CN104231047B - The paclitaxel derivatives and its preparation and use of water-soluble targeted activation - Google Patents
The paclitaxel derivatives and its preparation and use of water-soluble targeted activation Download PDFInfo
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Abstract
Paclitaxel derivatives the invention discloses water-soluble targeted activation and its production and use, the paclitaxel derivatives such as following structural：Wherein,It is taxol.R1It is Ala, Thr, Val or Ile；R2It is Ala, Thr, Val or Asn；N=1~150.The paclitaxel derivatives of the water-soluble targeted activation that the present invention is provided are compared with taxol, it is changed into the antineoplastic target medicine of water-soluble, characteristic with special activation characteristic and Immune enhancement, drug effect to suppressing growth and metastasis of tumours improves a lot, and toxicity is substantially reduced, with preferable potential applicability in clinical practice.
Description
Technical field
The present invention relates to medicine, and in particular to a kind of antineoplastic, more particularly to a kind of purple of water-soluble targeted activation
China fir 01 derivatives and preparation method thereof and preparing the purposes of antineoplastic.
Background technology
Taxol is a kind of now widely used effective antitumour medicine, is mainly used in various entity tumors such as ovary
The treatment of cancer and breast cancer, also has certain curative effect to lung cancer, colorectal cancer, melanoma, incidence cancer, lymthoma, brain tumor.So
And, because such medicine has serious toxic and side effect and sensitivity response, for example：Taxol has bone marrow toxicity, causes neutrality
Granulocyte is reduced, and with neurotoxicity and Cardiovascular Toxicity, and can trigger allergic reaction, to be overflowed and can cause local outside blood vessel
Inflammation, alopecia is weak and bring hepatotoxicity etc..So, clinically using when must limit its dosage.Accordingly, it would be desirable to
There is provided one kind can reduce taxol toxicity, and improve the taxol of medicine dosage and the targeting activation with height drug effect
Used as antineoplastic, this is problem demanding prompt solution to medicine.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned weak point, and research and design goes out water-soluble targeted activation
Taxol, while have the taxol drug of hypotoxicity, high-drug-effect, its compound appropriate because taxol is combined and subtract
Weak toxicity, simultaneously because compound is activated in tumor locus aggregation and selectivity and discharges taxol.
In order to achieve the above object, the invention provides a kind of paclitaxel derivatives of water-soluble targeted activation, the chemical combination
The structural formula of thing is：
In the compound,It is taxol.In the compound, R1
Selected from Ala (alanine), any one amino acid in Thr (threonine), Val (valine) or Ile (isoleucine)；R2Choosing
Any one amino acid from Ala (alanine), Thr (threonine), Val (valine) or Asn (asparagine)；N is selected
Arbitrary integer from 1~150.
The paclitaxel derivatives of water solubility targeted activation of the invention, wherein n=1, R1It is Ala, R2During for Ala, described purple
China fir 01 derivatives are compound S1, are represented with following structural:
The paclitaxel derivatives of water solubility targeted activation of the invention, wherein n=5, R1It is Ala, R2During for Ala, described purple
China fir 01 derivatives are compound S2, are represented with following structural:
The paclitaxel derivatives of water-soluble targeted activation of the present invention, wherein n=11, R1It is Ala, R2During for Ala,
Described paclitaxel derivatives are compound S3, are represented with following structural:
The paclitaxel derivatives of water-soluble targeted activation of the present invention, wherein n=150, R1It is Ala, R2During for Ala,
Described paclitaxel derivatives are compound S4, are represented with following structural：
The paclitaxel derivatives of water solubility targeted activation of the invention, wherein, described paclitaxel derivatives include the present invention
The compound S10-S24 of offer is obtained for embodiment 10-24, and its n is 5, R1And R2Structure is respectively following compounds：
| Numbering | ||
| S10 | Alanine | Threonine |
| S11 | Alanine | Valine |
| S12 | Alanine | Asparagine |
| S13 | Threonine | Alanine |
| S14 | Threonine | Threonine |
| S15 | Threonine | Valine |
| S16 | Threonine | Asparagine |
| S17 | Valine | Alanine |
| S18 | Valine | Threonine |
| S19 | Valine | Valine |
| S20 | Valine | Asparagine |
| S21 | Isoleucine | Alanine |
| S22 | Isoleucine | Threonine |
| S22 | Isoleucine | Valine |
| S24 | Isoleucine | Asparagine |
The paclitaxel derivatives of the water-soluble targeted activation that the present invention is provided, by combining institute on taxol compound
Amino acid side chain is stated, so as to reduce toxicity, simultaneously because the derivative can discharge Japanese yew in tumor locus aggregation and activation
Alcohol, reaches the effect for the treatment of tumour, can be made more low toxicity and effective antitumour medicine.The present invention provide water-soluble target to
The paclitaxel derivatives of activation are the innovations of the present inventor, first public to deliver.
