CN104447769B - A kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate - Google Patents

A kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate Download PDF

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CN104447769B
CN104447769B CN201410791090.0A CN201410791090A CN104447769B CN 104447769 B CN104447769 B CN 104447769B CN 201410791090 A CN201410791090 A CN 201410791090A CN 104447769 B CN104447769 B CN 104447769B
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erlotinib
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phthalocyanine
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CN104447769A (en
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薛金萍
张凤玲
黄琪
李俊
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Fuzhou University
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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
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    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines

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Abstract

The invention discloses a kind of molecular targeted anticancer photosensitizer erlotinib phthalocyanine conjugates and application thereof, introduce the erlotinib construction unit with alcoxyl long-chain at metal phthalocyanine macro ring periphery, its amphipathic, targeting of biocompatibility, photosensitizer can be increased.This conjugates is not easy to assemble, and is conducive to improving cellular uptake rate；Such compound structure is single simultaneously, there is not isomer, and product is easily purified.This compound is expected to improve the targeting of 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 productivity is higher, and raw material is easy to get, low cost, beneficially industrialized production.

Description

A kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate
This case is the divisional application of following application
The application number of original application: 201310240667.4
The applying date of original application: 2013-6-18
The denomination of invention of original application: a kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate.
Technical field
The invention belongs to organic and metal complex synthesis field, have and relate to a kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate and application thereof.
Background technology
Phthalocyanine is the macrocyclic compound that a class has good optical physics spectrochemical property, is applied to high-tech area, wherein Including semiconductor device, photovoltaic and solaode, electrostatic reprography, commutator, LB film optical dynamic therapy photosensitizer etc., its Middle as the great development prospect of photosensitizer.
In the multiformity of phthalocyanine compound and structure can " cutting ", for the phthalocyanine compounds required for people's appropriate design Thing provides may.The new function material that the formation that is connected with other functional functional group by phthalocyanine has complementary functions is phthalocyanine compounds One of important development direction of thing.But, there is synthesis difficulty in existing Substituted metallophthalocyanine, side reaction many mostly, The problems such as separating difficulty is big.There is a major issue is that phthalocyanine is less desirable to the targeting of tumor tissues, therefore simultaneously Research to photosensitizer targeting becomes a focus of research now.
Along with the development of molecular biology, progressively it is found in the difference of molecular level about normal cell and cancerous cell, Targeted drug for tumor also arises at the historic moment.These medicines are different from traditional chemotherapeutic agent, have the strongest targeting Property.Erlotinib (erlotinib)®, see compound 4 structure (wherein R1=R2=) it is by Roche (Roche) base The 4-phenylamino quinazoline ditosylate salt PTS developed jointly because of Tyke (Genentech) company, it is with human epidermal growth factor receptor Body (EGFR) is application point, a kind of specific TYR zymogenesis with in suppression EGF-R ELISA, can block swollen Oncocyte " growth signals ", as the work of " representative " of molecular targeted agents, popularization and application the most clinically.
Based on molecular target Drug therapy and optical dynamic therapy mechanism, propose to build photosensitizer conjugated with molecular target medicine The conception of thing, i.e. utilizes the targeting of target drug, the High Fragmentation power of optical dynamic therapy and the low supersession rate of phthalocyanine compound Feature, explores the structure influence factor of phthalocyanine-erlotinib conjugates performance.Described photosensitizer will be the high target of erlotinib Tropism, the photodynamic therapy characteristic of Phthalocyanine Zinc and the feature of Cellular retention phase length combine, and both can solve erlotinib Drug-resistant sex chromosome mosaicism, it is possible to improve the not strong problem of phthalocyanine complex targeting, make erlotinib to residual or sporadicly can divide Cloth sick cell around tumor tissues suppresses for a long time, inactivates, and is substantially reduced the risk of tumor recurrence after treatment.
Summary of the invention
It is an object of the invention to provide a kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate and answer With, this conjugates structure is single, there is not isomer, and product is easily purified；Synthetic method is fairly simple, and side reaction is few, productivity Higher, raw material is easy to get, low cost, beneficially industrialized production.
