CN109956932A - It is a kind of can activated form photosensitizer preparation tumor thermal therapy reagent in application - Google Patents
It is a kind of can activated form photosensitizer preparation tumor thermal therapy reagent in application Download PDFInfo
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- CN109956932A CN109956932A CN201711341762.8A CN201711341762A CN109956932A CN 109956932 A CN109956932 A CN 109956932A CN 201711341762 A CN201711341762 A CN 201711341762A CN 109956932 A CN109956932 A CN 109956932A
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
Abstract
The present invention provides one kind can application of the activated form photosensitizer in preparation tumor thermal therapy reagent.It is provided by the present invention can activated form photosensitizer itself do not have photo-thermal effect, and after being restored by nitro by nitroreductase in tumor hypoxia environment, apparent photo-thermal effect can be generated, and then realizes the targeting photo-thermal therapy of tumour, while also will not influence normal cell.
Description
Technical field
The present invention relates to oncotherapy reagent field, in particular to one kind can activated form photosensitizer in preparation tumour
Application in photo-thermal therapy reagent.
Background technique
It is well known that malignant tumour seriously endangers human life and health, wherein entity tumor accounts for clinical malignant tumour 85%
More than, and weary oxygen is then one of the important feature of entity tumor.Tumor hypoxia cell is in metabolism, molecular genetics and pathology
It changes in terms of physiology, to play very important effect in the evolution progression of tumour, and chemicotherapy is resisted
And lead to tumor by local recurrence, DISTANT METASTASES IN and prognosis mala.Light therapy, including photodynamic therapy (PDT) and photo-thermal therapy
(PTT), due to having the advantages that improve antitumous effect, reduce side effect and overcome multidrug resistance, it is introduced into cancer
In the clinical test for the treatment of.
Currently, to have had been approved by quick dose of some PDT lights certain specific to treat for food and drug administration (FDA)
Indication.However, PDT is highly dependent on O2, therefore, it is invalid in tumor hypoxia environment.On the contrary, PTT is as a kind of
New treatment technology, is not influenced by tumor hypoxia.However, current PTT photosensitizer (such as ICG) is usually that one kind can not turn
The form changed causes normal tissue and tumor tissues indiscriminate over the course for the treatment of once exposure can generate photo-thermal effect
Heating, and this may cause normal tissue and burns.Therefore, had by the exploitation of the PTT photosensitizer of microenvironment activated form very heavy
The meaning wanted.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention be to provide it is a kind of can activated form photosensitizer in preparation tumor thermal therapy reagent
Application in can activate photosensitizer itself not have photo-thermal effect employed in the present invention, and be gone back in weary oxygen environment
After original, apparent photo-thermal effect can be generated, and then realize the photo-thermal therapy of tumour, while also will not influence normal cell.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
It is a kind of can activated form photosensitizer preparation tumor thermal therapy reagent in application in application, it is described can activated form
Photosensitizer structure is as follows:
NO2-R1-R2-Xl-R3(1),
In compound (I), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub-
Alkylaryl, arlydene alkyl or substituted alkylene aryl；
R3For two area's luminescent dye molecule base of near-infrared；
X1For alkyl, imino group, amide groups, hydroxyl or ester group；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or
One of person IR1061 and its derivative.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, R3For IR1048
And its derivative molecular base.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, it is described to activate
Type photosensitizer structure is as follows:
In compound (II) or (II'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace sub- virtue
Base, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
X1For imino group, amide groups or ester group；
R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, replaces alkenylene, arlydene, takes
For arlydene, alkylidene aryl, alkenylene aryl, substituted alkylene aryl, replace alkenylene aryl, arlydene alkyl, sub- virtue
Base alkenyl replaces arlydene alkyl, or replaces arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue
Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
X2For halogen or tetrafluoroborate.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, the compound
(II) or in (II'),
R2For the alkylidene or substituted alkylene of C1~C30；X1For imino group, amide groups or ester group；R4For C0-C30
Alkylidene or substituted alkylene；R5For C2-C30 alkenylene or replace alkenylene；R6For the alkylidene or substitution time alkane of C2-C30
Base；R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl
Aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；R12、R18It is independently fluorine, chlorine, bromine or iodine；X2For
Halogen or tetrafluoroborate.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, it is described to activate
Type photosensitizer structure is as follows:
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, it is described to activate
The preparation step of type photosensitizer is as follows:
By NO2-R1-R2-Y1(i) and R3-Y2(ii) hybrid reaction to get it is described can activated form photosensitizer；
Wherein, in compound (i), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces sub- heteroaryl
Base；R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, alkylidene aryl or substituted alkylene
Aryl, arlydene alkyl or substituted alkylene aryl；Y1For amino, carboxyl or hydroxyl；
In compound (ii), R3For two area's luminescent dye molecule base of near-infrared, Y2For amino, halogen, hydroxyl or carboxyl；
It is furthermore preferred that two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or
One of IR1061 and its derivative.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, compound (i) knot
Structure are as follows:
Wherein, in compound (iii) or (iii'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or take
For arlydene, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue
Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
And/or the structure of compound (ii) are as follows:
Wherein, in compound (iv), R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, takes
For alkenylene, arlydene, replace arlydene, alkylidene aryl, alkenylene aryl, substituted alkylene aryl, substitution alkenylene virtue
Base arlydene alkyl, arlydene alkenyl, replaces arlydene alkyl, or replaces arlydene alkenyl；R6For the alkylidene of C2-C30
Or replace alkylidene；R7-R20It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkane
Base aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；Y2For amino, halogen, hydroxyl or carboxyl；X2For halogen
Element or tetrafluoroborate.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, the compound
(iii) or (iii') respectively by
(v') with
X3-R2-Y3(vi) it is made by condensation and deprotection；
Wherein, in compound (v) or (v'), R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkane
Base, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkyl at aryl；
In compound (vi), X3For halogen；R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace sub- virtue
Base, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Y3For with after protection group reaction
Amino, carboxyl perhaps hydroxyl and by hydrolysis to obtain corresponding amino, carboxyl or hydroxyl.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, the compound
(iii) or in (iii'):
R2For the alkylidene or substituted alkylene of C1~C30；X1For imino group, amide groups or ester group；R21、R22Respectively
It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkane
Base or substituted aryl alkyl；Y1For amino, hydroxyl or carboxyl；
And/or in compound (iv), R4For the alkylidene or substituted alkylene of C0-C30；R5For C2-C30 alkenylene or take
For alkenylene；R6For the alkylidene or substitution alkylidene of C2-C30；R7-R11、R13-R18、R19-R22It is independently hydrogen, C1-
The alkyl of C30 replaces alkyl, aryl, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkane
Base；R12、R18It is independently fluorine, chlorine, bromine or iodine；Y2For amino, halogen, hydroxyl or carboxyl；X2For halogen or tetrafluoro
Borate.
