was poured into crushed ice to quench the reaction, and left overnight in a refrigerator. The solvent was evaporated in vacuo to give the crude compound B, which was used in the next reaction without further purification.
Synthesis of Compound C:
Figure BDA0001875886960000205
compound 6 'and compound 7' were added to acetonitrile. The reaction was heated to 110 ℃ and refluxed for 24 hours. The solvent was evaporated in vacuo and the resulting solid was washed 3 times with diethyl ether to give compound C.
2. Dissolving the compound A and the compound B in ethanol, heating and refluxing, then adding the compound C, heating and refluxing, evaporating the solvent under vacuum, and purifying the obtained solid by column chromatography to obtain a target compound II.
The present invention will be further described with reference to the following examples.
EXAMPLE 1 Synthesis of Compound II-1 and its fluorescent Properties
As shown in FIG. 2, the synthesis of compound II-1 comprises the following steps:
1) synthesis of Compound 1: 0.97g of malononitrile and 0.62g of magnesium ethoxide were added to 10mL of ethanol, and 0.5mL of 3-hydroxy-3-methylbutan-2-one was added. The reaction was heated to 60 ℃ for 12 hours. The solvent was evaporated under vacuum and the resulting solid was purified by column chromatography to give the title compound 1.1H NMR(400MHz,CDCl3):δ(ppm):2.36(s,3H),1.63(s,6H)。
2) Synthesis of Compound 2: 20mL of dichloromethane and 20mL of DMF were added to a flask under ice-bath and stirred, 17.5mL of phosphorus oxychloride was added at constant pressure and stirred, 5.3mL of cyclohexanone was added, and the mixture was heated to 80 ℃ and reacted for 3 hours. After completion of the reaction, the product was poured into crushed ice to quench the reaction, and left overnight in a refrigerator. The solvent was evaporated under vacuum to give the crude compound 2, which was used in the next reaction without further purification.
3) Synthesis of Compound 4: 5g of 2, 3, 3-trimethyl-3H-indole and 6g of iodoethane are added to 20mL of acetonitrile. The reaction was heated to 110 ℃ and refluxed for 24 hours. The solvent was evaporated in vacuo and the resulting solid was washed 3 times with diethyl ether to give compound 4.
4) Synthesis of Compound II-1: 3.0g of Compound 1 and 1.99g of Compound 2 are dissolved in 50mL of ethanol, heated to 100 ℃ and refluxed for 4 hours, and then 2.75g of Compound 4 is added and refluxed for 6 hours. The solvent is distilled off under vacuum, and the obtained solid is purified by column chromatography to obtain the target compound II-1.1H NMR(400MHz,CDCl3):δ(ppm):8.13(d,1H),7.18(d,1H),7.30(t,2H),7.07(t,1H),6.85(d,1H),6.34(d,1H),5.72(d,1H),3.87(d,2H),2.61(d,4H),1.90(m,2H),1.75(s,6H),1.66(s,6H),1.35(t,3H)。
The ultraviolet absorption spectrogram and the fluorescence emission spectrogram of the compound II-1 in water and acetonitrile are respectively shown in FIG. 3 and FIG. 4. It can be seen that the absorption and emission spectra of compound II-1 in the two solvents are significantly different, with the absorption spectrum of II-1 in aqueous solution being broader and the emission being less. It is suggested that the physical properties of the compounds of the present invention in aqueous and organic solvents are different.
EXAMPLE 2 Synthesis of Compounds II-2 to II-15
Compounds II-2 to II-15 can be prepared in a similar manner to example 1.