For achieving the above object, the present invention adopts the following technical scheme that
The chemical structural formula of a kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate is as follows:
(1)
(2)；
Wherein M=Zn, Al, Si, Ga, m=0-8, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3。
The method preparing molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate as above includes following step Rapid:
(1) with compound 1:, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3With formamidine acetate it is Starting material, ethanol is reaction dissolvent, and microwave reaction obtains compound 2:, R=-H ,-CH3O、-OH、- CH2OCH2CH2OCH3；
(2) with compound 2 as starting material, compound 3 is obtained with phosphorus oxychloride reaction:, R=-H ,- CH3O、-OH、-CH2OCH2CH2OCH3；
(3) with compound 3 and 3-aminobenzene acetylene as starting material, react in isopropanol and obtain compound 4:, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3；
(4) with compound 4 as starting material, Boron tribromide is catalyst, and demethyl obtains compound 5:, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3；
(5) with compound 5 and compound 6:, m=0-8 is starting material, at potassium carbonate and N, Under conditions of dinethylformamide, react and obtain compound 7:, m= 0-8, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3；
(6) with compound 7 as starting material, under conditions of potassium carbonate and DMF, with 3-nitro neighbour's benzene Dimethoxy nitrile or the reaction of 4-nitrophthalonitrile, obtain compound 8a:, m= 0-8, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3Or compound 8b:, M=0-8, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3；
(7) with compound 8a or compound 8b and n-amyl alcohol, phthalonitrile and zinc or aluminum or gallium or silicon salt as starting material, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene or the lower erlotinib-phthalocyanine described in synthesis of lithium metal catalysis are conjugated Thing.
The preparation process of step (1) including: joins in ethanol for 1:1-2 in molar ratio by compound 1 and formamidine acetate, Microwave reaction 2-4h；After question response terminates, it is spin-dried for ethanol, thick product is obtained by extraction with dichloromethane and water；By volume ratio it is again The methylene chloride-methanol of 40-20:1 is that eluant crosses silicagel column, isolated compound 2.
The preparation process of step (2) including: by compound 2 and phosphorus oxychloride in molar ratio for 1:1-3, after reaction 4-9h, Rotation is evaporated off remaining phosphorus oxychloride, thick product is obtained by extraction with water and dichloromethane, crosses silicagel column and obtains compound 3.
The preparation process of step (3) including: with compound 3 and 3-aminobenzene acetylene in molar ratio as 1:1-2, joins different In propanol, after reaction 4-9h, being spin-dried for by isopropanol, the methylene chloride-methanol with volume ratio as 40-20:1 crosses silica gel for eluant Post isolated compound 4.
The preparation process of step (4) including: joins in Boron tribromide by compound 4, reacts 1-under the conditions of-78 DEG C 3h, is then reacted to room temperature at 0 DEG C, reacts 10-18h, and rotation is evaporated off Boron tribromide, is the dichloromethane of 40-20:1 by volume ratio Alkane-methanol is eluant, crosses silicagel column isolated compound 5.
The preparation process of step (5) including: by compound 5 and compound 6:, m=0- 8 join in DMF for 1:1-2 in molar ratio, react 4-9h under conditions of 40-80 DEG C, and question response terminates After, it is spin-dried for DMF, thick product is obtained by extraction with dichloromethane and water, with the methylene chloride-methanol that volume ratio is 40-20:1 for washing De-agent, crosses silicagel column isolated compound 7.
The preparation process of step (6) including: compound 7 and 3-nitrophthalonitrile or 4-nitrophthalonitrile is pressed Mol ratio is that 1:1-2 joins in DMF, reacts 4-9h under conditions of 40-100 DEG C, and question response terminates After, be spin-dried for DMF, after thick product is obtained by extraction with dichloromethane and water, with the methylene chloride-methanol that volume ratio is 40-20:1 be Eluant, crosses silicagel column isolated compound 8a or 8b.
The preparation process of step (7) including: being sequentially added in equipped with reflux condensate device and gas operated device two neck bottle Compound 8a or 8b, phthalonitrile and n-amyl alcohol, under nitrogen protection, be warming up to 100 DEG C, after question response thing dissolves, then add Enter zinc or aluminum or gallium or silicon salt, addition 1 after stirring to dissolving, 8-diazabicylo [5.4.0] 11 carbon-7-alkene or lithium metal, Back flow reaction 5-12h, after reaction terminates, vacuum rotary steam removes n-amyl alcohol, with CH2Cl2And CH3The volume ratio of OH is 40-20:1's Mixed solution, as eluant, is crossed silicagel column, after rotated evaporation and concentration, is obtained described molecular targeted anticancer photosensitizer angstrom sieve For Buddhist nun-phthalocyanine conjugates.
Erlotinib-phthalocyaconjugate conjugate as above is primarily useful for preparing the photosensitizer of optical dynamic therapy.