Preferably, it is of the present invention can activated form photosensitizer in tumor thermal therapy application in, compound (iii)
Structure are as follows:；The structure of compound (iii') are as follows:
And/or the structure of compound (iv) are as follows:
Compared with prior art, the invention has the benefit that
In the present invention it is used can activated form photosensitizer using 2- (2- nitroimidazole) ethamine as specificly-response group, to have
Engine dyeing material IR-1048 is precursor structure, itself does not have photo-thermal effect, and the nitro in photosensitizer molecule is by nitroreductase
(NTR) it being reduced into (i.e. IR1048-MZ is reduced to IR1048-MZH by NTR) after amino, photo-thermal effect greatly enhances, so as to
Realize the photo-thermal therapy for tumour；
Meanwhile in the present invention it is used can activated form photosensitizer not will receive the influence of reducing substances Vc, GSH, Cys etc.；
And in physiological conditions, the fluctuation of pH will not to the present invention can the light thermal property of activated form photosensitizer have an impact；
Further, the present invention can activated form photosensitizer excitation wavelength near infrared region, than swashing needed for traditional photosensitive agent
It is longer to send out wavelength, the penetration depth of light source, light injury of the reduced light source to tissue can be effectively improved；
Simultaneously as molecule is positively charged, thus the present invention can activated form photosensitizer can be very under the action of cell membrane negative electricity
It is fast to complete transmembrane movement.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is that 1 product MZ-BOC nuclear-magnetism of the embodiment of the present invention tests map；
Fig. 2 is 1 product MZ-BOC mass spectrometric measurement map of the embodiment of the present invention；
Fig. 3 is that 1 product MZ nuclear-magnetism of the embodiment of the present invention tests map；
Fig. 4 is 1 product MZ mass spectrometric measurement map of the embodiment of the present invention；
Fig. 5 is 1 product photosensitizer molecule IR1048-MZ nuclear-magnetism test chart of the embodiment of the present invention；
Fig. 6 is 1 product photosensitizer molecule IR1048-MZ mass spectrometric measurement figure of the embodiment of the present invention；
Fig. 7 is the reacting flow chart of the embodiment of the present invention 1；
Fig. 8 is the absorption light being added after the NTR solution of various concentration in 1 product IR1048-MZ solution of the embodiment of the present invention
Compose test chart；
Fig. 9 is the thermal imaging and temperature test figure after the NTR solution of various concentration is added in IR1048-MZ solution；
Wherein, (a) is thermal imaging test chart, (b) is temperature test figure；
Figure 10 is thermal imaging test chart after injecting IR1048-MZ to rat tail vertebral vein；
Wherein, (a) is mouse to be tested, (b) is mouse thermal imaging test chart；
Figure 11 is the test result of IR1048-MZ photo-thermal therapy mouse in-vivo tumour；
Wherein, (a) is gross tumor volume statistical results chart, (b) is mouse survival rate statistical results chart.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
In view of the photosensitizer currently used for tumor thermal therapy, for normal tissue, there may be the skills for the injuries such as burn
Art problem, the present invention provides it is a kind of it is novel, in tumor thermal therapy can activated form photosensitizer, the present invention can activated form
After photosensitizer is restored in tumor hypoxia environment by NTR, just there is good photo-thermal effect, it is thus possible to targetedly to tumour
The disadvantages of cell carries out photo-thermal therapy, avoids conventional photosensitizer cancer target performance poor.
