CN107417706B - With light, the quick active chlorin Artesunate conjugate of sound and the preparation method and application thereof - Google Patents
With light, the quick active chlorin Artesunate conjugate of sound and the preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Abstract
The present invention relates to one kind to have light, the quick active chlorin Artesunate conjugate of sound and the preparation method and application thereof, belongs to technical field of chemical medicine.It is of the present invention in light, the quick active chlorin Artesunate conjugate of sound in vitro antitumor activity evaluation to human liver cancer cell Hep G2 have different degrees of inhibiting effect.Photolytic activity and ultrasonic activity are above chlorin e 6 and Artesunate respectively as positive control.Can be used for the photodynamic therapy of oncotherapy, in Sonodynamic therapy method photosensitizer, sound sensitiser preparation.
Description
Technical field
There is light, the quick active chlorin Artesunate conjugate of sound and preparation method thereof and answer the present invention relates to one kind
With belonging to technical field of chemical medicine.
Background technique
Photodynamic therapy (Photodynamic therapy, PDT) and Sonodynamic therapy (Sonodynamic
Therapy, SDT), be respectively by photosensitizer (Photosensitizer) or photosensitizer (Sonosensitizer) in light or
Ultrasonic excitation issues biochemical reaction and kills tumour cell to reach a kind of medical technology of therapeutic purposes.Wherein photodynamics
Treatment (Photodynamic therapy, PDT) be using photosensitizer and visible light in having environment existing for oxygen, pass through light
Reaction generates active oxygen, makes death of neoplastic cells or apoptosis.Traditional treatment with surgical operation, chemotherapy, radiotherapy etc.
Method is compared, and PDT has the advantages that target tissue selectivity height, Small side effects, not damaged to internal organs；Sonodynamic therapy
(Sonodynamic therapy, SDT) is then on the basis of photodynamic therapy (Photodynamic therapy, PDT)
On a kind of new method that can be used for pernicious advanced tumors clinical treatment for growing up.It can be thin in tumour using sound sensitiser molecule
Enrichment intracellular replaces the light of photodynamic therapy to excite, generates and have cytotoxic singlet oxygen and shape using ultrasonic excitation
The effects of at ultrasonic cavitation, leads to apoptosis of tumor cells or death.Compared with photodynamic therapy, also have penetration power strong, nothing
The advantages that wound.Many Photosensitive compounds also have the quick effect of sound, and photosensitizer can be used as sound sensitiser and use.The report such as Yao Jianzhong
Road (synthesis of chlorin e 6 and its photosensitizer power and tumour photobiological activity, Chinese Journal of Pharmaceuticals, 2000,31 (5):
215-217) chlorin e 6 is superior to reference agent hematoporphyrin derivative (HPD) to the light power curative effect of mouse S 180 sarcoma,
In addition, Yao Jianzhong etc. also reports that (research of six lipid antifungal drug of novel dihydro porphin photosensitizer and ring, China are outstanding rich
Scholar's paper full-text database medical and health science and technology volume, E079-5) it a kind of is prepared by Phephorbide a, chlorin e 6
Chlorin derivative has photosensitive activity.Zheng Ruinian etc. also reports that (Chlorin e6 sound power is to human lung adenocarcinoma cell SPC A-
The effect of 1 growth, lung cancer in China magazine, 13 (3): 201-205) photosensitizer chlorin e 6 has a quick activity of sound simultaneously.But
There is also not high to tumor cells selectivity, active oxygen yield is low for such light, sound sensitiser, and required dosage is larger and in vivo
The disadvantages of clearance rate is slower.Artesunate is the semi-modified product of natural products qinghaosu, be reported with anti-malarial,
Antitumor isoreactivity.It is broken by the peroxide bridge of intramolecular, and induction generates active oxygen, and then makes tumour cell that apoptosis occur
Or it is dead.In view of the treatment principle of light, sound sensitiser, it is contemplated that designing the conjugate of a kind of chlorin and Artesunate, lead to
The generation quantity of enhancing active oxygen is crossed, the activity of light, sound sensitiser is improved, develops activity more preferably light, sound sensitiser for tumour
Light, Sonodynamic therapy.
Summary of the invention
The present invention has light, the quick active chlorin Artesunate conjugate of sound by the way that synthesis is a kind of, has obtained activity
It preferably can be used for the antitumoral compounds of light, Sonodynamic therapy.
Technical solution of the present invention:
One kind having light, the quick active chlorin Artesunate conjugate of sound, with following general formula I, II, III and
IV:
Wherein:
1.: R1, R2, R3Selected from H, methyl；
2.: work as R4, R5ForR6Selected from H, methoxyl group；
3.: work as R4, R6ForR5Selected from H, methoxyl group；
4.: work as R5, R6ForR4Selected from H, methoxyl group；
5.: R4, R5, R6For
6.: n is any integer in 1~8.
