CN103304569B - A kind of Erlotinib-phthalocyaconjugate conjugate and preparation method thereof - Google Patents
A kind of Erlotinib-phthalocyaconjugate conjugate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of target anticancer molecule erlotinib phthalocyanine conjugates and its preparation method and application, introduce the erlotinib with alcoxyl long-chain at the large ring periphery of metal phthalocyanine, can increase that it is amphipathic, the targeting of biocompatibility, photosensitizers.This erlotinib conjugates is not easy to assemble, and is conducive to improving cellular uptake rate; Such compound structure is single simultaneously, and there is not isomer, product is easily purified.This compound is expected to the targeting improving quick dose of Photodynamic Therapy, strengthens the activity of quick dose of Photodynamic Therapy simultaneously.Synthetic method of the present invention is fairly simple, and side reaction is few, and productive rate is higher, and raw material is easy to get, and cost is low, is conducive to suitability for industrialized production.
Description
Technical field
The invention belongs to organic and metal complex synthesis field, have and relate to a kind of target anticancer molecule erlotinib phthalocyanine conjugates and its preparation method and application.
Background technology
Phthalocyanine is the macrocylc compound that a class has good optical physics spectrochemical property, be applied to high-tech area, comprising semiconducter device, photovoltaic and solar cell, zerography, rectifier, LB film optical dynamic therapy photosensitizers etc., wherein has development prospect as photosensitizers.
The diversity of phthalocyanine compound and structural can " cutting ", the phthalocyanine compound required for people's appropriate design provides possibility.Functional to phthalocyanine and other functional group being connected, to form the new function material had complementary functions be one of important development direction of phthalocyanine compound.But there is synthesis difficulty in existing Substituted metallophthalocyanine, the problems such as side reaction is many, and separating difficulty is large mostly.Existence major issue is phthalocyanine is not simultaneously very desirable to the targeting of tumor tissues, therefore the research of photosensitizers targeting is become to a focus of research now.
Along with molecular biological development, about normal cell and cancer cells are progressively found in the difference of molecule aspect, the targeted drug for tumour also arises at the historic moment.These medicines are different from traditional chemotherapeutic agent, have very strong targeting.Erlotinib (erlotinib)
?, see compound 4 structure (wherein R
1=R
2=
) be the 4-phenylamino quinazoline ditosylate salt PTS developed jointly by Roche (Roche) Genentech (Genentech) company, it with Human epidermal growth factor receptor (EGFR) for point of application, with the specific TYR zymogenesis of one suppressed in EGF-R ELISA, tumour cell capable of blocking " growth signals ", as molecular targeted agents " representative " work, apply just clinically at present.
Based on molecular target pharmacological agent and optical dynamic therapy mechanism, the conception building photosensitizers and molecular target drug conjugates is proposed, namely utilize the High Fragmentation power of the targeting of target drug, optical dynamic therapy and the feature of the low supersession rate of phthalocyanine compound, explore the structure influence factor of phthalocyanine-erlotinib conjugates performance.
Summary of the invention
The object of the present invention is to provide a kind of target anticancer molecule erlotinib phthalocyanine conjugates and its preparation method and application, this complex structure is single, there is not isomer, and product is easily purified; Synthetic method is fairly simple, and side reaction is few, and productive rate is higher, and raw material is easy to get, and cost is low, is conducive to suitability for industrialized production.
For achieving the above object, the present invention adopts following technical scheme:
A kind of chemical structural formula of target anticancer molecule Erlotinib-phthalocyaconjugate conjugate is as follows:
（1）
（2）；
Wherein M=Zn, Al, Si, Ga, m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3.
The method preparing target anticancer molecule erlotinib phthalocyanine conjugates as above comprises the following steps:
(1) compound 1:
, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3with compound 2:
, m=2-8 is initiator, at K
2cO
3react with under DMF condition, cross silicagel column and obtain compound 3:
, m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3;
(2) with compound 3 and 3-nitrophthalonitrile or 4-nitrophthalonitrile at K
2cO
3react with under DMF condition, cross silicagel column and obtain compound 4a:
, m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3or compound 4b:
, m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3;
(3) with compound 4a or compound 4b and Pentyl alcohol, phthalonitrile and zinc or aluminium or gallium or silicon salt for initiator, 1, react under 8-diazabicyclo [5.4.0] 11 carbon-7-alkene or metallic lithium catalysis, cross silicagel column and obtain described target anticancer molecule erlotinib phthalocyanine conjugates.