Specifically, it is provided by the present invention can activated form photosensitizer structure it is as follows:
NO2-Rl-R2-Xl-R3(1),
In compound (I), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；It is excellent
Choosing, R1For the arlydene of C5~C15, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；It is further preferred that R1For
The inferior heteroaryl of C5~C15 replaces inferior heteroaryl, wherein inferior heteroaryl replaces the hetero atom in inferior heteroaryl to be
One of nitrogen, oxygen, sulphur are a variety of, and contained heteroatomic quantity is one in each inferior heteroaryl or substitution inferior heteroaryl
Or it is multiple；Such as R1It can be, but be not limited to: furans, thiophene, pyrroles, imidazoles, thiazole, pyrazoles, pyrans, pyridine, pyrimidine, quinoline
Quinoline or purine etc.；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub-
Alkylaryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene of the linear chain or branched chain of C0~C30, C0
The substituted alkylene of the linear chain or branched chain of~C30；It is furthermore preferred that R2For the alkylidene of the linear chain or branched chain of C1~C12, C1~
The substituted alkylene of the linear chain or branched chain of C12；It is further preferred that R2For the alkylidene of the linear chain or branched chain of C1~C6, C1~
The substituted alkylene of the linear chain or branched chain of C6, such as can be, but be not limited to methylene, ethylidene, propylidene, isopropylidene,
Butylidene, isobutylidene, pentylidene, isoamylidene, sub- neopentyl, hexylidene etc.；
R3For two area's luminescent dye molecule base of near-infrared, it is preferred that two area's luminescent dye molecule of near-infrared are as follows: IR1048 and
Its derivative, IR1050 and its derivative or one of IR1061 and its derivative；
Wherein, IR1048 structure is as follows:(tetrafluoro boric acid 1- fourth
Base -2- [2- [3- [(1- butyl -6- chlorobenzene [cd] indoles -2 (1H)-subunit) ethylidene] the chloro- 1- cyclohexene -1- base of -2-] ethylene
Base] -6- chlorobenzene [cd] indoles, CAS 155613-98-2)；
Wherein, IR1050 structure is as follows:(1-Butyl-2-[2-[3-
[(1-butyl-6-chlorobenz[cd]indol-2(1H)-ylidene)ethylidene]-2-chloro-5-methyl-
1-cyclohexen-1-yl] ethenyl] -6-chlorobenz [cd] indoliumtetrafluoroborate, No. CAS:
155614-00-9)；
Wherein, IR1061 structure is as follows:(tetrafluoro boric acid 4-
[2- [the chloro- 3- of 2- [(2,6- diphenyl -4H- thiapyran -4- subunit) ethylidene] -1- cyclohexene -1- base] vinyl] -2,6- hexichol
Base thio-pyrylium, No. CAS: 155614-01-0)；
And it as described above can activated form photosensitizer NO2-Rl-R2-X1-R3(I) in, R3It can be the near-infrared of structure as above
Two area's luminescent dye molecule bases, or two area's luminescent dye molecule derivative base of near-infrared for structure as above；
It is furthermore preferred that R3For IR1048 molecule base or R3For IR1048 derivative molecular base；
X1For imino group, amide groupsOr ester group
Preferably, it is provided by the present invention can activated form photosensitizer structure it is as follows:
That is, invention further provides one kind using nitroimidazole as specificly-response group, it is with IR-1048 derivative
Two area's luminescent dye molecule of near-infrared can activated form photosensitizer for precursor structure.
And the preferred structure can activated form photosensitizer in normal physiological context, there is no photo-thermal effects；And in tumour
In Cell hypoxia environment, increases since anoxic will lead to reduction stress, lead to the overexpression of nitroreductase (NTR), thus,
In tumor hypoxia environment, this preferably can activated form photosensitizer can be restored by NTR, nitryl group therein can be reduced to ammonia
Base, and the product after restoring then has apparent photo-thermal activity, can be further used as photo-thermal therapy reagent and apply, and this
So that the present invention can activated form photosensitizer have good neoplasm targeted therapy effect effect.
Further, in compound (II) or (II'), R2Alkylidene or substituted alkylene, sub- virtue for C0~C30
Base replaces arlydene, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Preferably,
R2For the alkylidene or substituted alkylene of C1~C30；It is furthermore preferred that R2For the alkylidene of the linear chain or branched chain of C1~C12, C1~
The substituted alkylene of the linear chain or branched chain of C12；It is further preferred that R2For the alkylidene of the linear chain or branched chain of C1~C6, C1~
The substituted alkylene of the linear chain or branched chain of C6, such as can be, but be not limited to methylene, ethylidene, propylidene, isopropylidene,
Butylidene, isobutylidene, pentylidene, isoamylidene, sub- neopentyl, hexylidene etc.；
X1For imino group, amide groupsOr ester group
R4For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia
Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl
Arlydene alkyl, or replace arlydene alkenyl；Preferably, R4For the alkylidene or substituted alkylene of C0-C30；It is furthermore preferred that
R4For the straight chain or the alkylidene of straight chain of C0-C12, the substituted alkylene of C0~C12；It is further preferred that R4For the straight of C0~C6
The alkylidene of chain or branch, the substituted alkylene of the linear chain or branched chain of C0~C6, such as R4It can be chemical bond (i.e. cyclohexenyl group
With X1Be connected directly), methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene,
Sub- neopentyl, hexylidene etc.；
R5For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia
Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl
Arlydene alkyl, or replace arlydene alkenyl；Preferably, R5For C2-C30 alkenylene or replace alkenylene；It is furthermore preferred that R5
For the straight chain of C2~C12 or alkenylene, the straight chain of C2~C12 or the substitution alkenylene of straight chain of straight chain；It is further preferred that R5
For the straight chain of C2-C6 or alkenylene, the straight chain of C2~C6 or the substitution alkenylene of straight chain of straight chain, for example, R5It can be sub- second
Alkenyl, allylidene, sub- isopropenyl, butenylidene, sub- isobutenyl, inferior pentenyl, sub- hexenyl etc.；
R6For the alkylidene or substitution alkylidene of C2-C30；Preferably, R6For the alkylidene of the linear chain or branched chain of C2~C12,
The substituted alkylene of the linear chain or branched chain of C1~C12；It is further preferred that R6For the alkylidene of the linear chain or branched chain of C2~C6,
The substitution alkylidene of the linear chain or branched chain of C2~C6, such as can be, but be not limited to ethylidine, propylidyne, secondary isopropyl, secondary fourth
Base, secondary isobutyl group, pentamethylene, secondary isopentyl, secondary neopentyl, hexylidyne etc.；
R7-R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue
Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
Preferably, R7-R11、R13-R18、R19-R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, takes
For aryl, alkylaryl, replace alkylaryl, aryl alkyl or substituted aryl alkyl；It is furthermore preferred that R7-R11、R13-R18、
R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl；It is further preferred that R7-R11、R13-R18、R19-R22Point
It is not independently the substitution alkyl of the linear chain or branched chain of hydrogen, the alkyl of the linear chain or branched chain of C1-C12, C1-C12；It is further excellent
Choosing, R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of the linear chain or branched chain of C1-C6, the straight chain of C1-C6 or branch
The substitution alkyl of chain, such as R7-R11、R13-R18、R19-R22Independently be hydrogen, methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
Preferably, R12、R18It is independently fluorine, chlorine, bromine or iodine；
X2For halogen or tetrafluoroborate.