Phthalocyanine-like compound is considered as most potential second filial generation photosensitizer.But owing to it is at target cell and target tissue In intake undesirable, effect is difficult to reach application request.Amphipathic phthalocyanine photosensitizer, such as hydroxyl, fluorine, oligomeric second two The substituted phthalocyanine derivates such as alcohol and oligomeric amine, has higher picked-up owing to having preferable affinity with target tissue cell Amount, becomes the emphasis researched and developed in recent years.In the present invention, the Erlotinib-phthalocyaconjugate conjugate of design is to utilize the second filial generation photosensitizer can Chemical tailoring and the feature of grafting, the active structure unit of some biological nature on binding on its molecule, it is desirable to improve tumor Tissue selectivity picked-up and a strategy of therapeutic effect.The most this novel photosensitive agent will be the high targeting of erlotinib Property, the photodynamic therapy characteristic of Phthalocyanine Zinc and the feature of Cellular retention phase length combine, and both can solve erlotinib medicine Thing drug resistance problems, it is possible to improve the not strong problem of phthalocyanine complex targeting, make erlotinib to residual or sporadicly can be distributed Sick cell around tumor tissues suppresses for a long time, inactivates, and is substantially reduced the risk of tumor recurrence after treatment.
The remarkable advantage of the present invention is:
(1) clearly enhancing the targeting of photosensitizer, photodynamic activity is higher；
(2) target compound structure is single, there is not isomer, the easy purification of product.Polysubstituted Phthalocyanine Zinc is because having , there is multiple isomer owing to each substituent group spatial distribution is different, and on phthalocyanine ring, have 8 α positions, occupy in multiple substituent groups Different α positions also creates different isomers.And structure is similar makes these isomer character the most close, it is difficult to separate.Single Substituted zinc phthalocyanine not there is problems in that.
(3) introducing polyglycol chain in the compound synthesized by, adding phthalocyanine-like compound picked-up in cell has It is beneficial to the use as light power clinical application.
(4) synthetic method is simple, it is only necessary to several steps just can complete, and side reaction is few, and raw material is easy to get, and low cost has It is beneficial to industrialized production.
Detailed description of the invention
A kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate is specifically made at the photosensitizer of optical dynamic therapy Standby process includes:
Step (1): compound 1 and formamidine acetate are joined in ethanol solution for 1:2-4 in molar ratio, microwave reaction 2- 4h.After question response terminates, be spin-dried for ethanol, after thick product is obtained by extraction with dichloromethane and water.Afterwards with methylene chloride-methanol for washing Silicagel column, isolated compound 2 are crossed in de-agent, and productivity is 80-92%.
Step (2): be 1:1-3 in molar ratio by compound 2 and phosphorus oxychloride, after reaction 4-9h, rotation is evaporated off remaining Phosphorus oxychloride, after thick product is obtained by extraction with water and dichloromethane.Crossing silicagel column below and obtain compound 3, productivity is 60%-85%
Step (3): with compound 3 and 3-aminobenzene acetylene be in molar ratio: 1:1-2, join in isopropanol.Reaction 4- After 9h, isopropanol is spin-dried for, after cross silicagel column isolated compound 4 with methylene chloride-methanol for eluant, productivity is 60- 82%
Step (4): join in Boron tribromide by compound 4, reacts 1-3h under the conditions of present-78 DEG C, then anti-at 0 DEG C Should arrive room temperature, react 10-18h, rotation is evaporated off Boron tribromide, after with methylene chloride-methanol be 40-20:1 be eluant, cross silicon Glue post isolated compound 5, productivity is 20-30%.
Step (5): by compound 5 and compound 6:, m=0-8 is 1 in molar ratio: 1-2 joins the Anhydrous potassium carbonate being subsequently added 4-8 equivalent in DMF (DMF), is 40-80 DEG C in temperature Under the conditions of react 4-9h, after question response terminates, be spin-dried for DMF, after thick product is obtained by extraction with dichloromethane and water, use dichloromethane Alkane-methanol is eluant, crosses silicagel column isolated compound 7.Productivity is 30-50%.
Step (6): be 1:1-2 in molar ratio by compound 7 and 3-nitrophthalonitrile or 4-nitrophthalonitrile Join in DMF (DMF), under conditions of 40-100 DEG C, react 4-9h, after question response terminates, be spin-dried for DMF, after thick product is obtained by extraction with dichloromethane and water, be eluant with methylene chloride-methanol, cross silicagel column isolated Compound 8a or 8b.
Step (7): be sequentially added into compound 8a or 8b in equipped with reflux condensate device and gas operated device two neck bottle, adjacent Benzene dicarbonitrile and n-amyl alcohol, under nitrogen protection, be warming up to 100 DEG C, after question response thing dissolves, be subsequently added into zinc, aluminum, gallium, silicon salt, Stirring adds the 1 of 0.5-1ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, constant temperature 150 DEG C, back flow reaction after dissolving 5-12h, after reaction terminates, vacuum rotary steam removes n-amyl alcohol, with CH2Cl2And CH3The volume ratio of OH is the mixed solution of 40-20:1 As eluant, crossing silicagel column, after rotated evaporation and concentration, obtain described Erlotinib-phthalocyaconjugate conjugate, productivity is 10- 25%。
We test the activity of the described compound some optical dynamic therapies in isolated cells, have the most also done animal Experiment.Experiment has obtained more satisfactory result.This kind of compound has good pharmaceutically active.And from body animal In test, it is understood that this compounds has preferable targeting.