The preparation process of step (1) comprising: by compound 1 and compound 2 in molar ratio for 1:1-2 adds in DMF, after both dissolving, join the K of 4-9 times of equivalent
2cO
3in, under 40-70 DEG C of nitrogen protection, react 4-8h; After question response terminates, being spin-dried for DMF, the thick product of rear dichloromethane extraction, is eluent subsequently with methylene chloride-methanol, crosses silicagel column separation and obtains compound 3.
The preparation process of step (2) comprising: by compound 3 and 3-nitrophthalonitrile or 4-nitrophthalonitrile in molar ratio for 1-2:1 joins in DMF, after waiting both to dissolve, add the K of 4-9 times of equivalent
2cO
3in, under 40-90 DEG C of nitrogen protection, react 4-10h; After reaction terminates, being spin-dried for DMF, the thick product of rear dichloromethane extraction, is then eluent with methylene chloride-methanol, crosses silicagel column separation and obtains compound 4a or 4b.
The preparation process of step (3) comprising: add compound 4a or 4b successively being equipped with in reflux condensate device and gas operated device two neck bottle; phthalonitrile and Pentyl alcohol; under nitrogen protection; be warming up to 100 DEG C; after question response thing dissolves; then zinc, aluminium, gallium, silicon salt is added; 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene or the metallic lithium of 0.5-1ml is added, back flow reaction 5-12h after being stirred to dissolving; after reaction terminates; vacuum rotary steam removing Pentyl alcohol, take methylene chloride-methanol as eluent, crosses silicagel column; after rotary evaporation is concentrated, obtain 5a
m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3, or 5b
m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3.
The volume ratio of described methylene chloride-methanol is 40-20:1.
Target anticancer molecule erlotinib phthalocyanine conjugates as above is applied to the photosensitizer drug preparing optical dynamic therapy.
Phthalocyanine-like compound is considered to the s-generation photosensitizers of most potentiality.But because its intake in target cell and target tissue is very poor, effect is difficult to reach application request.Amphipathic phthalocyanine photosensitizers, as the phthalocyanine derivates that hydroxyl, fluorine, oligoethylene glycol and oligomeric amine etc. replace, owing to having good affinity thus to have higher intake with target tissue cell, becomes the emphasis researched and developed in recent years.The Erlotinib-phthalocyaconjugate conjugate designed in the present invention utilizes s-generation photosensitizers can the feature of chemical tailoring and grafting, the active structure unit of some biological nature on binding on its molecule, expects the strategy improving the picked-up of tumor tissues selectivity and result for the treatment of.This novel photosensitive agent will the high targeting of erlotinib simultaneously, the feature of the photodynamic therapy characteristic of Phthalocyanine Zinc and Cellular retention phase length combines, both erlotinib Drug-resistant sex chromosome mosaicism can have been solved, also the not strong problem of phthalocyanine complex targeting can be improved, make erlotinib can to residual or the sick cell be sporadicly distributed in around tumor tissues suppresses for a long time, deactivation, greatly reduce the risk of tumor recurrence after treatment.
Remarkable advantage of the present invention is:
(1) clearly enhance the targeting of photosensitizers, photodynamic activity is very high.
(2) target compound structure is single, there is not isomer, the easy purifying of product.Because there is multiple substituting group, there is multiple isomer because each substituting group spatial distribution is different, and phthalocyanine ring have 8 α positions, occupy different α positions and also create different isomer in polysubstituted Phthalocyanine Zinc.And structural similitude makes these isomer character very close, be difficult to be separated.Just there is not such problem in mono-substituted zinc phthalocyanine.
(3) introduce polyglycol chain in the compound synthesized by, add the use that the picked-up of phthalocyanine-like compound in cell is conducive to as the clinical application of light power.
(4) synthetic method is simple, and only need several step just can complete, side reaction is few, and raw material is easy to get, and cost is low, is conducive to suitability for industrialized production.
Embodiment
A kind of concrete preparation process of the anticancer photosensitizer erlotinib and derivative-phthalocyanine conjugates with the optical dynamic therapy of targeting comprises:
Step (1): by compound 1 and compound 2 in molar ratio for 1:1-2 adds in DMF (DMF), after both dissolving, add the K of 4-9 times of equivalent
2cO
3in, under 40-70 DEG C of nitrogen protection, react 4-8h.After question response terminates, being spin-dried for DMF, the thick product of rear dichloromethane extraction, is washing and dehydrating integrated machine subsequently with methylene chloride-methanol, crosses silicagel column separation and obtains compound 3.Productive rate is 40-60%.