It is furthermore preferred that it is provided by the present invention can activated form photosensitizer structure it is as follows:
And the present invention as above can activated form photosensitizer preparation method can refer to it is as follows: by NO2-R1-R2-Y1(i) with
R3-Y2(ii) target photosensitizer compounds can be obtained in hybrid reaction, and preparation method is more convenient and operation is relatively simple, fits
In large-scale expanding production；
Wherein, in compound (i), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces sub- heteroaryl
Base；Preferably, R1For the arlydene of C5~C15, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；Further preferably
, R1For the inferior heteroaryl or substitution inferior heteroaryl of C5~C15, wherein inferior heteroaryl replaces miscellaneous in inferior heteroaryl
Atom be one of nitrogen, oxygen, sulphur or a variety of, and each inferior heteroaryl or replace inferior heteroaryl in contained heteroatomic quantity
For one or more；Such as R1It can be, but be not limited to: is furans, thiophene, pyrroles, imidazoles, thiazole, pyrazoles, pyrans, pyridine, phonetic
Pyridine, quinoline or purine etc.；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub-
Alkylaryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene or substituted alkylene of C1~C30；More
Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C12, the substituted alkylene of the linear chain or branched chain of C1~C12；Further
Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C6, the substituted alkylene of the linear chain or branched chain of C1~C6, such as can be with
For, but it is not limited to methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, Asia newly
Amyl, hexylidene etc.；
Y1For amino, carboxyl or hydroxyl；
In compound (ii), R3For two area's luminescent dye molecule base of near-infrared, it is preferred that two area's fluorescent dye of near-infrared point
Son are as follows: IR1048 and its derivative, IR1050 and its derivative or one of IR1061 and its derivative；
Y2For amino, halogen, hydroxyl or carboxyl.
It is further preferred that raw materials used structure is as follows in preparation method of the present invention:
Wherein, in compound (iii) or (iii'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or take
For arlydene, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For C1
The alkylidene or substituted alkylene of~C30；It is furthermore preferred that R2For the alkylidene of the linear chain or branched chain of C1~C12, C1~C12's
The substituted alkylene of linear chain or branched chain；It is further preferred that R2For the alkylidene of the linear chain or branched chain of C1~C6, C1~C6's is straight
The substituted alkylene of chain or branch, such as can be, but be not limited to methylene, ethylidene, propylidene, isopropylidene, butylidene,
Isobutylidene, pentylidene, isoamylidene, sub- neopentyl, hexylidene etc.；
Y1For amino, carboxyl or hydroxyl；
R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue
Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；Preferably, R21、R22It is independently hydrogen, C1-C30
Alkyl replaces alkyl；It is further preferred that R21、R22It is independently hydrogen, the alkyl of the linear chain or branched chain of C1-C12, C1-
The substitution alkyl of the linear chain or branched chain of C12；Still more preferably, R21、R22It is independently hydrogen, the straight chain of C1-C6 or branch
The substitution alkyl of the alkyl of chain, the linear chain or branched chain of C1-C6, such as R21、R22Independently be hydrogen, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
And:
Wherein, in compound (iv),
R4For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia
Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl
Arlydene alkyl, or replace arlydene alkenyl；Preferably, R4For the alkylidene or substituted alkylene of C0-C30；It is furthermore preferred that
R4For the straight chain or the alkylidene of straight chain of C0-C12, the substituted alkylene of C0~C12；It is further preferred that R4For the straight of C0~C6
The alkylidene of chain or branch, the substituted alkylene of the linear chain or branched chain of C0~C6, such as R4It can be chemical bond (i.e. cyclohexenyl group
With X1Be connected directly), methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene,
Sub- neopentyl, hexylidene etc.；
R5For the alkylidene of C0-C30, substituted alkylene, alkenylene, replace alkenylene, arlydene, substitution arlydene, Asia
Alkylaryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkenyl, replaces alkenylene aryl
Arlydene alkyl, or replace arlydene alkenyl；Preferably, R5For C2-C30 alkenylene or replace alkenylene；It is furthermore preferred that R5
For the straight chain of C2~C12 or alkenylene, the straight chain of C2~C12 or the substitution alkenylene of straight chain of straight chain；It is further preferred that R5
For the straight chain of C2-C6 or alkenylene, the straight chain of C2~C6 or the substitution alkenylene of straight chain of straight chain, for example, R5It can be sub- second
Alkenyl, allylidene, sub- isopropenyl, butenylidene, sub- isobutenyl, inferior pentenyl, sub- hexenyl etc.；
R6For the alkylidene or substitution alkylidene of C2-C30；Preferably, R6For the alkylidene of the linear chain or branched chain of C2~C12,