It is a further object of the present invention to provide the preparation method of the paclitaxel derivatives of the water-soluble targeted activation.
Paclitaxel derivatives it is yet another object of the invention to provide the water-soluble targeted activation are used to prepare anti-swelling
The purposes of tumor medicine, described purposes is for preparing anti-bladder cancer, the cancer of the brain, breast/breast cancer, cervical carcinoma, colon/rectum
Cancer, the cancer of the esophagus, kidney, liver cancer, lung cancer, nasopharyngeal carcinoma, cancer of pancreas, prostate cancer, cutaneum carcinoma, stomach cancer, the cancer of the uterus, oophoroma, testis
The purposes of ball cancer or leukemia medicine.
The paclitaxel derivatives of the water-soluble targeted activation that the present invention is provided, experimental design thinking is from by substantial amounts of
Compound experiment design prepares the complex compound of the mode of different connections, then by connecting complex compound to taxol
2 or 7 (on the OH of complex compound is connected in taxane molecule formula respectively the 7th or the 2nd), then by swollen
The size of activation efficiency carries out taxol efficiency screening, and screening gained compound successively in the presence of tumor tissue or Aspartase
In R1, R2, and n when taking different value to the inhibitory action of tumour, finally give toxicity reduction, release efficiency water-soluble target high
To the paclitaxel derivatives of activation.The structure of the paclitaxel derivatives of wherein water-soluble targeted activation synthesizes and reports first for us
Road.Targeting, activation, stabilization, toxicity of the structure of the compound different piece to the paclitaxel derivatives of water-soluble targeted activation
Had an immense impact on the function such as drug effect.The paclitaxel derivatives of water-soluble targeted activation can be connected chemically envelope by complicated
The toxicity of taxol is closed, and can be by asparagus fern ammonia in making its tumour cell or TAM in tumor tissues
Sour enzyme is effectively activated, and so as to be targeted to release toxicity, reaches the effect for the treatment of tumour.Obtain tumor-targeting, close toxicity and
Efficient activation is related to the structure-activity relationship of whole compound entirety.By R1, R2, and n screening study find R1,
R2, and the selection of n also has certain structure-activity relationship, but from experiment it can be seen that when the preferred spans of n are 1~150
The therapeutic effect of acquisition is almost identical.The taxol of tumor microenvironment targeted activation can effectively reduce the toxicity of taxol, but
The effect for the treatment of tumour is increased, strong structure-activity relationship is formd.
The present invention be found by experiment that (1) water solubility targeted activation taxol tumor locus have aggregation, be detained and
Activation effect, the characteristic with target tumor microenvironment.(2) taxol of water-soluble targeted activation can be special by tumor tissues
Property activation or fracture, generate taxol.(3) in vitro in internal metabolism the taxol of water-soluble targeted activation in blood
In do not activate, the characteristic with long-term blood stability and normal tissue organ low toxicity.(4) water-soluble targeted activation
The toxicity of taxol is substantially reduced compared to taxol.(5) link position of the both sides group of compound small peptide, and taxol with
Medicine activation release, and medicine dissolubility, stability and validity are all closely related.If medicine cannot be activated, medicine
Thing is a medicine for no cytotoxicity, will not have curative effect.(6) taxol of water-soluble targeted activation can swell various
Knurl is activated, and adds deliquescent change, can directly change the situation of taxol tumour indication limitation, is developed into broad spectrum activity
Antineoplastic, the length of the taxol of (7) water solubility targeted activation also has different influences, the i.e. medicine of n different lengths
Activation to overall medicine has an impact, and as n values increase, Activation Activity is slightly decreased, and the drug quality that equimolar is measured
Number increase, but because the increase of n values also can change drug metabolism, therefore overall drug effect is not reduced, this is also the present invention
The reason for protection domain is selected from 1~150 by n.(8) substantial amounts of protease hydrolytic enzyme is generally secreted during Nasopharyngeal neoplasms to degrade
Cytoplasm, so the targeted drug of protease hydrolytic enzyme activition has special curative effect to metastases treatment.