Following embodiment is expanded on further the present invention, but the present invention is not limited only to this.
Embodiment 1(M=Zn, m=3, R=-CH3O, α position is monosubstituted)
1), by 1.0g(5.07mmol) compound and 1.0g(10mmol) formamidine acetate joins in 20ml ethanol solution, Microwave reaction 3h.After question response terminates, be spin-dried for ethanol, after thick product is obtained by extraction with dichloromethane and water.Afterwards with dichloromethane- Methanol is that eluant crosses silicagel column, isolated compound 2.
), by 1g(4.8mmol) compound 2 joins 1.48g(9.7mmol) phosphorus oxychloride, after reaction 4-9h, rotation is evaporated off Go remaining phosphorus oxychloride, after thick product is obtained by extraction with water and dichloromethane.Compound 3 is obtained after silicagel column.
3), by 1g(4.46mmol) compound 3 and 1g(8.92mmol) 3-aminobenzene acetylene joins in isopropanol.Reaction After 4-9h, isopropanol is spin-dried for, then with methylene chloride-methanol as eluant, crosses silicagel column isolated compound 4.
4), by 2g(6.55mmol) compound 4 joins in Boron tribromide, first reacts 1h under the conditions of-78 DEG C, then from 0 DEG C is reacted to room temperature, reacts 16h, and rotation is evaporated off Boron tribromide, after with methylene chloride-methanol be 40-20:1 be eluant, mistake Silicagel column isolated compound 5.
5), by 2g(6.8mmol) compound 5 and 3.6g(10.3mmol) compound 6 (m=3) joins N, N-dimethyl In Methanamide (DMF), it is subsequently added 3.8g(27mmol) Anhydrous potassium carbonate, reacts 5h under conditions of temperature is 80 DEG C, treats anti- After should terminating, be spin-dried for DMF, after thick product is obtained by extraction with dichloromethane and water, be eluant with methylene chloride-methanol, cross silicon Glue post isolated compound 7.1H NMR (CDCl3, 400MHz): δ 8.64(s, 1 H, ArH), 8.12 (s, 1 H, ArH), 7.93 (s, 1 H, ArH), 7.81 (d, J = 7.8 Hz, 1 H, ArH), 7.47-7.39 (m, 2 H, ArH), 7.33 (s, 1 H, ArH), 4.77 (br s, 4 H, CH2), 4.35 (vt, J = 4.4 Hz, 4 H, CH2), 4.22 (s, 3 H, CH3), 4.07 (vt, J = 4.4 Hz, 2 H, CH2), 4.03 (brs, 1 H, NH), 3.96(vt, J = 4.4 Hz, 2 H, CH2), 3.80-3.76(m, 4 H, CH2), 3.62 (s, 1 H, CH), 2.0 (s, 1 H, OH).HRMS (ESI): m/z calculated for C25H29N3O6 [M+H]+, 468.2134; found, 468.2130.
6), by 2g (4.27mmol) compound 7 and 0.88g(5.1mmol) 3-nitrophthalonitrile joins N, N-bis- In methylformamide (DMF), under conditions of 60 DEG C, react 8h, after question response terminates, be spin-dried for DMF, rear dichloromethane and water Thick product is obtained by extraction, is eluant with methylene chloride-methanol, cross silicagel column isolated compound 8a.1H NMR (CDCl3, 400MHz): δ 8.64(s, 1 H, ArH), 8.12 (s, 1 H, ArH), 7.93 (s, 1 H, ArH), 7.81 (d, J = 7.8 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H, ArH), 7.47-7.39 (m, 3 H, ArH), 7.33 (s, 1 H, ArH), 7.31 (d, J = 7.6 Hz, 1 H, ArH), 7.26 (d, J = 7.6 Hz, 1 H, ArH), 4.77 (br s, 4 H, CH2), 4.35 (vt, J = 4.5 Hz, 4 H, CH2), 4.22 (s, 3 H, CH3), 4.07 (vt, J = 4.5 Hz, 2 H, CH2), 4.03 (brs, 1 H, NH), 3.96(vt,J = 4.5 Hz, 2 H, CH2), 3.80-3.76(m, 4 H, CH2), 3.62 (s, 1 H, CH). HRMS (ESI): m/z calculated for C33H31N5O6 [M+H]+,624.2822; found, 624.2810.