The substituted alkylene of the linear chain or branched chain of C1~C12；It is further preferred that R6For the alkylidene of the linear chain or branched chain of C2~C6,
The substitution alkylidene of the linear chain or branched chain of C2~C6, such as can be, but be not limited to ethylidine, propylidyne, secondary isopropyl, secondary fourth
Base, secondary isobutyl group, pentamethylene, secondary isopentyl, secondary neopentyl, hexylidyne etc.；
R7-R20It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl virtue
Base replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
Preferably, R7-R11、R13-R18、R19-R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, takes
For aryl, alkylaryl, replace alkylaryl, aryl alkyl or substituted aryl alkyl；It is furthermore preferred that R7-R11、R13-R18、
R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl；It is further preferred that R7-R11、R13-R18、R19-R22Point
It is not independently the substitution alkyl of the linear chain or branched chain of hydrogen, the alkyl of the linear chain or branched chain of C1-C12, C1-C12；It is further excellent
Choosing, R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of the linear chain or branched chain of C1-C6, the straight chain of C1-C6 or branch
The substitution alkyl of chain, such as R7-R11、R13-R18、R19-R22Independently be hydrogen, methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
Preferably, R12、R18It is independently fluorine, chlorine, bromine or iodine；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
Further, raw material as described aboveOrIt can be byOrWith X3-R2-Y3(vi) it is made by condensation and deprotection reaction；
I.e., it is possible to which used compound (v) or (v') and compound (vi) pass through substitution-hydrolysis (deprotection) two-step reaction system
, and the Y in compound (vi)3Substituent group is then Y1Product structure after being reacted with protective agent, and pass through second remove-insurance
Step is protected, it can be by Y3Reaction obtains Y1；
Wherein, in compound (v) or (v'), R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkane
Base, substituted aryl, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkyl at aryl；Preferably, R21、R22
It is independently hydrogen, the alkyl of C1-C30, substitution alkyl；It is further preferred that R21、R22It is independently hydrogen, C1-C12
The alkyl of linear chain or branched chain, C1-C12 linear chain or branched chain substitution alkyl；Still more preferably, R21、R22Independently
It is the substitution alkyl of the linear chain or branched chain of hydrogen, the alkyl of the linear chain or branched chain of C1-C6, C1-C6, such as R21、R22Independently
It is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl, hexyl etc.；
In compound (vi), X3For halogen；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replaces arlydene, alkylidene aryl or replace sub-
Alkylaryl, arlydene alkyl or substituted alkylene aryl；Preferably, R2For the alkylidene or substituted alkylene of C1~C30；More
Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C12, the substituted alkylene of the linear chain or branched chain of C1~C12；Further
Preferably, R2For the alkylidene of the linear chain or branched chain of C1~C6, the substituted alkylene of the linear chain or branched chain of C1~C6, such as can be with
For, but it is not limited to methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, Asia newly
Amyl, hexylidene etc.；
Y3For with amino, carboxyl or the hydroxyl after protection group reaction, and by hydrolysis to obtain corresponding amino, carboxylic
Base or hydroxyl；
For example, Y3It can be acyl group, ether, carbonyl amino, carboxyl or hydroxyl that perhaps ester group is protected.
Still more preferably, in preparation method of the present invention, raw materials used compound are as follows:
Or
And
Further, with compound(MZ) for, to the preparation method of the raw material into one
Step explanation, which can refer to as follows:
Embodiment 1
(1) preparation of MZ-BOC molecule:
2- nitroimidazole (0.5g, 4.42mmol) is dissolved with 2mLDMF, K is then added portionwise under agitation2CO3
(0.915g, 6.63mmol) and N-Boc- bromine ethamine (0.99g, 4.42mmol) reacts overnight under nitrogen protection；
Then, revolving removes solvent, and vacuum drying after obtained solid is dissolved in water, is extracted with ethyl acetate, collects organic
Phase, revolving remove solvent, and crude product re-crystallizing in ethyl acetate obtains dark yellow solid product MZ-BOC (0.10g, 89%).
Referring to Fig. 1 and Fig. 2, atlas analysis is as follows for product MZ-BOC nuclear-magnetism and mass spectrometric measurement map difference:
MZ-BOC:1HNMR(400MHz,DMSO-d6) δ 7.46 (s, 1H), 7.14 (s, 1H), 4.43 (t, J=5.6Hz,
2H), 3.36 (q, J=5.9Hz, 2H), 1.31 (s, 9H)；
HRMS(ESI+):m/zcalcdforC10H16N4O4:279.1064[M+Na+],found279.1060。
(2) preparation of MZ molecule
MZ-BOC (0.85g, 3.3mmol) is dissolved in methanol (2mL) and is then under agitation added 1.25MHCl's
Methanol solution (2mL), reacts 5h at room temperature；
Then, revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, rotates and removes solvent, vacuum drying,
Obtained solid crude product recrystallizing methanol obtains faint yellow solid product MZ (0.64g, 89%).