Step (2): by compound 3 and 3-nitrophthalonitrile or 4-nitrophthalonitrile in molar ratio for 1-2:1 joins in DMF, after waiting both to dissolve, added the K of 4-9 times of equivalent
2cO
3in, under 40-90 DEG C of nitrogen protection, react 4-10h.After reaction terminates, being spin-dried for DMF, the thick product of rear dichloromethane extraction, is then washing and dehydrating integrated machine with methylene chloride-methanol, crosses silicagel column separation and obtains compound 4a or 4b.Productive rate is 30-50%.
Step (3): add compound 4a or 4b successively being equipped with in reflux condensate device and gas operated device two neck bottle, phthalonitrile and Pentyl alcohol, under nitrogen protection; be warming up to 100 DEG C; question response thing then adds zinc, aluminium, gallium, silicon salt, adds 1 of 0.5-1ml after being stirred to dissolving after dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; constant temperature 150 DEG C, back flow reaction 5-12h, after reaction terminates; vacuum rotary steam removing Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 40-20:1 as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain 5a
m=0-8, R
1, R
2=-H or-OCH
2cH
2oCH
3, or 5b
m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3.Productive rate is 10-20%.
We test the activity of some optical dynamic therapies of described compound in isolated cells, have also done experimentation on animals simultaneously.Experiment obtains more satisfactory result.This kind of compound has good pharmaceutical activity.And from the test of animal mouselet, we know that this compounds has better targeting.
Following embodiment sets forth the present invention further, but the present invention is not limited only to this.
Embodiment 1(M=Zn, m=3, R
1=R
2=-OCH
2cH
2oCH
3, α is monosubstituted)
1) by compound 10.5g(1.27mmol) and compound 20.68g(1.95mmol) add in DMF (DMF), after both dissolving, add K
2cO
30.7g(5.07mmol), under 50 DEG C of nitrogen protections, 6h is reacted.After question response terminates, be spin-dried for DMF, then with the thick product of dichloromethane extraction, subsequently with the volume ratio of methylene chloride-methanol for 30:1 is for washing and dehydrating integrated machine, cross silicagel column be separated obtain compound 30.4g.Productive rate is 55%.
1hNMR (500MHz, CDCl
3):
δ8.41 (s, 1H, ArH), 7.84 (s, 1H, ArH), 7.45 (s, 1H, ArH), 7.16 (t,
j=8.0Hz, 1H, ArH), 6.89 (d,
j=8.0Hz, 1H, ArH), 6.59 (s, 1H, ArH), 6.41 (d,
j=8.0Hz, 1H, ArH), 4.49-4.45 (m, 4H, CH
2), 4.40-4.38 (m, 4H, CH
2), 3.80 (t,
j=4.5Hz, 2H, CH
2), 3.73 (t,
j=4.5Hz, 4H, CH
2), 3.67 (t,
j=4.5Hz, 2H, CH
2), 3.66-3.63 (m, 4H, CH
2), 3.39-3.37 (m, 4H, CH
2), 3.31 (s, 6H, CH
3), 3.12 (s, 1H, CH), 2.3 (brs, 1H, OH) .HRMS (ESI): m/zC
30h
39n
3o
8[M+H]
+, calculated value 570.2815; Measured value 570.2810.
2) by 1g(1.75mmol) compound 3 and 0.45g(2.6mmol) 3-nitrophthalonitrile joins in DMF, after when both dissolve, adds 1.45g(10.5mmol) K
2cO
3, under 70 DEG C of nitrogen protections, react 6h.Reaction terminate after, be spin-dried for DMF, the thick product of rear dichloromethane extraction, then with the volume ratio of methylene chloride-methanol for 40:1 is for washing and dehydrating integrated machine, cross silicagel column be separated obtain compound 4a(0.5g).Productive rate is 41.6%.