A kind of preparation method with light, the quick active chlorin Artesunate conjugate of sound, steps are as follows: 1. with
Chlorin e6 is raw material, dissolves DMF, concentration 0.1M；EDCI, N-Boc- fat straight diamine and DIPEA are sequentially added,
Obtain mixed solution A；Wherein, Chlorin e6:EDCI:N-Boc- fat straight diamine: the molar ratio of DIPEA is 1:1~2:1
~2:0.1~0.5；Mixed solution A reacts 2~20h at room temperature, obtains compound 1；Compound 1 is dissolved in dichloromethane again
Alkane, concentration 0.1M are added TFA at 0 DEG C, obtain mixed solution B, control TFA:CH2Cl2Volume ratio be 0.1~0.5:
1；Mixed solution B reacts 2~20h at room temperature, obtains compound 2；Compound 2 is dissolved in methylene chloride, concentration 0.1M,
At 0 DEG C, the Artesunate NHS of synthesis is added；Wherein, compound 2:Artesunate NHS molar ratio is 1:1~2,
2~8h is reacted at room temperature, obtains compound 3；The number of the straight chain carbon of the N-Boc- fat straight diamine is 2~9, reaction
Formula is as follows:
2. dissolving DMF, concentration 0.1M using Chlorin e6 as raw material；Sequentially add EDCI, N-Boc- fat straight chain
Diamines and DIPEA, obtain mixed solution A；Wherein, Chlorin e6:EDCI:N-Boc- fat straight diamine: mole of DIPEA
Than for 1:1~2:1~2:0.1~0.5；Mixed solution A reacts 2~20h at room temperature, adds iodomethane and Carbon Dioxide
Potassium, Chlorin e6: iodomethane: the molar ratio of Anhydrous potassium carbonate is 1:2~10:2~10, reacts 1~6 hour, obtains chemical combination
Object 1i；Compound 1i is dissolved in methylene chloride, concentration 0.1M is added TFA, obtains mixed solution C, controls at 0 DEG C
TFA:CH2Cl2Volume ratio be 0.1~0.5:1；Mixed solution C reacts 2~20h at room temperature, obtains compound 2i；By chemical combination
Object 2i is dissolved in methylene chloride, and the Artesunate NHS of synthesis is added at 0 DEG C in concentration 0.1M；Wherein, compound 2i:
Artesunate NHS molar ratio is 1:1~2, reacts 2~8h at room temperature, obtains compound 3i；The N-Boc- fat
The number of the straight chain carbon of straight diamine is 2~9, and reaction equation is as follows:
3. being dissolved in DMF using compound pheophytin a as raw material, concentration 0.1M sequentially adds EDCI and N-
Boc- fat straight diamine, wherein molar ratio 1:1~2:1 of pheophytin a:EDCI:N-Boc- fat straight diamine~
2,2~20h is reacted at room temperature, obtains pheophytin a amidate；By pheophytin a amidate, at 0 DEG C
It is dissolved in Acetone/5wt.%KOH, concentration 0.1M reacts 10h at room temperature, obtains compound 4, wherein Acetone/
The volume ratio 1:1 of 5wt.%KOH；Compound 4 is dissolved in methylene chloride again, TFA is added at 0 DEG C in concentration 0.1M,
TFA:CH2Cl2Volume ratio be 0.1~0.5:1, react 10h at room temperature, obtain compound 5；Compound 5 is dissolved in dichloro
The Artesunate NHS of synthesis is added at 0 DEG C in methane, concentration 0.1M；Compound 5:Artesunate NHS molar ratio
For 1:1~2,2~8h is reacted at room temperature, obtains compound 6；The number of the straight chain carbon of the N-Boc- fat straight diamine
It is 2~9, reaction equation is as follows:
4. being dissolved in DMF using compound pheophytin a as raw material, concentration 0.1M sequentially adds EDCI and N-
Boc- fat straight diamine, wherein molar ratio 1:1~2:1 of pheophytin a:EDCI:N-Boc- fat straight diamine~
2,2~20h is reacted at room temperature, obtains pheophytin a amidate；By pheophytin a amidate, at 0 DEG C
It is dissolved in 50wt.% methanol solution of sodium methylate, concentration 0.1M reacts 10h at room temperature, obtains compound 4i；Again by chemical combination
Object 4i is dissolved in methylene chloride, and at 0 DEG C TFA is added, wherein TFA:CH in concentration 0.1M2Cl2Volume ratio be 0.1~
0.5:1 reacts 10h at room temperature, obtains compound 5i；Compound 5i is dissolved in methylene chloride, concentration 0.1M, at 0 DEG C
Under, the Artesunate NHS of synthesis is added；Compound 5i:Artesunate NHS molar ratio is 1:1~2, at room temperature instead
2~8h is answered, compound 6i is obtained；The number of the straight chain carbon of the N-Boc- fat straight diamine is 2~9, and reaction equation is as follows:
5. being dissolved in CHCl using the chlorophyllin a that methylates as raw material3, concentration 0.1M, after ten minutes, addition is fatty for stirring
Straight diamine, wherein fatty straight diamine: CH2Cl2Volume ratio be 0.1~0.5:1, mixed solution D reacts 2 at room temperature~
For 24 hours, compound 7 is obtained；Compound 7 is dissolved in Acetone/5wt.%KOH at 0 DEG C, concentration 0.1M obtains mixing molten
Liquid E, mixed solution E react 2~14h at room temperature, obtain compound 8, wherein the volume ratio 1 of Acetone:5wt.%KOH:
1；TFA is added, reacts 10h at room temperature, obtains compound 5, TFA:CH2Cl2Volume ratio be 0.1~0.5:1；By compound 8
It is dissolved in methylene chloride, the Artesunate NHS of synthesis is added at 0 DEG C in concentration 0.1M；Compound 8:Artesunate
NHS molar ratio is 1:1~2, reacts 2~8h at room temperature, obtains compound 9；The straight chain carbon of the fatty straight diamine
Number is 2~9, and reaction equation is as follows:
6. being dissolved in CHCl using the chlorophyllin a that methylates as raw material3, concentration 0.1M, after ten minutes, addition is fatty for stirring
Straight diamine, fatty straight diamine: CH2Cl2Volume ratio be 0.1~0.5:1, mixed solution D reacts 2 at room temperature~for 24 hours,
Obtain compound 7；Compound 7 is dissolved in methylene chloride, the Artesunate of synthesis is added at 0 DEG C in concentration 0.1M
NHS；Compound 7:Artesunate NHS molar ratio is 1:1~2, reacts 2~8h at room temperature, obtains compound 9i；It is described
Fatty straight diamine straight chain carbon number be 2~9, reaction equation is as follows:
7. chlorin e 6 is dissolved in DMF, concentration 0.1M, EDCI, HOBt, N-Boc- fat straight chain two is sequentially added
Amine and TEA, chlorin e 6: EDCI:HOBt:N-Boc- fat straight diamine: the molar ratio of TEA be 1:3~6:3~6:3~
10h is reacted in 6::0.1~1 at room temperature, obtains compound 10；Compound 10 is dissolved in dry methylene chloride, concentration is
TFA, TFA:CH is added at 0 DEG C in 0.1M2Cl2Volume ratio be 0.1~1:1, react 10h at room temperature, at 0 DEG C, be added
The Artesunate NHS of synthesis；Compound 8:Artesunate NHS molar ratio is 1:1~2, obtains compound 11；Described
The number of the straight chain carbon of N-Boc- fat straight diamine is 2~9, and reaction equation is as follows:
Steps are as follows for the preparation method of the Artesunate NHS: Artesunate is dissolved in CH2Cl2In, concentration
EDCI is added at 0 DEG C for 0.1M, the molar ratio of Artesunate:EDCI is 1:1~2, and mixed solution F is protected in room temperature under nitrogen
Shield is lower to react 10min, and N-Hydroxysuccinimide, mole of Artesunate:N-Hydroxysuccinimide is added
Than obtaining intermediate A rtesunate NHS for 1:1~3.