Respectively referring to Fig. 3 and Fig. 4, atlas analysis is as follows for product MZ nuclear-magnetism and mass spectrometric measurement map:
MZ:1HNMR(400MHz,CD3OD): δ 7.48 (d, J=1.0Hz, 1H), 7.14 (d, J=1.1Hz, 1H), 4.50
(t, J=6.3Hz, 2H), 3.07 (t, J=6.3Hz, 2H)；
HRMS(ESI+):m/zcalcdforC5H8N4O2:157.0720[M+H+],found157.0725；179.0539[M+
Na+],found179.0537。
(3) preparation of photosensitizer molecule IR1048-MZ:
IR-1048 (37mg, 0.05mmol) is dissolved in anhydrous DMF (10mL), then into solution be added MZ (112.6mg,
0.5mmol), quickly stirring, and a period of time is reacted under 40 DEG C of nitrogen protections；
Then, revolving removes solvent, and silicagel column is crossed in vacuum drying, and methylene chloride: methanol makees eluent, and gradient elution removes
Solvent is removed, obtains solid product, IR1048-MZ,(6.44mg23%).
Referring to figs. 5 and 6, atlas analysis is as follows for product nuclear-magnetism and mass spectrometric measurement map difference:
IR1048-MZ:1HNMR (400MHz, Methanol-d4): δ 8.63 (d, J=7.5Hz, 1H), 8.17 (d, J=
7.6Hz, 1H), 8.11 (d, J=8.2Hz, 1H), 8.01 (d, J=12.8Hz, 1H), 7.96-7.84 (m, 5H), 7.72 (s,
1H), 7.51 (d, J=7.8Hz, 1H), 7.14 (s, 1H), 7.10 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=
7.8Hz, 1H), 6.15 (d, J=12.9Hz, 1H), 4.29-4.23 (m, 2H), 2.63-2.51 (m, 2H), 1.82-1.77 (m,
2H), 1.47 (td, J=15.3,14.4,7.8Hz, 4H), 1.12 (dq, J=14.5,7.7Hz, 4H), 1.01 (t, J=7.4Hz,
4H), 0.92 (dt, J=18.6,7.2Hz, 6H), 0.76-0.70 (m, 1H), 0.59 (t, J=7.2Hz, 3H)；
HRMS(ESI+):m/zcalcdforC45H45BCl2F4N6O2:771.2976[M-BF4 -]；found771.2975..
The reaction process of embodiment 1 is referring to Fig. 7.
Embodiment 2
(1) preparation of MZ-BOC molecule:
2- nitroimidazole (1.0g, 8.84mmol) is dissolved with 4mLDMF, K is then added portionwise under agitation2CO3
(1.83g, 13.26mmol) and N-Boc- bromine ethamine (1.98g, 8.84mmol) reacts overnight under nitrogen protection.
Revolving removes solvent, and vacuum drying, obtained solid is soluble in water, is then extracted with ethyl acetate, collects organic phase,
Revolving removes solvent.Gained crude product obtains dark yellow solid product MZ-BOC (0.19g, 83%) with re-crystallizing in ethyl acetate.
Product MZ-BOC nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(2) preparation of MZ molecule
MZ-BOC (1.7g, 6.6mmol) is dissolved in methanol (4mL), the methanol that 1.25MHCl is added under stirring condition is molten
Liquid (4mL), reacts 8h at room temperature；
Revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, and revolving removes solvent, vacuum drying.Obtained solid
Crude product recrystallizing methanol obtains faint yellow solid product MZ (1.16g, 81%).
Product MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(3) preparation of photosensitizer molecule IR1048-MZ:
IR-1048 (74mg, 0.1mmol) is dissolved in anhydrous DMF (15mL), then be added MZ (225.2mg,
1.0mmol), it quickly stirs, is reacted under 40 DEG C of nitrogen protections；
Revolving removes solvent, and vacuum drying crosses silicagel column, methylene chloride: methanol makees eluent, and gradient elution removes molten
Agent obtains solid product IR1048-MZ (10.08mg18%).
Product IR1048-MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
Embodiment 3
(1) preparation of MZ-BOC molecule:
2- nitroimidazole (1.5g, 13.26mmol) is dissolved with 6mLDMF, then, under agitation, is added portionwise
K2CO3(2.745g, 19.89mmol) and N-Boc- bromine ethamine (2.97g, 13.26mmol) reacts overnight under nitrogen protection.
Revolving removes solvent, and vacuum drying, obtained solid is soluble in water, is then extracted with ethyl acetate, collects organic phase,
Revolving removes solvent.Crude product obtains dark yellow solid product MZ-BOC (0.26g, 78%) with re-crystallizing in ethyl acetate.
Product MZ-BOC nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(2) preparation of MZ molecule
MZ-BOC (2.55g, 9.9mmol) is dissolved in methanol (6mL), is then added 1.25MHCl's under agitation
Methanol solution (6mL), reaction is stayed overnight at room temperature；
Revolving removes solvent, and obtained solid is washed with methanol, collects washing lotion, and revolving removes solvent, vacuum drying；Obtained solid
Crude product recrystallizing methanol obtains faint yellow solid product MZ (1.60g, 74%)；
Product MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.