7), in equipped with the 100ml two neck bottle of reflux condensate device and gas operated device, it is sequentially added into 0.30g(0.48mmol) Compound 8a, 0.55g(4.3mmol) phthalonitrile and 15ml n-amyl alcohol, under nitrogen protection, it is warming up to 100 DEG C, question response thing After dissolving, it is subsequently added into 0.46g(2.1mmol) zinc acetate, stirring adds the 1 of 0.5-1ml, 8-diazabicylo after dissolving [5.4.0] 11 carbon-7-alkene, constant temperature 150 DEG C, back flow reaction 6h, after reaction terminates, vacuum rotary steam removes n-amyl alcohol, with CH2Cl2 And CH3The volume ratio of OH be the mixed solution of 30:1 as eluant, cross silicagel column, after rotated evaporation and concentration, obtain targeting EGFR anticancer photosensitizer.1H NMR (DMSO-d6, 400MHz):δ 9.38-9.33 (m, 4 H, Pc-Hα), 9.21-9.18 (m, 2 H, Pc-Hα), 9.11 (d, J = 7.0 Hz, 1 H, Pc-Hα), 8.92 (d, J = 7.0 Hz, 1 H, Pc- Hβ), 8.84-8.81 (m, 6 H, Pc-Hβ), 8.72 (t, J = 7.5 Hz, 1 H, Pc-Hβ), 8.12 (s, 1 H, ArH), 7.93 (s, 1 H, ArH), 7.81 (d, J = 7.8 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.31 (d, J = 7.6 Hz, 1 H, ArH), 7.26 (d, J = 7.6 Hz, 1 H, ArH), 4.77 (br s, 4 H, CH2), 4.35 (vt, J = 4.5 Hz, 4 H, CH2), 4.22 (s, 3 H, CH3), 4.07 (vt, J = 4.5 Hz, 2 H, CH2), 4.03 (brs, 1 H, NH), 3.96(vt, J = 4.5 Hz, 2 H, CH2), 3.80-3.76(m, 4 H, CH2), 3.62 (s, 1 H, CH).HRMS (ESI): m/z calculated for C57H43N11O6Zn [M+H]+,1042.2767; found, 1042.2753.
Embodiment 2(M=Al, m=7, R=-H, α position is monosubstituted)
1), by 1g(mmol) compound and 1.0g(mmol) formamidine acetate joins in 20ml ethanol solution, microwave reaction 3h.After question response terminates, be spin-dried for ethanol, after thick product is obtained by extraction with dichloromethane and water.Afterwards with methylene chloride-methanol for washing Silicagel column, isolated compound 2 are crossed in de-agent.
2), by 1g(mmol) compound 2 joins 1.48g(mmol) phosphorus oxychloride, after reaction 4-9h, rotation is evaporated off remaining Remaining phosphorus oxychloride, after thick product is obtained by extraction with water and dichloromethane.Cross silicagel column below and obtain compound 3.
3), by 1g(mmol) compound 3 and 1g(mmol) 3-aminobenzene acetylene joins in isopropanol.After reaction 4-9h, Isopropanol is spin-dried for, after with methylene chloride-methanol as eluant, cross silicagel column isolated compound 4.
4), by 2g(6.55mmol) compound 4 joins in Boron tribromide, and under the conditions of-78 DEG C, first react 1h, then exist 0 DEG C is reacted to room temperature, reacts 16h, and rotation is evaporated off Boron tribromide, after with methylene chloride-methanol be 40-20:1 be eluant, mistake Silicagel column isolated compound 5.1H NMR (MeOD, 400MHz): δ 8.83 (s, 1 H, ArH), 7.92 (s, 1 H, ArH), 7.88 (s, 1 H, ArH), 7.74 (d, J = 7.8 Hz, 1 H, ArH), 7.52-7.37 (m, 2 H, ArH), 7.33 (d, J = 7.8 Hz, 1 H, ArH), 7.26 (s, 1 H, ArH), 4.01 (brs, 1 H, NH), 3.62 (s, 1 H, CH), 2.0 (s, 1 H, OH). HRMS (ESI): m/z calculated for C16H11N3O [M+H]+,262.0980; found, 262.0976.
5), by 2g(7.66mmol) compound 5 and 5.5g(11.4mmol) compound 6 (m=7) joins N, N-dimethyl In Methanamide (DMF), it is subsequently added 3.8g(27mmol) Anhydrous potassium carbonate, reacts 7h under conditions of temperature is 80 DEG C, treats anti- After should terminating, be spin-dried for DMF, after thick product is obtained by extraction with dichloromethane and water, be eluant with methylene chloride-methanol, cross silicon Glue post isolated compound 7.1H NMR (CDCl3, 400MHz): δ 8.59(s, 1 H, ArH), 8.36 (s, 1 H, ArH), 8.06 (s, 1 H, ArH), 7.99 (d, J = 7.8 Hz, 1 H, ArH), 7.53-7.49 (m, 3 H, ArH), 7.33 (s, 1 H, ArH), 5.02 (brs, 4 H, CH2), 4.83 (vt, J = 4.4 Hz, 4 H, CH2), 4.80-4.78 (m, 4 H, CH2), 4.62-4.58 (m, 4 H, CH2), 4.39 (vt, J = 4.4 Hz, 2 H, CH2), 4.27 (vt, J = 4.4 Hz, 2 H, CH2), 4.21 (brs, 1 H, NH), 4.15 (vt, J = 4.4 Hz, 4 H, CH2), 4.05 (vt, J = 4.4 Hz, 4 H, CH2), 3.95-3.91 (m, 4 H, CH2), 3.76 (s, 1 H, CH), 2.32 (s, 1 H, OH). HRMS (ESI): m/z calculated for C32H43N3O9 [M+H]+,614.3077; found, 614.3069.