1. Synthesis of Compound II-2
Figure BDA0001875886960000221
Compound 5 is used in place of Compound 1 in example 1, and the remaining reagents and methods are the same as those in step 4) of example 1, to produce Compound II-2,
1HNMR(400MHz,CDCl3)δ:8.60-8.59(d,2H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),3.20-3.18(t,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.75(s,3H),1.66(s,6H),1.56-1.53(m,4H),1.36-1.33(t,3H)。
2. synthesis of Compound II-3
Figure BDA0001875886960000222
Compound 5 and 6 are used in place of Compound 1 and Compound 4, respectively, in example 1, and the remaining required reagents and preparation methods are the same as in step 4) of example 1, to prepare Compound II-3,
1HNMR(400MHz,CDCl3)δ:8.60-8.59(d,2H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),3.20-3.18(t,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.75(s,3H),1.56-1.53(m,4H),1.36-1.33(t,3H)。
3. synthesis of Compound II-4
Figure BDA0001875886960000223
Compound 7 is used in place of Compound 1 in example 1, and the remaining necessary reagents and preparation methods are the same as those in step 4) of example 1, to prepare Compound II-4,
1HNMR(400MHz,CDCl3)δ:8.60-8.59(d,2H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),4.55(s,1H),3.87-3.72(q,2H),3.20-3.18(t,2H),3.12(t,1H),2.96-2.94(t,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.82-1.81(s,3H),1.75(s,3H),1.66(s,6H),1.56-1.53(m,4H),1.36-1.33(t,3H)。
4. synthesis of Compound II-5
Figure BDA0001875886960000231
Compound 7 and 6 are used in place of Compound 1 and Compound 4, respectively, in example 1, and the remaining required reagents and preparation methods are the same as in step 4) of example 1, to prepare Compound II-5,
1HNMR(400MHz,CDCl3)δ:8.60-8.59(d,2H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),4.55(s,1H),3.87-3.72(q,2H),3.20-3.18(t,2H),3.12(t,1H),2.96-2.94(t,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.82-1.81(s,3H),1.75(s,3H),1.56-1.53(m,4H),1.36-1.33(t,3H)。
5. synthesis of Compound II-6
Figure BDA0001875886960000232
Compound 8 is used in place of Compound 1 in example 1, and the remaining necessary reagents and preparation methods are the same as in step 4) of example 1, to prepare Compound II-6,
1HNMR(400MHz,CDCl3)δ:8.17-8.16(t,1H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),3.20-3.18(t,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.75(s,3H),1.66(s,6H),1.56-1.53(m,4H),1.36-1.33(t,3H)。
6. synthesis of Compound II-7
Figure BDA0001875886960000241
Compounds II-7 were prepared by substituting compounds 8 and 6 for compounds 1 and 4, respectively, in example 1, and the remaining necessary reagents and preparation methods were the same as in step 4) of example 1,
1HNMR(400MHz,CDCl3)δ:8.17-8.16(t,1H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),3.20-3.18(t,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.75(s,3H),1.56-1.53(m,4H),1.36-1.33(t,3H)。
7. synthesis of Compound II-8
Figure BDA0001875886960000242
Compound 9 is used in place of Compound 1 in example 1, and the remaining necessary reagents and preparation methods are the same as in step 4) of example 1, to prepare Compound II-8,
1HNMR(400MHz,CDCl3)δ:8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),2.60-2.57(t,4H),2.33-2.32(s,3H),1.91-1.88(m,2H),1.66(s,6H),1.36-1.33(t,3H)。
8. synthesis of Compound II-9
Figure BDA0001875886960000243
Compounds II-9 were prepared by substituting compounds 9 and 6 for compounds 1 and 4, respectively, in example 1, and the remaining necessary reagents and preparation methods were the same as in step 4) of example 1,
1HNMR(400MHz,CDCl3)δ:8.13-8.10(d,1H),7.98-7.96(d,1H),7.30-7.28(d,2H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),2.60-2.57(t,4H),2.33-2.32(s,3H),1.91-1.88(m,2H),1.36-1.33(t,3H)。
9. synthesis of Compound II-10