Described there is light, the quick active chlorin Artesunate conjugate of sound to be used to prepare anti-tumor drug or conduct
Active part prepares targeting antineoplastic medicine object.
Chlorin Artesunate conjugate of the present invention is in vitro in antitumor activity evaluation to human liver cancer cell
Hep G2 has different degrees of inhibiting effect.The quantity for generating active oxygen in the cell is higher than the chlorin as control
e6.Photolytic activity is higher than the chlorin e 6 as control.It can be used for photodynamic therapy, the Sonodynamic therapy of oncotherapy
The preparation of photosensitizer and sound sensitiser in method.
Detailed description of the invention
Fig. 1 is measurement (illumination) figure of each compound active oxygen (ROS) in the cell.
Specific embodiment
Below in conjunction with attached drawing and technical solution, a specific embodiment of the invention is further illustrated.
Following non-limiting embodiments can with a person of ordinary skill in the art will more fully understand the present invention, but not with
Any mode limits the present invention.
Embodiment 1
The synthesis of intermediate artesunate NHS ester
Artesunate is dissolved in CH2Cl2(5ml) is added EDCI (129.0mg), mixed solution is in room temperature at 0 DEG C
10min is reacted under nitrogen protection, and N-Hydroxysuccinimide (NHS, 78.2mg) mixed solution is added and reacts at room temperature
10h is added deionized water (20mL), using CH after reaction2Cl2It extracts (50mL × 3), organic phase uses anhydrous sodium sulfate
Dry, low pressure concentration, for concentrate by silica gel column chromatography, elution requirement is that (petrol ether/ethyl acetate=1:1) obtains intermediate
Artesunate NHS (248.1mg, 99%)1H-NMR(CDCl3, 400MHz, ppm) and δ: 5.71 (d, J=8.0Hz, 1H),
5.35 (s, 1H), 2.81~2.97 (m, 2H), 2.71~2.79 (m, 6H), 2.41~2.49 (m, 1H), 2.27 (td, J=
12.0Hz, 4.0Hz, 1H), 1.95 (dt, J=12.0Hz, 4.0Hz, 1H), 1.77~1.85 (m, 1H), 1.61~1.73 (m,
2H), 1.54 (dt, J=12.0Hz, 4.0Hz, 1H), 1.33~1.45 (m, 1H), 1.33 (s, 3H), 1.24~1.33 (m, 2H),
1.20 (dd, 1H, J=8.0Hz, 4.0Hz), 0.90~1.00 (m, 1H), 0.88 (d, J=8.0Hz, 3H), 0.76 (d, J=
8.0Hz,3H).HR-MS found:m/z:499.2285[M+NH4]+,calcd for C23H35N2O10,499.2292.
The synthesis of compound 1
Chlorin e 6 (100.0mg) is dissolved in DMF (2ml), sequentially adds EDCI (17.0mg), N-Boc-
Ethylenediamine (35.3mg) and DIPEA (0.012ml) mixed solution react 10h at room temperature, are added after reaction
5% citric acid solution, adjustment pH are 4, and methylene chloride extracts (50mL × 3), and organic phase is dry using anhydrous sodium sulfate, low-press thick
Contracting, concentrate pass through silica gel column chromatography, elution requirement CH2Cl2/ MeOH=9:1 obtains compound 1 (92.0mg, 74%).1H-NMR(DMSO-d6,400MHz,ppm)δ:9.75(s,1H,10-H),9.72(s,1H,5-H),9.16(s,1H,20-H),
8.67 (br, 1H, N-H), 8.29 (dd, 1H, J=16.0,8.0Hz, 31-H), 7.09 (br, 1H, N-H), 6.22 (d, 1H, J=
16.0Hz, 32a-H), 5.96 (d, 1H, J=8.0Hz, 32b-H), 5.88 (br, 1H, 151a-H), 5.36 (br, 1H, 151b-
H),4.84(br,1H,18-H),4.64(br,1H,17-H),3.80(br,2H,81-H),3.59(s,3H,121-CH3),3.52
(s, 3H, 21-CH3), 3.43 (s, 3H, 71-CH3), 2.98~3.10 (m, 4H ,-CH2-CH2-), 2.70~2.76 (m, 1H,
172a-H), 2.22~2.42 (m, 2H, 172b-H, 171a-H), 1.50~1.80 (m, 7H, 181-CH3,171b-H, 82-
CH3),1.24(s,9H,Boc-CH3),-1.66(s,1H,N-H),-1.89(s,1H,N-H).HR-MS found:m/z:
739.3804[M+H]+,calcd for C41H51N6O7,739.3819.