1hNMR (500MHz, CDCl
3):
δ8.44 (s, 1H, ArH), 7.61 (t,
j=8.5Hz, 1H, ArH), 7.41 (s, 1H, ArH), 7.25 (d,
j=8.5Hz, 1H, ArH), 7.24 (s, 1H, ArH), 7.18 (d,
j=8.0Hz, 1H, ArH), 7.01 (t,
j=8.0Hz, 1H, ArH), 6.74 (d,
j=8.0Hz, 1H, ArH), 6.70 (s, 1H, ArH), 6.55 (d,
j=8.0Hz, 1H, ArH), 4.43-4.39 (m, 2H, CH
2), 4.38-4.35 (m, 4H, CH
2), 3.88 (t,
j=4.5Hz, 2H, CH
2), 3.81 (t,
j=4.5Hz, 2H, CH
2), 3.72-3.69 (m, 4H, CH
2), 3.68-3.66 (m, 4H, CH
2), 3.57-3.55 (m, 4H, CH
2), 3.51-3.49 (m, 4H, CH
2), 3.39 (s, 6H, CH
3), 3.12 (s, 1H, CH) .HRMS (ESI): m/zC
38h
41n
5o
8[M+H]
+, calculated value 696.3033; Measured value 696.3021.
3) in the 100ml two neck bottle that reflux condensate device and gas operated device are housed, 0.25g compound 4a is added successively; the Pentyl alcohol that 0.406g phthalonitrile and 10ml newly steam, under nitrogen protection, is warming up to 100 DEG C; after question response thing dissolves; then add 0.35g zinc acetate, after being stirred to dissolving, add 1,8-diazabicylo [5.4.0] the 11 carbon-7-alkene of 0.8ml; back flow reaction 5h; after reaction terminates, vacuum rotary steam removing Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 30:1 as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain 5a.
1hNMR (500MHz, DMSO-d
6):
δ9.38 (s, 1H, Pc-H
α), 9.19 (brs, 3H, Pc-H
α), 9.02 (brs, 2H, Pc-H
α), 8.85 (brs, 1H, Pc-H
α), 8.63 (sbr, 1H, Pc-H
β), 8.54 (s, 1H, Pc-H
β), 8.44-8.41 (m, 6H, Pc-H
β), 8.33 (s, 1H, ArH), 7.47 (s, 1H, ArH), 7.34 (s, 1H, ArH), 7.23 (t,
j=8.0Hz, 1H, ArH), 6.88 (d,
j=8.0Hz, 1H, ArH), 6.82 (s, 1H, ArH), 6.47 (d,
j=8.0Hz, 1H, ArH), 4.51-4.48 (m, 4H, CH
2), 4.42-4.39 (m, 4H, CH
2), 4.02 (t,
j=4.5Hz, 4H, CH
2), 3.94 (t,
j=4.5Hz, 2H, CH
2), 3.87 (t,
j=4.5Hz, 2H, CH
2), 3.83-3.81 (m, 4H, CH
2), 3.77-3.74 (m, 4H, CH
2), 3.56 (s, 6H, CH
3), 3.08 (s, 1H, CH) .HRMS (ESI): m/zC
62h
53n
11o
8zn [M+H]
+, calculated value 1144.3448; Measured value 1144.3438.
Embodiment 2(M=Al, m=6, R
1=R
2=-OCH
2cH
2oCH
3, β is monosubstituted)
1) by compound 10.5g(1.27mmol) and compound 20.68g(1.95mmol) add in DMF (DMF), after both dissolving, add K
2cO
30.7g(5.07mmol), under 50 DEG C of nitrogen protections, 6h is reacted.After question response terminates, be spin-dried for DMF, then with the thick product of dichloromethane extraction, subsequently with the volume ratio of methylene chloride-methanol for 30:1 is for washing and dehydrating integrated machine, cross silicagel column be separated obtain compound 30.4g.Productive rate is 55%.
1hNMR (500MHz, CDCl
3):
δ8.36 (s, 1H, ArH), 7.41 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.01 (t,
j=8.0Hz, 1H, ArH), 6.74 (d,
j=8.0Hz, 1H, ArH), 6.59 (s, 1H, ArH), 6.41 (d,
j=8.0Hz, 1H, ArH), 4.32-4.29 (m, 4H, CH
2), 4.26-4.22 (m, 4H, CH
2), 3.70 (t,
j=4.5Hz, 2H, CH
2), 3.60 (t,
j=4.5Hz, 4H, CH
2), 3.56 (t,
j=4.5Hz, 2H, CH
2), 3.54-3.52 (m, 4H, CH
2), 3.50-3.48 (m, 4H, CH
2), 3.46-3.43 (m, 4H, CH
2), 3.40-3.38 (m, 4H, CH
2), 3.36-3.34 (m, 4H, CH
2), 3.24 (s, 6H, CH
3), 3.06 (s, 1H, CH), 2.0 (brs, 1H, OH) .HRMS (ESI): m/zC
36h
51n
3o
11[M+H]
+, calculated value 702.3602; Measured value 702.3605.