Figure BDA0001875886960000251
Compound 10 is used in place of Compound 1 in example 1, and the remaining necessary reagents and preparation method are the same as in step 4) of example 1, to prepare Compound II-10,
1HNMR(400MHz,CDCl3)δ:8.75-8.71(m,1H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.85-7.76(m,1H),7.40-7.28(m,4H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.75(s,6H),1.66(s,6H),1.36-1.33(t,3H)。
10. synthesis of Compound II-11
Figure BDA0001875886960000252
Compounds II-11 were prepared by substituting compounds 10 and 6 for compounds 1 and 4, respectively, in example 1, and the remaining necessary reagents and preparation methods were the same as in step 4) of example 1,
1HNMR(400MHz,CDCl3)δ:8.75-8.71(m,1H),8.13-8.10(d,1H),7.98-7.96(d,1H),7.85-7.76(m,1H),7.40-7.28(m,4H),7.08-7.05(t,1H),6.86-6.85(d,1H),6.36-6.33(d,1H),5.71-5.69(d,1H),3.87-3.72(q,2H),2.60-2.57(t,4H),1.91-1.88(m,2H),1.75(s,6H),1.36-1.33(t,3H)。
11. synthesis of Compound II-12
Figure BDA0001875886960000261
Compound 11 is used in place of Compound 2 in example 1, and the remaining necessary reagents and preparation methods are the same as in step 4) of example 1, to prepare Compound II-12,
1HNMR(400MHz,CDCl3)δ:7.34(d,1H),7.26(d,2H),7.06(d,1H),6.79(d,4H),6.51(m,4H),5.41(m,2H),5.01(t,1H),4.67(d,2H),4.13(q,2H)2.84(t,1H),2.36(d,4H),1.79(t,3H),1.66(s,6H),1.35(s,6H)。
12. synthesis of Compound II-13
Figure BDA0001875886960000262
Compound 12 is used in place of Compound 2 in example 1, and the remaining necessary reagents and preparation methods are the same as in step 4) of example 1, to prepare Compound II-13,
1HNMR(400MHz,CDCl3)δ:7.34(d,1H),7.26(d,2H),7.06(d,1H),6.79(d,4H),6.51(m,4H),5.41(m,2H),5.01(t,1H),4.67(d,1H),4.13(q,1H)2.84(t,1H),2.36(d,4H),1.79(t,3H),1.66(s,6H),1.35(s,6H)。
13. synthesis of Compound II-14
Figure BDA0001875886960000263
Compound 13 is used in place of Compound 4 in example 1, and the remaining necessary reagents and preparation methods are the same as those in step 4) of example 1, to prepare Compound II-14,
1HNMR(400MHz,CDCl3)δ:7.34(d,2H),7.26(d,2H),7.06(d,2H),6.79(d,4H),6.51(m,4H),5.41(m,2H),5.01(t,1H),4.67(d,2H),4.13(q,2H)2.84(t,1H),2.36(d,4H),1.79(t,3H),1.66(s,6H),1.35(s,6H)。
14. synthesis of Compound II-15
Figure BDA0001875886960000271
Compound 14 is used in place of Compound 2 in example 1, and the remaining necessary reagents and preparation methods are the same as those in step 4) of example 1, Compound 16 is obtained, Compound 16 and nitroimidazole derivative are stirred in DMF solvent at 55 ℃ for 24 hours, the solvent is distilled off under vacuum, the solid obtained is purified by column chromatography to obtain the objective Compound II-15,
1HNMR(400MHz,CDCl3)δ:8.33(d,2H),7.34(d,2H),7.26(d,2H),7.06(d,2H),6.79(d,4H),6.51(m,4H),5.41(m,2H),5.01(t,1H),4.54(t,2H),4.67(d,2H),4.13(q,2H),3.61(t,2H),2.84(t,1H),2.36(d,4H),1.79(t,3H),1.66(s,6H),1.35(s,6H)。
example 3 preparation method of micro-nano structure
Taking a micro-nano structure self-assembled by a compound II-1 as an example, II-1 is dissolved in DMSO (or an organic solvent such as ethanol) to prepare a storage solution with the concentration of 2mM, and a small amount of the storage solution is added into deionized water to prepare a working solution with the concentration of 20 μ M. And (3) dripping 10 mu L of the solution onto a silicon wafer, observing and photographing under a Transmission Electron Microscope (TEM) and an Atomic Force Microscope (AFM), wherein the micro-nano structure in the form of the vesicle can be obviously observed, and the attached figure 5 shows the photographing result of the transmission electron microscope. According to the observation result, the particle size of the micro-nano structure self-assembled by the compound II-1 is about 30-150 nm.