The synthesis of compound 2
Compound 1 (56.2mg) is dissolved in methylene chloride (2ml), at 0 DEG C, 0.2ml TFA is added, mixed solution is in room
Temperature is lower to react 10h, and after reaction, low pressure concentration removes solvent and TFA, and concentrate is by silica gel column chromatography, elution requirement
CH2Cl2/ MeOH=8:1 obtains compound 2 (40.1mg, 82%)1H-NMR(DMSO-d6,400MHz,ppm)δ:9.74(s,
1H, 10-H), 9.68 (s, 1H, 5-H), 9.11 (s, 1H, 20-H), 8.78 (br, 1H, N-H), 8.36 (dd, 1H, J=16.0,
8.0Hz, 31-H), 6.45 (d, 1H, J=16.0Hz, 32a-H), 6.16 (d, 1H, J=8.0Hz, 32b-H), 5.85 (br, 1H,
151a-H),5.48(br,1H,151b-H),4.88(br,1H,18-H),4.61(br,1H,17-H),3.83(br,2H,81-
), H 3.56 (s, 3H, 121-CH3), 3.34 (s, 3H, 21-CH3), 3.18 (s, 3H, 71-CH3), 2.96~3.16 (m, 4H ,-
), CH2-CH2- 2.65~2.69 (m, 1H, 172a-H), 2.24~2.30 (m, 2H, 172b-H, 171a-H), 1.69~1.71
(m, 3H, 181-CH3), 1.56~1.62 (m, 1H, 171b-H), 1.21~1.24 (m, 3H, 82-CH3), 1.06~1.22 (m,
2H,-NH2),-1.93(s,1H,N-H),-2.48(s,1H,N-H).HR-MS found:m/z:639.3284[M+H]+,calcd
for C36H43N6O5,639.3895.
The synthesis of compound 3
Compound 2 (25.0mg) is dissolved in methylene chloride (2ml), and at 0 DEG C, pre-synthesis Artesunate is added
NHS (28.8mg), mixed solution react 2h at room temperature, and after reaction, low pressure concentration removes solvent, and concentrate passes through silica gel
Column chromatography, elution requirement CH2Cl2/ MeOH=8:1 obtains compound 3 (28.0mg, 72%)1H-NMR(DMSO-d6,
400MHz,ppm)δ:9.79(s,1H,10-H),9.71(s,1H,5-H),9.15(s,1H,20-H),8.98(br,1H,N-H),
8.40 (br, 1H, N-H), 8.34~8.37 (m, 1H, 31-H), 6.40~6.47 (m, 1H, 32a-H), 6.14~6.16 (m,
1H, 32b-H), 5.92 (br, 1H, 151a-H), 5.02~5.63 (m, 3H), 4.72 (br, 1H), 4.58 (br, 1H), 3.82
(br, 2H), 3.55 (s, 3H), 3.36~3.42 (m, 4H), 3.34 (s, 3H), 3.18 (s, 3H), 2.20~2.80 (m, 8H),
1.98~2.20 (m, 2H), 1.60~1.96 (m, 11H), 0.84~1.42 (m, 7H), 0.22~0.78 (m, 7H), -1.93 (s,
1H,N-H),-2.48(s,1H,N-H).HR-MS found:m/z:1005.4944[M+H]+,calcd for C55H69N6O12,
1005.4973.
Embodiment 2
The synthesis of compound 4
Pheophytin a (100.0mg) is dissolved in DMF (1ml) and sequentially adds EDCI (38.0mg), N-Boc-
ethylenediamine(30.0mg).Mixed solution reacts 10h at room temperature, after reaction, 10ml water is added and dissolves, and two
Chloromethanes extracts (50mL × 3), and organic phase is dry using anhydrous sodium sulfate, and low pressure concentration, concentrate is washed by silica gel column chromatography
De- condition is (CH2Cl2/ MeOH=50:1), obtain intermediate product 17- (N-Boc-ethylenediamide) pheophytin
A. at 0 DEG C, intermediate product is dissolved in Acetone/5%KOH (2ml, 50:50, v/v) mixed solution and is reacted at room temperature
5% citric acid solution is added in 10h after reaction, and adjustment pH is 5, filters, obtains compound 4 (53.6mg, 43%)1H-
NMR(DMSO-d6,400MHz,ppm)δ:9.77(s,1H,10-H),9.69(s,1H,5-H),9.12(s,1H,20-H),8.34
(dd, 1H, J=16.0,8.0Hz, 31- H), 7.85 (br, 1H, N-H), 6.71 (br, 1H, N-H), 6.45 (d, 1H, J=
16.0Hz,32a- H), 6.15 (d, 1H, J=8.0Hz, 32b-H),5.44(br,1H,151a- H), 4.81~5.03 (m, 1H, 151b-
), H 4.37~4.71 (m, 2H), 3.82 (br, 2H, 81-H),3.55(s,3H,121-CH3),3.50(s,3H,21-CH3),3.33
(s,3H,71-CH3), 2.81~3.07 (m, 4H ,-CH2-CH2), 2.17~2.49 (m, 1H, 172a- H), 1.79~2.13 (m,
2H,172b-H,171a- H), 1.52~1.78 (m, 4H), 1.24 (s, 9H, Boc-CH3),1.08(s,3H)-1.98(s,1H,N-
H),-2.54(s,1H,N-H).HR-MS found:m/z:739.3829[M+H]+,calcd for C41H51N6O7,
739.3819.