2) by 1g(1.75mmol) compound 3 and 0.45g(2.6mmol) 4-nitrophthalonitrile joins in DMF, after when both dissolve, adds 1.45g(10.5mmol) K
2cO
3, under 70 DEG C of nitrogen protections, react 6h.Reaction terminate after, be spin-dried for DMF, the thick product of rear dichloromethane extraction, then with the volume ratio of methylene chloride-methanol for 40:1 is for washing and dehydrating integrated machine, cross silicagel column be separated obtain compound 4a(0.5g).Productive rate is 41.6%.
1hNMR (500MHz, CDCl
3):
δ8.36 (s, 1H, ArH), 7.41 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.01 (t,
j=8.0Hz, 1H, ArH), 6.74 (d,
j=8.0Hz, 1H, ArH), 6.59 (s, 1H, ArH), 6.41 (d,
j=8.0Hz, 1H, ArH), 4.32-4.29 (m, 4H, CH
2), 4.26-4.22 (m, 4H, CH
2), 3.70 (t,
j=4.5Hz, 2H, CH
2), 3.60 (t,
j=4.5Hz, 4H, CH
2), 3.56 (t,
j=4.5Hz, 2H, CH
2), 3.54-3.52 (m, 4H, CH
2), 3.50-3.48 (m, 4H, CH
2), 3.46-3.43 (m, 4H, CH
2), 3.40-3.38 (m, 4H, CH
2), 3.36-3.34 (m, 4H, CH
2), 3.24 (s, 6H, CH
3), 3.06 (s, 1H, CH), 2.0 (brs, 1H, OH) HRMS (ESI): m/zC
44h
53n
5o
11,[M+H]
+, calculated value 828.3820; Measured value 828.3814.
3) in the 100ml two neck bottle that reflux condensate device and gas operated device are housed, 0.25g compound 4a is added successively, the Pentyl alcohol that 0.406g phthalonitrile and 10ml newly steam, under nitrogen protection; be warming up to 100 DEG C; question response thing then adds 0.35g zinc acetate, adds 1 of 0.8ml after being stirred to dissolving after dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; constant temperature 150 DEG C, back flow reaction 5h, after reaction terminates; vacuum rotary steam removing Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 30:1 as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain 5a.
1hNMR (500MHz, DMSO-d
6):
δ9.41 (s, 1H, Pc-H
α), 9.27 (brs, 3H, Pc-H
α), 9.18 (brs, 2H, Pc-H
α), 9.01 (brs, 1H, Pc-H
α), 8.77 (sbr, 1H, Pc-H
β), 8.69 (s, 1H, Pc-H
β), 8.23-8.18 (m, 6H, Pc-H
β), 8.36 (s, 1H, ArH), 7.41 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.01 (t,
j=8.0Hz, 1H, ArH), 6.74 (d,
j=8.0Hz, 1H, ArH), 6.70 (s, 1H, ArH), 6.55 (d,
j=8.0Hz, 1H, ArH), 4.43-4.39 (m, 4H, CH
2), 4.38-4.35 (m, 4H, CH
2), 3.91 (t,
j=4.5Hz, 4H, CH
2), 3.88 (t,
j=4.5Hz, 2H, CH
2), 3.81 (t,
j=4.5Hz, 2H, CH
2), 3.72-3.69 (m, 4H, CH
2), 3.68-3.66 (m, 4H, CH
2), 3.57-3.55 (m, 4H, CH
2), 3.51-3.49 (m, 4H, CH
2), 3.44-3.41 (m, 4H, CH
2), 3.39 (s, 6H, CH
3), 3.12 (s, 1H, CH) .HRMS (ESI): m/zC
68h
65n
11o
11clAl
,[M+H]
+, calculated value 1274.4447; Measured value 1274.4440.
Embodiment 3(M=Si, m=8, R
1=R
2=H, α are monosubstituted)
1) by compound 10.5g(1.27mmol) and compound 20.68g(1.95mmol) add in DMF (DMF), after both dissolving, add K
2cO
30.7g(5.07mmol), under 50 DEG C of nitrogen protections, 6h is reacted.After question response terminates, be spin-dried for DMF, then with the thick product of dichloromethane extraction, subsequently with the volume ratio of methylene chloride-methanol for 30:1 is for washing and dehydrating integrated machine, cross silicagel column be separated obtain compound 3 (0.4g).