Example 4 is similar to the compound structure of the invention, but the charged cyanine compound (cyanine) can not form a micro-nano structure by self-assembly
4 charged cyanine compounds ICG, Cy-1, Cy-2 and Cy-3 are respectively prepared into 2mM storage solution in DMSO, and a small amount of the storage solution is added into deionized water to prepare 20 mu M working solution. The particle sizes of the cyanine compounds are measured by DLS, and the 4 cyanine compounds ICG, Cy-1, Cy-2 and Cy-3 are found to be incapable of measuring the particle sizes, which indicates that the cyanine compounds ICG, Cy-1, Cy-2 and Cy-3 cannot form micro-nano structures in water.
Example 5 comparison of characteristic data of micro-nano structure formed by self-assembly of compound of the invention
When the compounds II-1, II-12 to II-15 were treated in the same manner as in example 3, it was found that the compounds II-1 and II-12 to II-15 both formed micro-nano structures in aqueous solution (FIG. 6), and the characteristic data are as follows:
Figure BDA0001875886960000281
as can be seen from the table above, the particle size of the compounds II-1, II-12 to II-15 can be measured, and the particle size range is 10-300nm, which belongs to a micro-nano structure. The morphological observation shows that the compounds II-1, II-12 to II-15 all form a vesicle structure.
We tested examples of other compounds of the present invention and found that the compounds of the present invention all form micro-nano structures in aqueous solution, while none of the 4 kinds of cyanine compounds described in reference example 4 can form micro-nano structures in aqueous solution, which indicates that the non-electric charge of the compounds is important for the formation of micro-nano structures.
Example 6 calculation of the Quantum yield of the Compounds of the invention
Preparing the compound II-1 of the invention into 2mM DMSO stock solution, then adding 10 mu L of the compound II-1 into 2mL of solution with different polarities (comprising water, dimethyl sulfoxide, N-dimethylformamide, methanol, ethanol, acetone, dichloromethane and acetonitrile), and testing ultraviolet by using an ultraviolet spectrophotometerAbsorption, finding the maximum absorption wavelength. And calculating the molar extinction coefficient of II-1 in the solution with different polarities through an ultraviolet absorption spectrogram. Fluorescence emission spectra were measured on a fluorescence spectrophotometer with excitation at the wavelength of maximum absorption, and the data were plotted against origin and the integrated area calculated. Calculation of fluorescence quantum yield from the data obtained
Figure BDA0001875886960000284
Figure BDA0001875886960000283
The characteristic parameters of the compound II-1 in the solutions of different polarities are obtained as follows:
Figure BDA0001875886960000282
Figure BDA0001875886960000291
as can be seen from the table, the compound II-1 has different characteristic parameters in solutions with different polarities, particularly the maximum absorption wavelength and the maximum excitation wavelength in water are obviously different from those of other organic solvents, the quantum yield is obviously reduced, and the photothermal effect is stronger. The essence of the phenomenon is that the compound II-1 forms a micro-nano structure in a self-assembly manner in an aqueous solution, and the physical characteristics and characteristic parameters of the compound II-1 are changed due to the change of structural properties, so that the change is beneficial to improving the photo-thermal effect and the light stability. In fact, not only compound II-1 has such characteristics, but also other compounds of the present invention have similar properties, and can self-assemble in aqueous solution to form micro-nano structures.
EXAMPLE 7 Compound II-1 photothermal Effect in vitro and photothermal stability
3mL of each of 4 groups of samples were added to the cuvette and the cuvette was sealed with a lid.
Sample No. 1 was 3mL of deionized water;
sample No. 2 was 10. mu.M II-1 prepared by adding 15. mu.L stock solution of II-1(2 mM in DMSO) to 3mL of deionized water;
sample No. 3 was 20. mu.M II-1 prepared by adding 30. mu.L of stock solution of II-1(2 mM in DMSO) to 3mL of deionized water;
sample No. 4 was 40. mu.M II-1 prepared by adding 60. mu.L stock solution of II-1(2 mM in DMSO) to 3mL of deionized water.