6), by 2g (3.26mmol) compound 7 and 1.0g(4.8mmol) 3-nitrophthalonitrile joins N, N-diformazan In base Methanamide (DMF), under conditions of 60 DEG C, react 8h, after question response terminates, be spin-dried for DMF, rear dichloromethane and water extraction Obtain thick product, be eluant with methylene chloride-methanol, cross silicagel column isolated compound 8a.1H NMR (CDCl3, 400MHz): δ 8.64 (s, 1 H, ArH), 8.12 (s, 1 H, ArH), 7.93 (s, 1 H, ArH), 7.81 (d, J = 7.8 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H, ArH), 7.47-7.39 (m, 2 H, ArH), 7.89(d, J = 7.8 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.31 (d, J = 7.6 Hz, 1 H, ArH), 7.26 (d, J = 7.6 Hz, 1 H, ArH), 5.22 (m, 4 H, CH2), 4.93(vt, J = 4.5 Hz, 4 H, CH2), 4.77 (br s, 4 H, CH2), 4.56 (m, 4 H, CH2), 4.35 (vt, J = 4.5 Hz, 4 H, CH2), 4.07 (vt, J = 4.5 Hz, 4 H, CH2), 4.03 (brs, 1 H, NH), 3.96 (vt, J = 4.5 Hz, 4 H, CH2), 3.80-3.76(m, 4 H, CH2), 3.62 (s, 1 H, CH). HRMS (ESI): m/z calculated for C40H45N5O9 [M+H]+,740.3295; found, 740.3280.
7), in equipped with the 100ml two neck bottle of reflux condensate device and gas operated device, it is sequentially added into 0.30g (0.405mmol) compound 8a, 0.55g(4.3mmol) phthalonitrile and 15ml n-amyl alcohol, under nitrogen protection, it is warming up to 100 DEG C, after question response thing dissolves, it is subsequently added into 0.46g(3.4mmol) anhydrous Aluminum chloride, stirring adds the 1 of 0.5ml after dissolving, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, back flow reaction 6h, after reaction terminates, vacuum rotary steam removes n-amyl alcohol, with CH2Cl2And CH3The volume ratio of OH be the mixed solution of 30:1 as eluant, cross silicagel column, after rotated evaporation and concentration, obtain Described molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate.1H NMR (DMSO-d6, 400MHz): δ 9.36- 9.32 (m, 4 H, Pc-Hα), 9.25-9.21 (m, 2 H, Pc-Hα), 9.14 (d, J = 7.0 Hz, 1 H, Pc- Hα), 9.01 (d, J = 7.0 Hz, 2 H, Pc- Hβ), 8.81-8.79 (m, 4 H, Pc-Hβ), 8.75 (t, J = 7.5 Hz, 2 H, Pc-Hβ), 8.69 (s, 1 H, ArH), 8.32 (s, 1 H, ArH), 7.95 (d, J = 7.8 Hz, 1 H, ArH), 7.74 (t, J = 7.6 Hz, 1 H, ArH), 7.89(d, J = 7.8 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.31 (d, J = 7.6 Hz, 1 H, ArH), 7.26 (d, J = 7.6 Hz, 1 H, ArH), 5.22 (m, 4 H, CH2), 4.93(vt, J = 4.5 Hz, 4 H, CH2), 4.77 (br s, 4 H, CH2), 4.56 (m, 4 H, CH2), 4.35 (vt, J = 4.5 Hz, 4 H, CH2), 4.07 (vt, J = 4.5 Hz, 4 H, CH2), 4.03 (brs, 1 H, NH), 3.96 (vt, J = 4.5 Hz, 4 H, CH2), 3.80- 3.76 (m, 4 H, CH2), 3.55 (s, 1 H, CH). HRMS (ESI): m/z calculated for C64H57N11O8ClAl[M+H]+,1170.3974;found, 1170.3950.
Embodiment 3(M=Si, m=1, R=-CH2OCH2CH2OCH3, α position is monosubstituted)
1), 1.0g compound 1 and 1.0g formamidine acetate is joined in 20ml ethanol solution, microwave reaction 3h.Question response After end, be spin-dried for ethanol, after thick product is obtained by extraction with dichloromethane and water.It is that eluant crosses silicon with methylene chloride-methanol afterwards Glue post, isolated compound 2.