TAM (M2 types) is different from monocyte and inflammatory type macrophage (M1 types), and confirmation flag is just
It is the expression of Aspartase.The cytokine induction monocyte transformation of tumors secrete is TAM, tumour
Associated macrophages can stimulate the strong immunosupress of generation and directly help tumor cell invasion and transfer.It is of the invention to grind
Studying carefully middle discovery tumor microenvironment release property taxol has killing TAM, immunosuppressant in decrease microenvironment
Cell factor and promote through toxicity cd8 cell immunological enhancement.Wherein more importantly tumor microenvironment release property taxol
Only in tumor by local activation, overall immune system can be damaged different from classic chemotherapy medicine, tumour micro-loop in experiment of the invention
Border release property taxol and PD-1 suppress antibody has strong synergistic therapeutic action, can solve the problem that immunization therapy is difficult and chemotherapeutic
The drawbacks of thing is used in combination.
Application of the paclitaxel derivatives of water-soluble targeted activation of the present invention in antineoplastic is prepared, the medicine
Thing is the pharmaceutical composition being made up of with pharmaceutic adjuvant the paclitaxel derivatives of water-soluble targeted activation.
The taxol that the present invention demonstrates water-soluble targeted activation of the invention by campaign has antineoplastic target
Property.Special Activation Activity and the characteristic of Immune enhancement, relative to taxol, the drug effect for suppressing growth and metastasis of tumours has very
Big raising, and the toxicity of medicine substantially reduces, with extraordinary application prospect.So far, not yet there are patent and document
Report, therefore, it is used to treat human tumor the invention provides a kind of taxol drug of novel water-soluble targeted activation
Effective ways, with extraordinary application prospect, there is larger social benefit.
Specific embodiment
Technical scheme is described further with reference to embodiment.
Embodiment 1：The synthesis of the taxol of water-soluble targeted activation
1) synthesis of two (2- methoxy ethoxies acetyl group) -1B ethyl esters (I)
2- (2- methoxy ethoxies) acetic acid (161mg, 1.2mmol) is dissolved in DMF (10mL),
After ice bath cooling, stirring is lower to add 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (462mg,
1.2mmol), N, N- diisopropyl ethyl amine (313mg, 2.4mmol) and 1B ethyl ester dihydrochloride (100mg,
0.4mmol), finish, be stirred overnight at room temperature, remove solvent under reduced pressure, the inverted post for preparing of crude product purifies to obtain I (128mg, yield：
77.8%).
2) synthesis of two (2- methoxy ethoxies acetyl group) -1Bs (II)
Two (2- methoxy ethoxies acetyl group) -1Bs (122mg, 0.3mmol) are dissolved in tetrahydrofuran (15mL)
In, lithium hydroxide (39mg, 0.9mmol) aqueous solution (5mL) is added dropwise at being cooled to 0 DEG C, reaction 2 hours is stirred at room temperature.Ice bath is cold
But pH is adjusted to 2 with concentrated hydrochloric acid under, is freezed after tetrahydrofuran is evaporated off, obtain crude product II (112mg, yield：99%) it is, not purified direct
For next step.
3) two (2- methoxy ethoxies acetyl group)-L-Lys-L-Ala-L-Ala-L-Asn (Trt)-to aminobenzyl alcohol
(III) synthesis
Two (2- methoxy ethoxies acetyl group) -1Bs (112mg, 0.3mmol) are dissolved in N, N- dimethyl formyls
Be added dropwise in amine (10mL), at being cooled to 0 DEG C 3- (diethoxy neighbour acyloxy) -1,2,3- phentriazine -4- ketone (109mg,
0.36mmol), L-Ala-L-Ala-L-Asn (Trt)-to aminobenzyl alcohol (188mg, 0.3mmol) and N, N- diisopropyl ethyl
Amine (117mg, 0.9mmol), finishes, and is stirred overnight at room temperature.Remove solvent under reduced pressure, the inverted post for preparing of crude product purifies to obtain III
(159mg, yield：54.0%).
4) two (2- methoxy ethoxies acetyl group)-L-Lys-L-Ala-L-Ala-L-Asn (Trt)-PAB pair
The synthesis of nitrophenyl carbonate (VI)
Two (2- methoxy ethoxies acetyl group)-L-Lys-L-Ala-L-Ala-L-Asn (Trt)-right are added in there-necked flask
Aminobenzyl alcohol (167mg, 0.17mmol) is dissolved in tetrahydrofuran (10mL), and p-nitrophenyl chloroformate ester is added dropwise at being cooled to 0 DEG C
(73mg, 0.36mmol) and pyridine (39mg, 0.50mmol).It is stirred overnight at room temperature, removes solvent, the inverted system of crude product under reduced pressure
Standby post purifies to obtain VI (153mg, yield：78.5%).