(3) preparation of photosensitizer molecule IR1048-MZ:
IR-1048 (111mg, 0.15mmol) is dissolved in anhydrous DMF (25mL), then be added MZ (337.8mg,
1.5mmol), it quickly stirs, reacts 10h under 50 DEG C of nitrogen protections；
Revolving removes solvent, and vacuum drying crosses silicagel column, methylene chloride: methanol makees eluent, and gradient elution removes molten
Agent obtains solid product IR1048-MZ (15.96mg, 19%).
Product IR1048-MZ nuclear-magnetism and Mass Spectrometer Method map and analysis result are in the same manner as in Example 1.Experimental example 1
Using IR1048-MZ prepared in embodiment 1 as test compound, following experiment test is carried out:
(1) NTR solution (the NTR final concentration difference of various concentration is added into the IR1048-MZ solution that concentration is 5 μ g/mL
Are as follows: 0,1,2,3,4,5,6,7,8,9,10 μ g/mL), the absorption spectrum of each solution is then surveyed with ultraviolet-visible spectrophotometer.
As a result as shown in figure 8, by Fig. 8 result it is found that with NTR concentration increase, suction of the solution at 900-1100nm
Receipts gradually increase.It can be seen that NTR has the function of exciting IR1048-MZ infrared absorbance.
(2) NTR solution (the NTR final concentration difference of various concentration is added into the IR1048-MZ solution that concentration is 5 μ g/mL
Are as follows: 0,1,2,3,4,5,6,7,8,9,10 μ g/mL), then with 808nm (300mWcm-2) laser shine 3 minutes, use thermal imaging system
Solution is imaged, and records the temperature of corresponding solution, shown in thermal imaging result such as Fig. 9 (a) after laser irradiation 3 minutes,
Shown in the temperature such as Fig. 9 (b) of solution after laser irradiation 3 minutes；
By the testing result of Fig. 9 (a) and Fig. 9 (b) it is found that in the presence of no NTR (i.e. the final concentration of 0 μ g/mL of NTR),
There is no photo-thermal effects by IR1048-MZ, and after NTR is added, IR1048-MZ is reduced to IR1048-MZH (i.e. on IR1048-MZ
Nitro is reduced to amino), there is apparent photo-thermal temperature rise effect, it can be seen that, NTR has activation IR1048-MZ photo-thermal activity
The effect of.
(3) 200 μ LIR1048-MZ solution are injected intravenously in injection mouse body (dosage 0.2mg/kg) by tail bone,
After 14h, 808nm (300mWcm-2) laser shine 3 minutes, and mouse is imaged with thermal imaging system, as a result such as Figure 10
It is shown；
Wherein, Figure 10 (a) is the mouse for receiving treatment, and Figure 10 (b) is the thermal imaging knot of mouse after laser irradiation 3 minutes
Fruit is tumor locus in virtual coil in figure.
By the thermal imaging result of Figure 10 (b) it is found that after photo-thermal therapy three minutes, the temperature of tumor locus reaches 58 DEG C, light
Thermal effect is obvious.It can be seen that IR1048-MZ have good photo-thermal therapy effect, and be capable of targeting for tumour
Cell area carries out photo-thermal therapy.
(4) 24 tumor-bearing mices are randomly divided into 4 groups, every group 5.
Wherein, 200 μ L physiological saline of every tail vein injection of the mouse of physiological saline group, without illumination；
200 μ L physiological saline of every tail vein injection of physiological saline+laser group mouse, and with 808nm (300mWcm-2)
Laser shine 3 minutes；
The 200 μ LIR1048-MZ of every tail vein injection of mouse (40 μ g/ are only) of IR1048-MZ group, without illumination；
200 μ L μ LIR1048-MZ of every mouse tail vein injection of IR1048-MZ+ laser group (40 μ g/ are only), and use 808nm
(300mWcm-2) laser shine 3 minutes.
Measurement record mouse gross tumor volume and mouse survival rate every three days, as a result respectively such as Figure 11 (a) and Figure 11 (b) institute
Show.
The experimental result of Figure 11 (a) is it is found that the growth of IR1048-MZ+ Laser on Mice tumour plays apparent inhibition work
With, and obviously subside after 5 days, without recurrence sign in 30 days, and add mouse and blank control group of the photosensitizer without illumination
The tumor growth rate of mouse is almost the same, it can be seen that, photosensitizer provided by the present invention has tumour after laser initiation
Apparent photo-thermal therapy effect；
Meanwhile by the experimental result of Figure 11 (b) it is found that the mouse (physiological saline group) of untreated after 30 days the death rate it is high
Up to 100%, mouse (IR1048-MZ+ laser group) death rate after treatment is 0%, and cure rate improves 100%.It can be seen that
Photosensitizer of the present invention has good therapeutic effect for tumour, can be realized effective, the thorough treatment of tumour, and controlling
It will not occur repeatedly after treatment.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. one kind can activated form photosensitizer preparation tumor thermal therapy reagent in application, which is characterized in that it is described to activate
Type photosensitizer structure is as follows:
NO2-R1-R2-X1-R3(I),
In compound (I), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, alkylidene aryl or substituted alkylene
Aryl, arlydene alkyl or substituted alkylene aryl；
R3For two area's luminescent dye molecule base of near-infrared；
X1For alkyl, imino group, amide groups, hydroxyl or ester group；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or
One of IR1061 and its derivative.