1hNMR (500MHz, CDCl
3):
δ8.49 (s, 1H, ArH), 7.62 (s, 1H, ArH), 7.36 (s, 1H, ArH), 7.28 (t,
j=8.0Hz, 1H, ArH), 7.19 (t,
j=8.0Hz, 1H, ArH), 7.01 (t,
j=8.0Hz, 1H, ArH), 6.88 (d,
j=8.0Hz, 1H, ArH), 6.75 (s, 1H, ArH), 6.55 (d,
j=8.0Hz, 1H, ArH), 4.89-4.86 (m, 4H, CH
2), 4.78-4.75 (m, 4H, CH
2), 3.92 (t,
j=4.5Hz, 2H, CH
2), 3.77 (t,
j=4.5Hz, 4H, CH
2), 3.64 (t,
j=4.5Hz, 2H, CH
2), 3.55-3.53 (m, 2H, CH
2), 3.49-3.47 (m, 4H, CH
2), 3.43-3.40 (m, 4H, CH
2), 3.30-3.28 (m, 4H, CH
2), 3.26 (s, 6H, CH
3), 3.15 (s, 1H, CH), 1.90 (brs, 1H, OH) .HRMS (ESI): m/zC
40h
59n
3o
13,[M+H]
+, calculated value 790.4126; Measured value 790.4109.
2) by 1g(1.75mmol) compound 3 and 0.45g(2.6mmol) 3-nitrophthalonitrile joins in DMF, after when both dissolve, adds 1.45g(10.5mmol) K
2cO
3, under 70 DEG C of nitrogen protections, react 6h.Reaction terminate after, be spin-dried for DMF, the thick product of rear dichloromethane extraction, then with the volume ratio of methylene chloride-methanol for 40:1 is for washing and dehydrating integrated machine, cross silicagel column be separated obtain compound 4a(0.5g).
1hNMR (500MHz, CDCl
3):
δ8.46 (s, 1H, ArH), 7.76 (t,
j=8.5Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.31 (d,
j=8.5Hz, 1H, ArH), 7.29 (s, 1H, ArH), 7.22 (d,
j=8.0Hz, 1H, ArH), 7.18 (t,
j=8.0Hz, 1H, ArH), 7.01 (t,
j=8.0Hz, 1H, ArH), 6.88 (d,
j=8.0Hz, 1H, ArH), 6.82 (s, 1H, ArH), 6.74 (d,
j=8.0Hz, 1H, ArH), 6.59 (t,
j=8.0Hz, 1H, ArH), 4.71-4.69 (m, 4H, CH
2), 4.66-4.64 (m, 4H, CH
2), 3.97 (t,
j=4.5Hz, 2H, CH
2), 3.77 (t,
j=4.5Hz, 4H, CH
2), 3.64 (t,
j=4.5Hz, 2H, CH
2), 3.62-3.59 (m, 4H, CH
2), 3.49-3.47 (m, 2H, CH
2), 3.43-3.40 (m, 4H, CH
2), 3.21-3.19 (m, 4H, CH
2), 3.17 (s, 6H, CH
3), 3.08 (s, 1H, CH) .HRMS (ESI): m/zC
48h
61n
5o
13,[M+H]
+, calculated value 916.4344; Measured value 916.4338.
3) in the 100ml two neck bottle that reflux condensate device and gas operated device are housed, 0.25g compound 4a is added successively, the Pentyl alcohol that 0.406g phthalonitrile and 10ml newly steam, under nitrogen protection; be warming up to 100 DEG C; question response thing then adds 0.35g silicon tetrachloride, adds 1 of 0.8ml after being stirred to dissolving after dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; constant temperature 150 DEG C, back flow reaction 5h, after reaction terminates; vacuum rotary steam removing Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 30:1 as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain 5a (0.09g).