The synthesis of compound 5
Compound 4 (28.0mg) is dissolved in methylene chloride (1ml), at 0 DEG C, 0.1ml TFA is added, mixed solution is in room
Temperature is lower to react 10h, and after reaction, low pressure concentration removes solvent and TFA, and concentrate is by silica gel column chromatography, elution requirement
CH2Cl2/ MeOH=8:1 obtains compound 5 (22.2mg, 92%)1H-NMR(DMSO-d6,400MHz,ppm)δ:9.76(s,
1H, 10-H), 9.67 (s, 1H, 5-H), 9.10 (s, 1H, 20-H), 8.35 (dd, 1H, J=16.0,8.0Hz, 31-H),7.86
(br, 1H, N-H), 6.67 (br, 1H, N-H), 6.42 (d, 1H, J=16.0Hz, 32a- H), 6.12 (d, 1H, J=8.0Hz, 32b-
H),5.42(br,1H,151a- H), 4.77~4.99 (m, 1H, 151b- H), 4.36~4.68 (m, 2H), 3.83 (br, 2H, 81-
H),3.53(s,3H,121-CH3),3.50(s,3H,21-CH3),3.31(s,3H,71-CH3), 2.76~3.02 (m, 4H ,-CH2-
CH2), 2.15~2.43 (m, 1H, 172a- H), 1.77~2.11 (m, 2H, 172b-H,171a- H), 1.56~1.76 (m, 4H),
1.16~1.08 (m, 2H), 1.08 (s, 3H) -1.96 (s, 1H, N-H), -2.44 (s, 1H, N-H) .HR-MS found:m/z:
639.3293[M+H]+,calcd for C36H43N6O5,639.3895.
The synthesis of compound 6
Compound 5 (14.0mg) is dissolved in methylene chloride (2ml), and at 0 DEG C, pre-synthesis intermediate is added
Artesunate NHS (28.8mg), mixed solution react 2h at room temperature, and after reaction, low pressure concentration removes solvent, dense
Contracting object passes through silica gel column chromatography, elution requirement CH2Cl2/ MeOH=8:1 obtains compound 6 (15.0mg, 68%)1H-NMR
(DMSO-d6,400MHz,ppm)δ:9.77(s,1H,10-H),9.72(s,1H,5-H),9.13(s,1H,20-H),8.34(dd,
1H, J=16.0,8.0Hz, 31- H), 7.86~8.06 (m, 2H, 32a- H, N-H), 6.44 (d, 1H, J=16.0Hz, 32b-H),
6.16 (d, 1H, J=8.0Hz), 5.41~5.63 (m, 3H), 4.92~5.12 (m, 1H), 4.58 (br, 1H), 3.80 (br,
2H), 3.55 (s, 3H), 3.53~3.55 (m, 2H), 3.29 (br, 3H), 3.17 (br, 3H), 3.05 (br, 2H), 2.56~
2.59 (m, 4H), 1.820~2.41 (m, 9H), 1.55~1.81 (m, 5H), 1.42~1.51 (m, 4H), 0.84~1.42 (m,
7H), 0.52~0.78 (m, 7H), -1.93 (s, 1H, N-H), -2.48 (s, 1H, N-H) .HR-MS found:m/z:
1005.4938[M+H]+,calcd for C55H69N6O12,1005.4973.
Embodiment 3
The synthesis of compound 7
Methylation chlorophyllin a (102.0mg) is dissolved in CHCl3After ten minutes, 0.2ml ethylenediamine is added in (2ml), stirring,
Mixed solution reacts 10h at room temperature, and after reaction, low pressure concentration removes solvent, and concentrate passes through silica gel column chromatography, elution
Condition is (CH2Cl2/ MeOH=3:1), obtain compound 7 (92.2mg, 82%)1H-NMR(CDCl3,400MHz,ppm)δ:
9.56 (s, 1H, 10-H), 9.50 (s, 1H, 5-H), 8.78 (s, 1H, 20-H), 7.91 (dd, 1H, J=20.0,12.0Hz, 31-
), H 7.05 (t, 1H, J=4Hz, N-H), 6.20 (d, 1H, J=20.0Hz, 32a- H), 5.99 (d, 1H, J=12.0Hz, 32b-
), H 5.47 (d, 1H, J=20.0Hz, 151a- H), 5.18 (d, 1H, J=20.0Hz, 151b- H), 4.42~4.46 (m, 1H),
4.33 (dd, 1H, J=8.0,4.0Hz), 3.64 (s, 3H, 121-CH3), 3.60~3.64 (m, 2H), 3.57 (s, 3H, 21-
CH3), 3.39 (s, 3H), 3.37 (s, 3H), 3.24~3.32 (m, 2H ,-CH2-),3.15(s,3H,71-CH3),2.76(t,2H,
J=8.0Hz ,-CH2), 2.48~2.54 (m, 1H, 172a- H), 2.11~2.20 (m, 2H, 172b-H,171a-H),1.80(d,
1H, J=8.0Hz), 1.62~1.70 (m, 3H, 82-CH3),1.42(br,2H,NH2),-1.98(s,1H,N-H),-2.54(s,
1H,N-H).HR-MS found:m/z:667.3601[M+H]+,calcd for C38H46N6O5,667.3608.
The synthesis of compound 8
Compound 7 (50.0mg) is dissolved in Acetone/5%KOH (2ml, 50:50, v/v) mixed solution at 0 DEG C
10h is reacted at room temperature, 5% citric acid solution is added after reaction, and adjustment pH is 5, filters, obtains compound 8
(25.6mg, 60%)1H-NMR(CDCl3,400MHz,ppm)δ:9.58(s,1H,10-H),9.51(s,1H,5-H),8.79(s,
1H, 20-H), 7.92 (dd, 1H, J=20.0,12.0Hz, 31- H), 7.04~7.08 (m, 1H, N-H), 6.22 (d, 1H, J=
20.0Hz,32a- H), 5.98 (d, 1H, J=12.0Hz, 32b- H), 5.46 (d, 1H, J=20.0Hz, 151a-H),5.16(d,1H,
J=20.0Hz, 151b- H), 4.42~4.45 (m, 1H), 4.32 (dd, 1H, J=8.0,4.0Hz), 3.64 (s, 3H, 121-
CH3), 3.60~3.64 (m, 2H), 3.57 (s, 3H, 21-CH3), 3.24~3.32 (m, 2H ,-CH2-),3.15(s,3H,71-
CH3), 2.74 (t, 2H, J=8.0Hz ,-CH2), 2.48~2.52 (m, 1H, 172a- H), 2.11~2.22 (m, 2H, 172b-H,
171a- H), 1.78~1.82 (m, 1H), 1.60~1.73 (m, 6H, 181-CH3,82-CH3),1.42(br,2H,NH2),-1.98
(s,1H,N-H),-2.45(s,1H,N-H).HR-MS found:m/z:639.3273[M+H]+,calcd for C36H43N6O5,
639.3895.