Each sample was irradiated with a 808nm laser for 5 minutes, while temperature data was recorded every 5 seconds using a thermal imager, and the temperatures corresponding to time were plotted in origin, as shown in FIG. 7. Sample No. 1 had almost no change in temperature over 5 minutes, only a 2 ℃ rise. The temperature of sample No. 2 is raised from room temperature 30 ℃ to 54 ℃ and is raised to 24 ℃. The temperature of sample No. 3 was raised from room temperature 30 ℃ to 62 ℃ and to 32 ℃. The temperature of sample No. 4 was raised from room temperature 30 ℃ to 77 ℃ and 47 ℃.
Thus, the compound II-1 has excellent photothermal effect. Meanwhile, the photothermal conversion efficiency of samples 2, 3 and 4 was calculated, and it was found that the photothermal conversion efficiency of sample 2 was 60.4%, the photothermal conversion efficiency of sample 3 was 61%, and the photothermal conversion efficiency of sample 4 was 60%. Also, it was demonstrated that the compound II-1 had an extremely excellent photothermal effect.
We selected sample No. 3 to test the photothermal stability experiment. As shown in fig. 8, sample No. 3 was irradiated with a 808nm laser for 9 minutes, then raised from room temperature of 30 ℃ to 62 ℃, and then naturally cooled to room temperature, and then irradiated with a 808nm laser for 9 minutes again, and then naturally cooled, and repeated 5 times. In these 5 replicates sample No. 3 was found to be heated from room temperature to at least 55 c and 25 c each time under 808nm laser irradiation. The commercially available compound ICG with a similar structure does not have such a feature, and after 9 minutes of irradiation, the temperature rises by 15 ℃ and then returns to room temperature, and the temperature cannot rise again by laser irradiation.
Therefore, the compound II-1 disclosed by the invention not only has an excellent photo-thermal effect, but also has excellent photo-thermal stability which other small organic molecule fluorescent compounds do not have, overcomes the defect of the small organic molecule compound in the aspect of photo-thermal stability, and has a potential clinical application prospect. Other compounds of the invention also have similar properties.
Example 8 detection of cell photothermal assay
HeLa cells were digested from the flask with trypsin, centrifuged, and DMEM medium containing 10% serum and 1% double antibody was added and mixed well. mu.L of the cells were stained with Compound II-1 (20. mu.M) for 30 minutes. After removal, centrifugation was performed, washing was performed 2 times with PBS, and after centrifugation, 20. mu.L of the medium and 20. mu.L of Trypan blue were added. mu.L of the mixture was placed on a cell counting plate and photographed under a fluorescent microscope. In the absence of laser irradiation, bright living cells were observed under a microscope, and the cell survival rate was 92%. The cells are irradiated for 6 minutes by a 808nm laser, and almost all blue dead cells are observed under a microscope, and the cell death rate is up to 100 percent. HeLa cells were cultured in 96-well plates 10 per well4Cells, 24 later live/dead staining. The cells were irradiated for 6 minutes under a 808nm laser and photographed by observation under a fluorescence microscope, and the cells were all red, indicating that the cells were dead by 100%, while the control group (compound only, no laser irradiation) was observed under a fluorescence microscope that the cells were all green and all cells were alive. The compound has extremely low toxicity, but the photothermal effect of the compound has extremely high cancer cell killing power, and the compound has bright prospect in the clinical application of photothermal treatment of cancer in the future. Other compounds of the invention also have similar photothermal therapeutic effects.
Example 9 cellular imaging experiments
Lysosome dyes Lyso-Green (75nM) and II-1(8 μ M) were added to the culture medium of the cells for cell staining for 30 minutes, after staining was washed twice with PBS, photographs were observed under a confocal fluorescence microscope, and the photographs of the Green channel and the red channel were combined to find the cells were yellow with no distinct red and Green colors, as shown in fig. 9. Indicating that the red and green channels are nearly completely coincident, compound II-1 is a lysosome-targetable dye.