2. according to claim 1 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that R3For
IR1048 and its derivative molecular base.
3. according to claim 1 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that described
Can activated form photosensitizer structure it is as follows:
Or
In compound (II) or (II'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, Asia
Alkylaryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
X1For imino group, amide groups or ester group；
R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, replaces alkenylene, arlydene, replaces Asia
Aryl, alkenylene aryl, substituted alkylene aryl, replaces alkenylene aryl, arlydene alkyl, arlydene alkene at alkylidene aryl
Base replaces arlydene alkyl, or replaces arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R22Independently it is hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, takes
Haloalkylaryl, aryl alkyl or substituted aryl alkyl；
X2For halogen or tetrafluoroborate.
4. according to claim 3 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that described
In compound (II) or (II'),
R2For the alkylidene or substituted alkylene of C1~C30；
X1For imino group, amide groups or ester group；
R4For the alkylidene or substituted alkylene of C0-C30；
R5For C2-C30 alkenylene or replace alkenylene；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl
Aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
R12、R18It is independently fluorine, chlorine, bromine or iodine；
X2For halogen or tetrafluoroborate.
5. according to claim 4 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that described
Can activated form photosensitizer structure it is as follows:
Or
6. it is of any of claims 1-5 can application of the activated form photosensitizer in tumor thermal therapy, feature exists
In, it is described can activated form photosensitizer preparation step it is as follows:
By NO2-R1-R2-Y1(i) and R3-Y2(ii) hybrid reaction to get it is described can activated form photosensitizer；
Wherein, in compound (i), R1For the arlydene of C5~C30, inferior heteroaryl, replace arlydene, or replaces inferior heteroaryl；
R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene, alkylidene aryl or substituted alkylene
Aryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
In compound (ii), R3For two area's luminescent dye molecule base of near-infrared,
Y2For amino, halogen, hydroxyl or carboxyl；
Preferably, two area's luminescent dye molecule of near-infrared are as follows: IR1048 and its derivative, IR1050 and its derivative, or
One of IR1061 and its derivative.
7. can application of the activated form photosensitizer in tumor thermal therapy according to claim 6, which is characterized in that compound (i)
Structure are as follows:
Or
Wherein, in compound (iii) or (iii'), R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace sub-
Aryl, alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；
Y1For amino, carboxyl or hydroxyl；
R21、R22Independently it is hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, takes
Haloalkylaryl, aryl alkyl or substituted aryl alkyl；
And/or the structure of compound (ii) are as follows:
Wherein, in compound (iv), R4、R5Independently it is the alkylidene of C0-C30, substituted alkylene, alkenylene, replaces Asia
Alkenyl, arlydene replace arlydene, alkylidene aryl, alkenylene aryl, substituted alkylene aryl, replace alkenylene aryl, Asia
Aryl alkyl, arlydene alkenyl replace arlydene alkyl, or replace arlydene alkenyl；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R20Independently it is hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, takes
Haloalkylaryl, aryl alkyl or substituted aryl alkyl；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
8. according to claim 7 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that described
Compound (iii) or (iii') respectively by
With X3-R2-Y3
(vi) it is made by condensation and deprotection；
Wherein, in compound (v) or (v'), R21、R22It is independently hydrogen, halogen, the alkyl of C1-C30, substitution alkyl, virtue
Base, alkylaryl, replaces alkylaryl, aryl alkyl or substituted aryl alkyl at substituted aryl；
In compound (vi), X3For halogen；R2For the alkylidene or substituted alkylene of C0~C30, arlydene or replace arlydene,
Alkylidene aryl or substituted alkylene aryl, arlydene alkyl or substituted alkylene aryl；Y3For with the ammonia after protection group reaction
Base, carboxyl perhaps hydroxyl and by hydrolysis to obtain corresponding amino, carboxyl or hydroxyl.
9. according to claim 7 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that described
In compound (iii) or (iii'):
R2For the alkylidene or substituted alkylene of C1~C30；
X1For imino group, amide groups or ester group；
R21、R22Independently it is hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkylaryl, replaces alkyl
Aryl, aryl alkyl or substituted aryl alkyl；
Y1For amino, hydroxyl or carboxyl；
And/or in compound (iv), R4For the alkylidene or substituted alkylene of C0-C30；
R5For C2-C30 alkenylene or replace alkenylene；
R6For the alkylidene or substitution alkylidene of C2-C30；
R7-R11、R13-R18、R19-R22It is independently hydrogen, the alkyl of C1-C30, substitution alkyl, aryl, substituted aryl, alkyl
Aryl replaces alkylaryl, aryl alkyl or substituted aryl alkyl；
R12、R18It is independently fluorine, chlorine, bromine or iodine；
Y2For amino, halogen, hydroxyl or carboxyl；
X2For halogen or tetrafluoroborate.
10. according to claim 9 can application of the activated form photosensitizer in tumor thermal therapy, which is characterized in that change
Close the structure of object (iii) are as follows:
The structure of compound (iii') are as follows:
And/or the structure of compound (iv) are as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN112679486A (en) * | 2021-01-18 | 2021-04-20 | 南开大学 | Preparation and application of photosensitizer based on nitroreductase response |
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