The synthesis of compound 9
Compound 8 is dissolved in CH2Cl2(2ml) is added Artesunate NHS (28.7mg), mixed solution at 0 DEG C
2h is reacted at room temperature, and after reaction, low pressure concentration removes solvent, and concentrate is by silica gel column chromatography, elution requirement
CH2Cl2/ MeOH=8:1 obtains compound 9 (21.0mg, 53%)1H-NMR(DMSO-d6,400MHz,ppm)δ:9.75(s,
1H, 10-H), 9.72 (s, 1H, 5-H), 9.11 (s, 1H, 20-H), 8.96 (br, 1H, N-H), 8.24~8.34 (m, 2H), 6.38
~6.46 (m, 1H, 32a- H), 6.12~6.16 (m, 1H, 32b-H),5.92(br,1H,151a- H), 5.20~5.62 (m, 4H),
4.60 (br, 1H), 4.48 (br, 1H), 3.14~3.82 (m, 15H), 2.46~2.68 (m, 4H), 1.98~2.34 (m, 5H),
1.50~1.98 (m, 9H), 1.30~1.50 (br, 2H), 0.96~1.50 (m, 8H), 0.48~0.88 (m, 7H), -1.86 (s,
1H,N-H),-2.18(s,1H,N-H).HR-MS found:m/z:1005.4954[M+H]+,calcd for C55H69N6O12,
1005.4973.
Embodiment 4
The synthesis of compound 10
Chlorin e 6 (120.0mg) is dissolved in DMF (2ml), sequentially adds EDCI (126.7mg), HOBt (89.5mg),
N-Boc-ethylenediamine (105.7mg), TEA (0.1ml).Mixed solution reacts 10h at room temperature, after reaction,
Low pressure concentration, for concentrate by silica gel column chromatography, elution requirement is (CH2Cl2/ MeOH=19:1), obtain compound 10
(186.0mg, 90%)1H-NMR(CDCl3,400MHz,ppm)δ:9.72(s,1H,10-H),9.58(s,1H,5-H),8.82
(s, 1H, 20-H), 8.43 (m, 1H, N-H), 8.01 (dd, 1H, J=20.0,12.0Hz, 31-H),7.00(m,1H,N-H),
6.30 (d, 1H, J=20.0Hz, 32a- H), 6.19 (d, 1H, J=12.0Hz, 32b-H),6.08(m,2H,N-H),5.82(m,
2H, N-H), 5.20~5.45 (m, 2H), 4.48~4.52 (m, 2H), 3.90 (br, 2H), 3.69~3.83 (m, 2H), 3.55
~3.71 (m, 2H), 3.38~3.40 (m, 6H), 3.34 (s, 3H), 3.07~3.28 (m, 4H), 2.84~3.06 (m, 4H),
2.27 (br, 2H), 1.80~2.04 (m, 2H), 1.60~1.68 (m, 6H), 1.40 (s, 9H), 1.26 (s, 18H), -1.94 (s,
1H,N-H),-2.42(s,1H,N-H).HR-MS found:m/z:1023.6005[M+H]+,calcd for C55H79N10O9,
1023.6031.
The synthesis of compound 11
Compound 10 (105.0mg) is dissolved in dry methylene chloride (1ml), at 0 DEG C, 0.1ml TFA is added, mixes
It closes solution and reacts 10h at room temperature, after reaction, low pressure concentration removes solvent and TFA, concentrate are re-dissolved in CH2Cl2
Artesunate NHS (156.8mg) is added in (2ml), and mixed solution reacts 2h at room temperature, after reaction, low pressure concentration
Solvent is removed, concentrate passes through silica gel column chromatography, elution requirement CH2Cl2/ MeOH=8:1, obtain compound 11 (75.0mg,
40%)1H-NMR(CDCl3,400MHz,ppm)δ:9.73(s,1H,10-H),9.63(s,1H,5-H),9.14(s,1H,20-
), H 8.10 (dd, 1H, J=16.0,8.0Hz, 31-H),8.00(br,1H,N-H),7.78(br,1H,N-H),7.03(m,2H,
), N-H 6.65 (m, 2H, N-H), 6.38 (d, 1H, J=16.0Hz, 32a- H), 6.17 (d, 1H, J=8.0Hz, 32b-H),5.45
~5.55 (m, 2H), 5.32~5.54 (m, 2H), 4.98~5.22 (m, 2H), 4.68~4.90 (m, 2H), 4.58 (br, 1H),
4.41 (br, 1H), 3.68~3.92 (m, 10H), 3.75 (s, 3H), 3.49 (s, 3H), 3.32~3.44 (m, 2H), 3.31 (s,
3H), 2.56~2.90 (m, 12H), 2.30~2.22 (m, 6H), 2.06~2.30 (m, 6H), 1.10~1.46 (m, 30H),
0.68~1.00 (m, 21H) .HR-MS found:m/z:1821.9525 [M+H]+,calcd for C97H133N10O24,
1823.1770.
Application examples 1
1. Anticancer Activity in vitro is evaluated:
Photodynamic activity:
3,6,9,11, Chlorin e6 of compound, Artesunate (ART) are dissolved with DMSO, -4 DEG C of preservations；It uses
When, the ultimate density < 0.1% of DMSO is diluted to cell culture fluid.