5) two (2- methoxy ethoxies acetyl group)-L-Lys-L-Ala-L-Ala-L-Asn- PAB p-nitrophenyls
The synthesis of base carbonic ester (V)
By two (2- methoxy ethoxies acetyl group)-L-Lys-L-Ala-L-Ala-L-Asn (Trt)-PAB pair
Nitrophenyl carbonate (VI) (100mg, 0.087mmol) is dissolved in trifluoroacetic acid (1mL), is instilled two and is dripped, and oil pump is used immediately
Drain, obtain crude product V (80mg), it is not purified to be directly used in next step.
6) conjunction of two (2- methoxy ethoxies acetyl group)-L-Ala-L-Ala-L-Asn- PABs taxol (S1)
Into
By two (2- methoxy ethoxies acetyl group)-L-Lys-L-Ala-L-Ala-L-Asn- PAB p-nitrophenyls
Base carbonic ester (80mg, 0.088mmol) and taxol (76mg, 0.089mmol) use dry DMF
(10mL) is dissolved, and DMAP (22mg, 0.18mmol) is added at being cooled to 0 DEG C, is stirred overnight at room temperature.Add taxol (38mg,
0.044mmol), continue to be stirred overnight.Reaction solution is poured into ethyl acetate, merges organic phase, washing, anhydrous sodium sulfate is done
Dry, rotary evaporation removes solvent, and the inverted post for preparing of crude product purifies to obtain target product S1 (25mg, yield：37.5%).LC-MS
Testing result is as follows:The corresponding mass-to-charge ratio of eluting peak is 1619.It is corresponding molecular weight to be obtained with Structure Calculation
7) synthesis of compound S2, S3, S4 differs only in step 7 with reference to the synthesis of S1) the alkoxy that uses of synthesis
The difference of the molecular weight of substituted acetic acid.Wherein, the synthesis of S2 is that, with 3,6,9,12,15,18- six oxa- nonadecanoic acids substitute 2- (2-
Methoxy ethoxy) acetic acid；The synthesis of S3 is with the dioxas 37 of 3,6,9,12,15,18,21,24,27,30,33,36- ten
Acid substitutes 2- (2- methoxy ethoxies) acetic acid；The synthesis of S4 is to substitute 2- (2- methoxy ethoxies) second with many oxa fatty acids
Acid；The corresponding mass-to-charge ratio of mass spectrum (MS) testing result S2, S3 is respectively 1619,1972,2500 and obtains molecular weight with Structure Calculation
1619.71,1972.13 it is corresponding with 2500.77.Substance assistant laser desorpted ionized/flight time mass spectrum (MALDI-TOF-
MS) detection S4 molecular weight is about 14739, and it is corresponding to obtain molecular weight 14739.59 with Structure Calculation.
8)
| Numbering | n | Proterties | Mass Spectrometer Method | Fluorescence | Yield (milligram) | Yield |
| S1 | 1 | White powder | 1619 | Nothing | 25 | 37.5% |
| S2 | 5 | White powder | 1972 | Nothing | 245 | 43.3% |
| S3 | 11 | White powder | 2500 | Nothing | 456 | 66.4% |
| S4 | 150 | White powder | 14739 | Nothing | 645 | 34.6% |
9) synthetic method of embodiment 10~24 is close with embodiment S2, and raw material is different when simply amino acid is connected, such as following table
It is shown.By corresponding R1Amino acid and R2Amino acid is dissolved in N,N-dimethylformamide, be separately added into condensing agent (such as 1- ethyls-
(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate) reaction, in 0 DEG C of -25 DEG C of reaction 0.5-2h, add aspartoyl
Amine；, in 0 DEG C of -25 DEG C of reaction 2-24h.Reaction solution uses purification process after, obtains 3 peptides, by tripeptides by the method in embodiment 1
It is that synthetic mesophase replaces preparation S10-S24 compounds to substitute Ala-Ala-Asn.Mass spectrum (MS) testing result confirms S10-S24 chemical combination
Successively such as following table, the molecular weight predicted with Structure Calculation is consistent thing molecular weight.
(n=5)
The property of the paclitaxel derivatives of water-soluble targeted activation and control compound obtained in the embodiment of the present invention of embodiment 2
Can compare
(1) sample treatment
The paclitaxel derivatives of water-soluble targeted activation obtained in the embodiment of the present invention, compound S1, S2, S3 and S4 are (real
A 10-11 is applied to be obtained) and above-mentioned preparation control compound C1, C2, C3, C4, C5, C6. by freeze-drying (- 70 DEG C),
Desinfection chamber is dispensed.Before zoopery, S1, S2, S3 and S4 can be redissolved in desinfection chamber by following two solvent scheme:It is molten
Agent 1 (water for injection) or solvent 2 (45% alcohol, 55% water for injection).S1, S2, S3 and S4 can in solvent 1 and solvent 2
It is completely dissolved, redissolves concentration and be diluted to required concentration up to 10 mg/mls, then with water for injection, and control compounds (C1,
C2, C3, C4, C5, C6) it is unsatisfactory for the formulation requirements of medicine, such as table 1 below.