1hNMR (500MHz, DMSO-d
6):
δ9.38 (s, 1H, Pc-H
α), 9.19 (brs, 3H, Pc-H
α), 9.02 (brs, 2H, Pc-H
α), 8.85 (brs, 1H, Pc-H
α), 8.63 (sbr, 1H, Pc-H
α), 8.54 (s, 1H, Pc-H
β), 8.44-8.41 (m, 6H, Pc-H
β), 8.33 (s, 1H, ArH), 7.47 (s, 1H, ArH), 7.34 (s, 1H, ArH), 7.23 (t,
j=8.0Hz, 1H, ArH), 7.19 (t,
j=8.0Hz, 1H, ArH), 6.88 (d,
j=8.0Hz, 1H, ArH), 6.82 (s, 1H, ArH), 6.79 (t,
j=8.0Hz, 1H, ArH), 6.47 (d,
j=8.0Hz, 1H, ArH), 4.71-4.69 (m, 4H, CH
2), 4.66-4.64 (m, 4H, CH
2), 3.97 (t,
j=4.5Hz, 2H, CH
2), 3.77 (t,
j=4.5Hz, 4H, CH
2), 3.64 (t,
j=4.5Hz, 2H, CH
2), 3.62-3.59 (m, 4H, CH
2), 3.49-3.47 (m, 2H, CH
2), 3.43-3.40 (m, 4H, CH
2), 3.21-3.19 (m, 4H, CH
2), 3.17 (s, 6H, CH
3), 3.08 (s, 1H, CH) .HRMS (ESI): m/zC
70h
73n
11o
13cl
2si
,[M+H]
+, calculated value 1374.4615; Measured value 1374.4603.
Application example 1(M=Zn, m=4, R
1=R
2=
, α, β position is monosubstituted)
The in vitro light power antitumour activity of (5a) and (5b) two kinds of ZnPcS2P2es is carried out desk study, for certain reference value can be provided in body (mouse) experiment from now on, there is more important meaning.Main research comprises the cytotoxicity of phthalocyanine as photosensitizers.The cytotoxicity experiment of photosensitizers generally includes phototoxicity and dark toxicity test two portions, adopts mtt assay (tetrazolium reduction method) to measure.MTT(3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt) Cleaning Principle is that succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-fast bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and in dead cell, there is no succinodehydrogenase, therefore can not produce first a ceremonial jade-ladle, used in libation.Use DMSO(dimethyl sulfoxide (DMSO)) dissolve viable cell produce first a ceremonial jade-ladle, used in libation, measure its absorption value by microplate reader at 570nm wavelength place, can indirectly reflect viable cell quantity.Within the scope of certain cell count, the amount that MTT first a ceremonial jade-ladle, used in libation is formed is directly proportional to viable count.
The attached cell that growth conditions is good, goes down to posterity with 0.25% trysinization, prepares 2 × 10 with RPMI1640 substratum (containing 10% calf serum)
4cells/ml cell suspension, by every hole 180ml(about containing 4000 tumour cells) be inoculated in 96 well culture plates, put 37 DEG C, 5%CO
2attach overnight is cultivated, adherent rear dosing in incubator; Blank group is established in experiment, and (blank refers to that control group is not except adding except phthalocyanine, and other conditions are consistent with given the test agent group.), (solvent control refers to that control group does not add cell to solvent control group, other conditions are consistent with given the test agent group) and given the test agent group, phthalocyanine is formulated as DMSO(in advance containing 5% Viscotrol C) storing solution, all through organic membrane filter (0.22 μm) after all drug solution preparing, during use, phthalocyanine dilute with water is different concns, and in final concentration, the content of DMSO is 1%.Every concentration sets 6 parallel holes, and the medicine that every hole adds 20 μ l different concns is placed in incubator hatches.Light poison experiment: after 24 hours, remove the substratum containing liquid, change 100 μ l fresh cultures, then irradiate cell with laser apparatus, 670nm wavelength laser, irradiation energy density is 1.5J/cm
2.Illumination is complete, 96 orifice plates is refitted in 37 DEG C, 5%CO
2incubator in, continue cultivate.Dark poison experiment is then directly put into incubator and is continued to cultivate after having changed fresh culture, operating process avoids illumination as far as possible, after 24h, every hole adds PBS solution (4mg/ml) the 10 μ l of MTT, hatch 4 hours for 37 DEG C, careful supernatant discarded after 4 hours, every hole adds 200mlDMSO and dissolves first a ceremonial jade-ladle, used in libation particle, after slight concussion makes first a ceremonial jade-ladle, used in libation dissolve completely, by OD value under microplate reader mensuration 570nm wavelength.