Example 10 mouse tumor imaging experiment
Subcutaneous injection 10 into the left side of 6-week-old female nude mice74T1 cells, growth of tumor volume to 60mm3. To the tail vein thereof, 200. mu.L of II-1(1mg/mL) was injected. After injection, the time periods were monitored with a live imager at various times. As shown in figure 11 of the drawings,the fluorescence intensity at the tumor site was found to gradually increase with time. After 24 hours, the other sites in the body had no compound and were all concentrated at the tumor site (fig. 10). Then dissecting the tumor, and carrying out fluorescence imaging on the heart, the liver, the spleen, the lung, the kidney and the tumor, wherein the fluorescence of the tumor part is very strong, the liver has weak fluorescence, and other parts have no fluorescence. This demonstrates that compound II-1 targets tumor sites very well. Moreover, no abnormality such as spasm and convulsion occurs in the body of a nude mouse within 24 hours, which proves that the compound II-1 has almost no toxicity and extremely high safety.
Example 11 photoacoustic imaging experiments in photothermal therapy in mice
Experimental groups mice were injected intravenously with 200. mu.L of II-1 (300. mu. moL) from the tail, and the tumor sites of the mice were irradiated with 808nm laser for 10 minutes while continuously taking pictures with a photo-thermal imaging instrument. Under the irradiation of laser, the temperature of the tumor part can rise to 60 ℃, and as can be seen from fig. 12, the temperature of the tissues around the tumor is not increased, which shows that the II-1 has the advantage of low damage to the tissues around the tumor when being used for the photothermal therapy.
Example 12 photothermal therapy experiments in mice
Nude mice were divided into 4 groups. Group 1 mu.L of II-1 (300. mu. moL) was injected into mice via the tail vein, and the tumor sites of the mice were irradiated with 808nm laser for 5 minutes. Group 2 was injected with 200. mu.L of II-1 (300. mu. moL) without laser irradiation. Group 3 was injected with saline and laser irradiated for 5 minutes. Group 4 saline was injected without laser irradiation. Tumor volume was measured daily with a vernier caliper for each group of mice and recorded for 30 days.
As shown in FIG. 13, the tumor volume before photothermal therapy in group 1 of nude mice after photothermal therapy was 70mm3On the left and right sides, after photo-thermal treatment, the tumor broke the next day, no obvious tumor growth is seen along with the increase of time, the tumor broke part starts to heal, and the broke part heals completely at the 16 th day and has a small scar. Tumor volume change as shown in fig. 13, the mice in the experimental group (group 1) had tumor elimination after laser irradiation, and had no recurrence within 20 days. While the control ( groups 2, 3 and 4) mice had a continuous increase in tumor size and had grown up within 20 days25 times. The change of the body weight of the mice is shown in figure 14, the body weight of the mice in the experimental group and the body weight of the mice in the control group have no abnormal change, and no obvious side effect of II-1 is seen. Dissecting mice 20 days after experiment, and slicing tumor, liver and lung&And E, dyeing and observing. The tumor cells are detected to be apoptotic, and no obvious damage is seen to the lung and the liver. The II-1 is proved to have excellent photo-thermal treatment capability, no damage to internal organs, small side effect, and relative safety and reliability.
The experiments show that the compound II-1 has excellent photo-thermal tumor killing effect under 808nm laser irradiation, has high safety and wide application prospect in clinical photo-thermal cancer treatment. Other compounds of the invention have been shown to have similar photothermal therapeutic effects.
Example 13 photodynamic effect test
Experimental group Carboxy-H was added to 3mL of water2DCFDA compound, working concentration of compound 25. mu.M, was added with compound II-1 (final concentration of 10. mu.M). Control group was added with H at the same concentration without II-12O2. Another control group was supplemented with carboxy-H alone2A DCFDA compound. After the sample was cooled to room temperature, the fluorescence emission spectrum was measured by irradiating with a 808nm laser for 10 minutes (Ex ═ 495nm, Em ═ 530 nm). As shown in FIG. 15, the fluorescence intensity of the experimental group is much higher than that of the control group, indicating that Compound II-1 can generate Reactive Oxygen Species (ROS) with excellent photodynamic effect. Other compounds of the invention were also shown to have similar photodynamic effects.