), 1g compound 2 is joined 1.51g phosphorus oxychloride, reaction 4-9h after, rotation remaining phosphorus oxychloride is evaporated off, Thick product is obtained by extraction afterwards with water and dichloromethane.Cross silicagel column below and obtain compound 3.
3), 1g compound 3 and 1g3-aminobenzene acetylene is joined in isopropanol.After reaction 4-9h, isopropanol is spin-dried for, After with methylene chloride-methanol as eluant, cross silicagel column isolated compound 4.
4), 2g compound 4 is joined in Boron tribromide, under the conditions of-78 DEG C, first react 1h, be then reacted at 0 DEG C Room temperature, react 16h, rotation Boron tribromide is evaporated off, after with methylene chloride-methanol be 40-20:1 be eluant, cross silicagel column separate Obtain compound 5.
5), by 2g compound 5 and 1.9g compound 6(m=1) join in DMF (DMF), add subsequently Enter 4.1g Anhydrous potassium carbonate, under conditions of temperature is 60 DEG C react 6h, after question response terminates, be spin-dried for DMF, after use dichloromethane Thick product is obtained by extraction with water, is eluant with methylene chloride-methanol, cross silicagel column isolated compound 7.
6), by 2g (3.26mmol) compound 7 and 1.07g(4.8mmol) 3-nitrophthalonitrile joins N, N-bis- In methylformamide (DMF), under conditions of 60 DEG C, react 8h, after question response terminates, be spin-dried for DMF, rear dichloromethane and water Thick product is obtained by extraction, is eluant with methylene chloride-methanol, cross silicagel column isolated compound 8a.1H NMR (DMSO- d6, 400MHz): δ 11.49 (s, 1 H, NH), 8.84 (s, 1 H, NCHN=), 8.40 (s, 1 H, ArH), 7.86 (s, 1 H, ArH), 7.77 (d, J = 8.0 Hz, 1 H, ArH), 7.61 (t, J = 7.6 Hz, 1 H, ArH), 7.48 (t, J = 8.0 Hz, 1 H, ArH), 7.40 (d, J = 8.0 Hz, 2 H, ArH), 7.25 (d, J = 7.6 Hz, 1 H, ArH), 7.23 (d, J = 7.6 Hz, 1 H, ArH), 4.38 (t, J = 4.4 Hz, 2 H, CH2), 4.27 (s, 1 H, CH), 4.21 (t, J = 4.8 Hz, 2 H, CH2), 3.82 (t, J = 4.8 Hz, 2 H, CH2), 3.77 (t, J = 4.4 Hz, 2 H, CH2), 3.34 (s, 3 H, CH3). HRMS (ESI): m/z calculated for C29H23N5O4 [M+H]+,506.1828;found, 506.1825.
7), in equipped with the 100ml two neck bottle of reflux condensate device and gas operated device, 0.30g compound 8a it is sequentially added into, 0.55g phthalonitrile and 15ml n-amyl alcohol, under nitrogen protection, be warming up to 100 DEG C, after question response thing dissolves, be subsequently added into The anhydrous Silicon chloride. of 0.43g, stirs to dissolving and adds the 1 of 0.5-1ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, Back flow reaction 6h, after reaction terminates, vacuum rotary steam removes n-amyl alcohol, with CH2Cl2And CH3The volume ratio of OH is that the mixing of 30:1 is molten Liquid, as eluant, is crossed silicagel column, after rotated evaporation and concentration, is obtained described molecular targeted anticancer photosensitizer erlotinib-phthalein Cyanines conjugates.1H NMR (DMSO-d6, 400MHz): δ 11.28 (s, 1 H, NH), 9.24-9.22 (m, 3 H, Pc-Hα), 9.18-9.15 (m, 2 H, Pc-Hα), 9.05 (d, J = 7.0 Hz, 1 H, Pc-Hα), 8.79 (s, 1 H, NCHN=), 8.69 (d, J = 7.0 Hz, 1 H, Pc-Hα), 8.40 (s, 1 H, ArH), 8.19-8.08 (m, 6 H, Pc-Hβ), 7.92 (t, J = 7.5 Hz, 1 H, Pc-Hβ), 7.86 (s, 1 H, ArH), 7.82 (d, J = 8.0 Hz, 1 H, ArH), 7.53 (d, J = 7.5 Hz, 1 H, Pc-Hβ), 7.51 (t, J = 8.0 Hz, 1 H, ArH), 7.47 (d, J = 8.0 Hz, 2 H, ArH), 4.44 (t, J = 4.4 Hz, 2 H, CH2), 4.31 (s, 1 H, CH), 4.25 (t, J = 4.8 Hz, 2 H, CH2), 3.88 (t, J = 4.8 Hz, 2 H, CH2), 3.83 (t, J = 4.4 Hz, 2 H, CH2), 3.17 (s, 3 H, CH3). HRMS (ESI): m/z calculated for C53H35N11O4Cl2Si [M+H]+,988.2099;found,988.2065.