We adopt mtt assay to determine two kinds of phthalocyanines and kill and wound curve to HepG2 human hepatoma cell.Curve is killed and wounded to HepG2 cell under illumination and non-illuminated conditions.Illumination wavelength is 670nm, and light energy density is 1.5J/cm
2.Data by three times independently parallel laboratory test obtain, with the process of Mean ± SEM mode.By the known two kinds of phthalocyanines of experimental data under non-illuminated conditions to cell without any lethal effect, and they kill and wound the IC of HepG2 cell under certain illumination condition
50value (half inhibiting rate) is respectively 0.020 μM, 0.045 μM.And only need the phthalocyanine of 0.5 μM just almost can kill whole cancer cells, therefore they all show very high light power antitumour activity.Extremely low dark toxicity and higher phototoxicity illustrate that these two kinds of phthalocyanines all reach the requirement of desirable photosensitizers, are expected to be developed as efficient photosensitive drug.
The foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.
Claims (7)
1. molecular targeted anticancer photosensitizer phthalocyanine-erlotinib conjugates, is characterized in that: its chemical structural formula is as follows:
（1）
（2）；
Wherein M=Zn, Al, Si, Ga, m=0-8, R
1, R
2=-H or-OCH
2cH
2oCH
3.
2. prepare a method for molecular targeted anticancer photosensitizer phthalocyanine-erlotinib conjugates as claimed in claim 1, it is characterized in that: comprise the following steps:
(1) compound 1:
, R
1, R
2=-H or-OCH
2cH
2oCH
3with compound 2:
, m=0-8 is initiator, at K
2cO
3react with under DMF condition, cross silicagel column and obtain compound 3:
, m=0-8, R
1, R
2=-H or-OCH
2cH
2oCH
3;
(2) with compound 3 and 3-nitrophthalonitrile or 4-nitrophthalonitrile at K
2cO
3react with under DMF condition, cross silicagel column and obtain compound 4a:
, m=0-8, R
1, R
2=-H or-OCH
2cH
2oCH
3or compound 4b:
, m=0-8, R
1, R
2=-H or-OCH
2cH
2oCH
3;
(3) with compound 4a or compound 4b and Pentyl alcohol, phthalonitrile and zinc or aluminium or gallium or silicon salt for initiator, 1, react under 8-diazabicyclo [5.4.0] 11 carbon-7-alkene or metallic lithium catalysis, cross silicagel column and obtain described molecular targeted anticancer photosensitizer phthalocyanine-erlotinib conjugates.
3. method according to claim 2, is characterized in that: the preparation process of step (1) comprising: by compound 1 and compound 2 in molar ratio for 1:1-2 adds in DMF, after both dissolving, join the K of 4-9 times of equivalent
2cO
3in, under 40-70 DEG C of nitrogen protection, react 4-8h; After question response terminates, being spin-dried for DMF, the thick product of rear dichloromethane extraction, is eluent subsequently with methylene chloride-methanol, crosses silicagel column separation and obtains compound 3.
4. method according to claim 2, it is characterized in that: the preparation process of step (2) comprising: by compound 3 and 3-nitrophthalonitrile or 4-nitrophthalonitrile in molar ratio for 1-2:1 joins in DMF, Deng both dissolve after, add the K of 4-9 times of equivalent
2cO
3in, under 40-90 DEG C of nitrogen protection, react 4-10h; After reaction terminates, being spin-dried for DMF, the thick product of rear dichloromethane extraction, is then eluent with methylene chloride-methanol, crosses silicagel column separation and obtains compound 4a or 4b.
5. method according to claim 2, it is characterized in that: the preparation process of step (3) comprising: add compound 4a or 4b successively being equipped with in reflux condensate device and gas operated device two neck bottle, phthalonitrile and Pentyl alcohol, under nitrogen protection, be warming up to 100 DEG C, after question response thing dissolves, then zinc is added, aluminium, gallium, silicon salt, 1 of 0.5-1ml is added after being stirred to dissolving, 8-diazabicylo [5.4.0] 11 carbon-7-alkene or metallic lithium, back flow reaction 5-12h, after reaction terminates, vacuum rotary steam removing Pentyl alcohol, take methylene chloride-methanol as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain 5a
m=Zn, Al, Si, Ga, m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3, or 5b
m=Zn, Al, Si, Ga, m=0-8, R
1, R
2=-H ,-OCH
3or-OCH
2cH
2oCH
3.
6. the method according to claim 3,4 or 5, is characterized in that: the volume ratio of described methylene chloride-methanol is 40-20:1.
7. the molecular targeted anticancer photosensitizer phthalocyanine-application of erlotinib conjugates in the photosensitizer drug preparing optical dynamic therapy as claimed in claim 1.
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