EXAMPLE 14 photoacoustic imaging test
Experimental group to 1mL of water, 2.5, 5, 10, 20. mu.L of compound II-1 ( concentration 5, 10, 20, 40. mu.M, respectively) was added, and the test solution was placed in the prosthesis to perform photoacoustic imaging test, and the test results showed that the photoacoustic signal increased with the increase in the concentration of compound II-1, and the photoacoustic signal was strongest at 750nm (FIG. 16). This example demonstrates that compound II-1 has a significant photoacoustic signal.
Example 15 photoacoustic imaging assay in mice
Subcutaneous injection 10 into the left side of 6-week-old female nude mice74T1 cells, growth of tumor volume to 60mm3. 200 μ LII-1(300 μmoL) was injected into mice via the tail vein. And monitoring with a multispectral photoacoustic tomography imager at different times. As shown in fig. 17, no signal was observed within 2 hours after injection, and a distinct photoacoustic signal was observed at the tumor site at hour 4. With time, the tumor site has photoacoustic signals up to 24 hours. This example demonstrates that compound II-1 has excellent tumor targeting as well as excellent photoacoustic signaling.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the embodiments, it will be apparent to those skilled in the art that the technical solutions described in the foregoing embodiments may be modified or some technical features may be substituted equally; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.

Claims (7)

1. A compound with a structure shown in a formula (III), an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof,
Figure FDA0001875886950000011
in the formula (III):
X2selected from O, S or-CR20R20’-；
Y3、Y4、Y5Each independently selected from H, hydroxyl, halogen atom, substituted or unsubstituted amino or alkoxy;
t1、t2、t3each independently selected from an integer of 0 to 5;
R13、R13’、R14each independently selected from-CN, -CF3，F，-SO2CF3，-NO2，-COOEt，-SO2ph，
Figure FDA0001875886950000012
Figure FDA0001875886950000013
R15Is- (CH)2)m-、
Figure FDA0001875886950000014
m is an integer of 0 to 5;
R16and R17Together forming a connection that is one of:
Figure FDA0001875886950000015
or R16、R17And X2Together form the following connection
Figure FDA0001875886950000016
Wherein R isa、Rb、Rc、Rd、Re、Rf、RgEach independently selected from H, halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted carboxy, substituted or unsubstituted hydroxy and substituted or unsubstituted amino;
R18、R18’、R20and R20' are each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group;
when the group is substituted, the substituent is mono-or polysubstituted.
2. The compound of claim 1, wherein t is1And t2Are all 1, t3Is 0.
3. The compound of claim 1, wherein R is13、R13' are all-CN, R14is-CN or
Figure FDA0001875886950000021
4. The compound of claim 1, wherein R is18、R18' each is independently selected from H, - (CH)2)qCH3、-(CH2)qCF3、-(CH2)qCHCH2、-(CH2)qCCH、-(CH2)qOH、-(CH2)qCOOH、-(CH2)qNH2、-(CH2)qCHO、-(CH2)qCO(CH2)q’CH3、-(CH2)qO(CH2)r’CH3、
Figure FDA0001875886950000022
Figure FDA0001875886950000023
Wherein q, q' are each independently selected from integers from 0 to 12.
5. The compound of claim 1,
said Y is3And Y5Are all H;
Y4is Cl, Br or-NR21R21’-；
t1、t2Are all 1, t3Is 0;
R21、R21' are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylSubstituted or unsubstituted alcohol group, substituted or unsubstituted ether group, substituted or unsubstituted aldehyde group, substituted or unsubstituted carboxyl group, substituted or unsubstituted amido group, substituted or unsubstituted ester group and substituted or unsubstituted amino group.
6. The compound of claim 1, wherein the compound is compound II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14, or II-15.
7. A pharmaceutical composition comprising
1) A therapeutically effective dose of a compound of any one of claims 1-6, its isomer, pharmaceutically acceptable salt, hydrate or solvate thereof, and
2) a pharmaceutically acceptable carrier.
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