Application example 1(M=Zn, m=3, R=-CH3O, α, β position are monosubstituted)
The in vitro light power active anticancer of (8a) and (8b) two kinds of phthalocyanine Zn complexes has been carried out desk study, for from now on Certain reference value can be provided in body (mice) experiment and clinical practice, there is more important meaning.Main research Including phthalocyanine as the cytotoxicity of photosensitizer.The cytotoxicity experiment of photosensitizer generally includes phototoxicity and dark toxicity test two Part, uses mtt assay (tetrazolium reducing process) to measure.MTT(3-(4,5-dimethylthiazole-2)-2,5-diphenyl four nitrogen Azoles bromide) Cleaning Principle is that the succinate dehydrogenase in living cells mitochondrion can make exogenous MTT be reduced to water-fast indigo plant Purple crystal first a ceremonial jade-ladle, used in libation (Formazan) is also deposited in cell, and there is no succinate dehydrogenase in dead cell, thus without generation First a ceremonial jade-ladle, used in libation.Use DMSO(dimethyl sulfoxide) dissolve the first a ceremonial jade-ladle, used in libation that living cells produces, at 570nm wavelength, measure it by microplate reader and absorb Value, can reflect living cells quantity indirectly.In the range of certain cell number, 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, passes on 0.25% trypsinization, (little containing 10% by RPMI 1640 culture medium Ox blood serum) prepare 2 × 104Cells/ml cell suspension, by every hole 180 μ l(containing about 4000 tumor cells) it is inoculated in 96 hole trainings Support in plate, put 37 DEG C, 5% CO2In incubator, cultivation is adherent overnight, adherent rear dosing；Experiment sets blank group (blank Refer to matched group in addition to being not added with phthalocyanine, other conditions are consistent with given the test agent group.), (solvent control refers to right solvent control group Being not added with cell according to 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% Oleum Ricini) storing solution, all through organic membrane filter (0.22 m) after all drug solution preparing, during use, phthalocyanine dilute with water is different dense Degree, in final concentration, the content of DMSO is 1%.Every concentration sets 6 parallel holes, and every hole adds the medicine of 20 l variable concentrations and is placed on Hatch in incubator.Light poison is tested: after 24 hours, removes the culture medium containing medicinal liquid, changes 100 l fresh cultures, then use Cell is irradiated by laser instrument, 670nm wavelength laser, and irradiation energy density is 1.5J/cm2 .Illumination is complete, by 96 orifice plates It is refitted in 37 DEG C, 5% CO2Incubator in, continue cultivate.Dark poison experiment is then directly placed into cultivation after having changed fresh culture Continuing in case to cultivate, illumination is avoided in operating process as far as possible, after 24h, and PBS solution (4mg/ml) the 10 μ l of every hole addition MTT, 37 DEG C Hatching 4 hours, careful supernatant discarded after 4 hours, every hole adds 200 μ l DMSO and dissolves first a ceremonial jade-ladle, used in libation granule, and slight concussion makes first a ceremonial jade-ladle, used in libation complete After CL, measure OD value under 570nm wavelength by microplate reader.
We use mtt assay to determine two kinds of phthalocyanines killing curve to HepG2 human hepatoma cell.In illumination and unglazed Killing curve to HepG2 cell under the conditions of according to.Illumination wavelength is 670 nm, and light energy density is 1.5 J cm-2.Data Obtained by three independent parallel laboratory tests, process in Mean ± SEM mode.Two kinds of phthalocyanines are understood unglazed according to bar by experimental data Under part, cell is not had any lethal effect, and they kill the IC of HepG2 cell under certain illumination condition50Value (half Suppression ratio) it is respectively 0.030 μM, 0.050 μM.And have only to 0.5 phthalocyanine of μ μM and the most almost can kill whole cancerous cell, Therefore they all show the highest light power active anticancer.Extremely low dark toxicity and higher phototoxicity explanation both phthaleins Cyanines have all reached the requirement of preferable photosensitizer, are expected to exploitation for efficient photosensitive drug.
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent with Modify, all should belong to the covering scope of the present invention.

Claims (2)

1. a molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate, it is characterised in that: its chemical structural formula is as follows:
(1)
(2)；
Wherein M=Zn, m=0-8, R=-H ,-CH3O、-OH、-CH2OCH2CH2OCH3。
2. a molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate as claimed in claim 1 is preparing light power Application in treatment photosensitizer drug.
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