The HepG2 liver cancer cells of logarithmic growth phase will be in, with 5 × 103A/sky is inoculated in 96 orifice plates, and every hole is added
After culture for 24 hours, 100 μ L medical fluids are added, final concentration is respectively 100 μm of ol/L, 30 μm of ol/L, 10 μm of ol/ in 100 μ L of cell suspension
L, the untested compound of 1 μm of ol/L, 0.1 μm of ol/L, 0.01 μm of ol/L, setting blank group (containing culture solution, cell-free), control group
(culture cell not dosing), cell is in 37 DEG C of incubator (5%CO2) in be incubated for for 24 hours after, carry out phototoxicity experiments.Culture plate away from
It is 20cm, light intensity 1.7J/cm from light source height2, wavelength 660nmLED, time 2min place into 37 DEG C of incubator (5%CO2) in
After being incubated for for 24 hours, the 20 μ L of MTT solution that concentration is 5mg/mL is added in every hole, is continued to cultivate 4h, is siphoned away supernatant, 100 μ are added
LDMSO.Microplate reader measures the absorbance (OD value) in each hole under 570nm wavelength, calculates IC50.It the results are shown in Table 1.
Sound photodynamic activity:
The difference of activity rating of sharing the same light operation is: 96 orifice plates that medical fluid is added is placed on the device of bottom hair ultrasound,
De aerated water is added, makes to be suspended on the water surface, places into 37 DEG C away from ultrasonic vocalization probe 2cm, ultrasonic excitation (2MHz, 2W) 2min
Incubator (5%CO2) in be incubated for for 24 hours after, the 20 μ L of MTT solution that concentration is 5mg/mL is added in every hole, continues to cultivate 4h, siphon away
100 μ LDMSO are added in clear liquid.Microplate reader measures the absorbance (OD value) in each hole under 570nm wavelength, calculates IC50.It the results are shown in Table 2.
Dark toxicity activity:
The difference of activity rating of sharing the same light operation is: 96 orifice plates that medical fluid is added being placed in 2min in darkroom, place into 37
DEG C incubator (5%CO2) in be incubated for for 24 hours after, the 20 μ L of MTT solution that concentration is 5mg/mL is added in every hole, continues to cultivate 4h, siphon away
100 μ LDMSO are added in supernatant.Microplate reader measures the absorbance (OD value) in each hole under 570nm wavelength, calculates IC50。
External photolytic activity and dark toxicity of 1 target compound of table to HepG2 liver cancer cells
External sound photodynamic activity and dark toxicity of 2 target compound of table to HepG2 liver cancer cells
2. the measurement of reactive oxygen species (ROS)
The HepG2 liver cancer cells of logarithmic growth phase will be in, with 5 × 104A/sky is inoculated in 24 orifice plates, and every hole is added
After culture for 24 hours, 100 μ L medical fluids are added in 100 μ L of cell suspension, and blank group is arranged in the untested compound of final concentration of 30 μm of ol/L
(containing culture solution, cell-free), control group (culture cell not dosing), cell is in 37 DEG C of incubator (5%CO2) in be incubated for 10h after,
Culture solution is removed, is washed 2 times with PBS buffer solution, DCF-DA is added and is dissolved in the culture solution without serum, final concentration of 20 μM, is protected from light
It stands 20min to be washed 2 times with PBS buffer solution, be added new without pink culture solution, illumination.Wavelength 660nmLED, time
2min, excitation wavelength 495nm measure the fluorescent absorption in each hole under 530nm wavelength, see Fig. 1.
Claims (3)
1. one kind has light, the quick active chlorin Artesunate conjugate of sound, which is characterized in that the chlorin is green
Artemisic succinate conjugate has following general formula I, II, III or IV:
Wherein:
1.: R1, R2, R3Selected from H, methyl；
2.: work as R4, R5ForR6Selected from H, methoxyl group；
3.: work as R4, R6ForR5Selected from H, methoxyl group；
4.: work as R5, R6ForR4Selected from H, methoxyl group；
5.: R4, R5, R6For
6.: n is any integer in 1~8.
2. a kind of preparation method with light, the quick active chlorin Artesunate conjugate of sound, which is characterized in that step is such as
Under:
1. dissolving DMF, concentration 0.1M using Chlorin e6 as raw material；Sequentially add EDCI, N-Boc- fat straight diamine
And DIPEA, obtain mixed solution A；Wherein, Chlorin e6:EDCI:N-Boc- fat straight diamine: the molar ratio of DIPEA is
1:1~2:1~2:0.1~0.5；Mixed solution A reacts 2~20h at room temperature, obtains compound 1；Compound 1 is dissolved again
In methylene chloride, concentration 0.1M is added TFA at 0 DEG C, obtains mixed solution B, controls TFA:CH2Cl2Volume ratio be
0.1~0.5:1；Mixed solution B reacts 2~20h at room temperature, obtains compound 2；Compound 2 is dissolved in methylene chloride, it is dense
Degree is that the Artesunate NHS of synthesis is added at 0 DEG C in 0.1M；Wherein, compound 2:Artesunate NHS molar ratio is
1:1~2 react 2~8h at room temperature, obtain compound 3；The number of the straight chain carbon of the N-Boc- fat straight diamine is
2~9, reaction equation is as follows:
2. dissolving DMF, concentration 0.1M using Chlorin e6 as raw material；Sequentially add EDCI, N-Boc- fat straight diamine
And DIPEA, obtain mixed solution A；Wherein, Chlorin e6:EDCI:N-Boc- fat straight diamine: the molar ratio of DIPEA is
1:1~2:1~2:0.1~0.5；Mixed solution A reacts 2~20h at room temperature, adds iodomethane and Anhydrous potassium carbonate,
Chlorin e6: iodomethane: the molar ratio of Anhydrous potassium carbonate is 1:2~10:2~10, reacts 1~6 hour, obtains compound
1i；Compound 1i is dissolved in methylene chloride, concentration 0.1M is added TFA at 0 DEG C, obtains mixed solution C, control TFA:
CH2Cl2Volume ratio be 0.1~0.5:1；Mixed solution C reacts 2~20h at room temperature, obtains compound 2i；By compound 2i
It is dissolved in methylene chloride, the Artesunate NHS of synthesis is added at 0 DEG C in concentration 0.1M；Wherein, compound 2i:
Artesunate NHS molar ratio is 1:1~2, reacts 2~8h at room temperature, obtains compound 3i；The N-Boc- fat
The number of the straight chain carbon of straight diamine is 2~9, and reaction equation is as follows:
3. being dissolved in DMF using compound pheophytin a as raw material, concentration 0.1M sequentially adds EDCI and N-Boc- rouge
Fat straight diamine, wherein molar ratio 1:1~2:1~2 of pheophytin a:EDCI:N-Boc- fat straight diamine, in room
Temperature is lower to react 2~20h, obtains pheophytin a amidate；By pheophytin a amidate, it is dissolved at 0 DEG C
Acetone/5wt.%KOH, concentration 0.1M, reacts 10h at room temperature, obtains compound 4, wherein Acetone:5wt.%
The volume ratio 1:1 of KOH；Compound 4 is dissolved in methylene chloride again, TFA, TFA:CH is added at 0 DEG C in concentration 0.1M2Cl2
Volume ratio be 0.1~0.5:1, react 10h at room temperature, obtain compound 5；Compound 5 is dissolved in methylene chloride, concentration
The Artesunate NHS of synthesis is added at 0 DEG C for 0.1M；Compound 5:Artesunate NHS molar ratio is 1:1~2,
2~8h is reacted at room temperature, obtains compound 6；The number of the straight chain carbon of the N-Boc- fat straight diamine is 2~9, instead
Answer formula as follows:
4. being dissolved in DMF using compound pheophytin a as raw material, concentration 0.1M sequentially adds EDCI and N-Boc- rouge
Fat straight diamine, wherein molar ratio 1:1~2:1~2 of pheophytin a:EDCI:N-Boc- fat straight diamine, in room
Temperature is lower to react 2~20h, obtains pheophytin a amidate；By pheophytin a amidate, it is dissolved at 0 DEG C
50wt.% methanol solution of sodium methylate, concentration 0.1M, reacts 10h at room temperature, obtains compound 4i；It is again that compound 4i is molten
In methylene chloride, concentration 0.1M TFA is added, wherein TFA:CH at 0 DEG C in solution2Cl2Volume ratio be 0.1~0.5:1,
10h is reacted at room temperature, obtains compound 5i；Compound 5i is dissolved in methylene chloride, concentration 0.1M is added and closes at 0 DEG C
At Artesunate NHS；Compound 5i:Artesunate NHS molar ratio is 1:1~2, reacts 2~8h at room temperature, obtains
To compound 6i；The number of the straight chain carbon of the N-Boc- fat straight diamine is 2~9, and reaction equation is as follows:
5. being dissolved in CHCl using the chlorophyllin a that methylates as raw material3, concentration 0.1M, after ten minutes, fatty straight chain two is added in stirring
Amine, wherein fatty straight diamine: CH2Cl2Volume ratio be 0.1~0.5:1, mixed solution D reacts 2 at room temperature~for 24 hours, obtains
To compound 7；Compound 7 is dissolved in Acetone/5wt.%KOH at 0 DEG C, concentration 0.1M obtains mixed solution E, mixes
It closes solution E and reacts 2~14h at room temperature, obtain compound 8, wherein the volume ratio 1:1 of Acetone:5wt.%KOH；It is added
TFA reacts 10h at room temperature, obtains compound 5, TFA:CH2Cl2Volume ratio be 0.1~0.5:1；Compound 8 is dissolved in
The Artesunate NHS of synthesis is added at 0 DEG C in methylene chloride, concentration 0.1M；Compound 8:Artesunate NHS rubs
You react 2~8h at room temperature, obtain compound 9 than being 1:1~2；The number of the straight chain carbon of the fatty straight diamine is
2~9, reaction equation is as follows:
6. being dissolved in CHCl using the chlorophyllin a that methylates as raw material3, concentration 0.1M, after ten minutes, fatty straight chain two is added in stirring
Amine, fatty straight diamine: CH2Cl2Volume ratio be 0.1~0.5:1, mixed solution D reacts 2 at room temperature~for 24 hours, is changed
Close object 7；Compound 7 is dissolved in methylene chloride, the Artesunate NHS of synthesis is added at 0 DEG C in concentration 0.1M；Change
Conjunction object 7:Artesunate NHS molar ratio is 1:1~2, reacts 2~8h at room temperature, obtains compound 9i；The fat
The number of the straight chain carbon of straight diamine is 2~9, and reaction equation is as follows:
7. chlorin e 6 is dissolved in DMF, concentration 0.1M, sequentially add EDCI, HOBt, N-Boc- fat straight diamine and
TEA, chlorin e 6: EDCI:HOBt:N-Boc- fat straight diamine: the molar ratio of TEA is 1:3~6:3~6:3~6::
0.1~1,10h is reacted at room temperature, obtains compound 10；Compound 10 is dissolved in dry methylene chloride, concentration is
TFA, TFA:CH is added at 0 DEG C in 0.1M2Cl2Volume ratio be 0.1~1:1, react 10h at room temperature, at 0 DEG C, be added
The Artesunate NHS of synthesis；Compound 8:Artesunate NHS molar ratio is 1:1~2, obtains compound 11；Described
The number of the straight chain carbon of N-Boc- fat straight diamine is 2~9, and reaction equation is as follows:
Steps are as follows for the preparation method of the Artesunate NHS: Artesunate is dissolved in CH2Cl2In, concentration is
EDCI is added at 0 DEG C in 0.1M, and the molar ratio of Artesunate:EDCI is 1:1~2, and mixed solution F is protected in room temperature under nitrogen
N-Hydroxysuccinimide, the molar ratio of Artesunate:N-Hydroxysuccinimide is added in lower reaction 10min
For 1:1~3, intermediate A rtesunate NHS is obtained.
3. the compound 3,6,9,11 that claim 2 is prepared is used to prepare the anti-tumor drug for HepG2 liver cancer cells
Or the targeting antineoplastic medicine object of HepG2 liver cancer cells is directed to as active part preparation.
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