Table 1：Screening drug solubility experiment:The missing of approximate heterogeneity or taxol 7 or 2 in control compound
Connect and group (the 7th or the 2nd in Docetaxel molecular formula, is connected to respectively on pharmaceutical preparation dissolubility influence
OH on) on pharmaceutical preparation dissolubility influence.Small peptide ammino acid in AAN, AANL, AANK difference representation compound in following table
Connection, A：Ala、N：Asn、L：Leu、K：Lys.
Such as table 1 below.Taxol is water insoluble, and improved taxol dissolution characteristics occur great variety, molten in water
Xie Du increases, and the change of dissolution characteristics has tremendous influence to the formulation protocol of medicine.With traditional water insoluble taxol medicine
Thing is compared, and S1, S2, S3 and S4 can produce the pharmaceutical preparation of solubility, and S2 can be directly water-soluble, can improve injection dosage and treatment
Effect, avoids taxol such as from using anaphylaxis auxiliary material castor oil, is that medicine can develop the huge advance for using, and indicates water-soluble target
Taxol to activation has extraordinary novelty and application prospect.
Table 1：Screening drug solubility experiment：The missing of approximate heterogeneity or taxol 7 or 2 in control compound
Connection influences on pharmaceutical preparation dissolubility.
| Compound | Solvent 1 | Solvent 2 |
| C1:AAN- group 2- taxols (2 connections) | It is insoluble | It is insoluble |
| C2:Group 1-AAN- taxols (2 connections) | It is insoluble | It is insoluble |
| C3:AAN- taxols (2 connections) | It is insoluble | It is insoluble |
| C4:Group 1-AAN- group 2- taxols (7 connections) | It is insoluble | It is insoluble |
| C5:Group 1-AANL- group 2- taxols (2 connections) | It is insoluble | It is insoluble |
| C6:Group 1-AANK- group 2- taxols (2 connections) | It is insoluble | It is insoluble |
| S1 | It is insoluble | Dissolving |
| S2 | Dissolving | Dissolving |
| S3 | Dissolving | Dissolving |
| S4 | Dissolving | Dissolving |
Group 1:
Group 2:
The result of table 1 illustrates that paclitaxel derivatives solubility property of the invention occurs great variety, at solvent 1 (water for injection)
Or the dissolubility in solvent 2 (45% alcohol, 55% water for injection) increases, the change of dissolution characteristics has huge to the preparation of medicine
Influence.And the insoluble formulation requirements that can not meet medicine of control compounds (C1, C2, C3, C4, C5, C6).Therefore with it is insoluble
Compared in the taxol drug of water, S1, S2, S3 and S4 can prepare the pharmaceutical preparation of solubility, can improve injection dosage and curative effect,
Existing taxol drug is avoided to use the defect of anaphylaxis auxiliary material castor oil etc., with extraordinary novelty and application prospect.
The method and content range of embodiment 3 S1, S2, S3 and S4 (embodiment 10-11 is obtained) assay.
S1, S2, S3 and S4 using analytic type HPLC (Agilent 1220 (Agilent 1220series), 5 μm of C8 posts,
4.6mm ID x250mm, mobile phase is 0~95% acetonitrile (ACN) purity in 95%-99%).
Activation efficiency experiment of the tumor tissues of embodiment 4 to the paclitaxel derivatives of water solubility targeted activation of the invention
S1, S2, S3 and S4 sample compound (embodiment 10-11 be obtained), using solvent 1 (50% water for injection, 45%~
49% alcohol, 1%~5% Tween 80) unified dissolving, and dilute with water 10 is again to 1 mg/ml.In experiment of the invention,
The sample compound of 1 mg/ml, tumour are added in the tumor tissues homogenate (pH6.0) of 100 micrograms acidifying at a temperature of 37 degree
Enzyme in tissue homogenate can result in release taxol, the reduction of detection compound and the increase of taxol are capable of by HPLC and
Comparison of tumor tissue finds that compound S1 of the invention, S2, S3, S4 are connected to screening to the activation efficiency of medicine by screening
Compound in have highest activation efficiency.
Table 2：The compound of the S1 in different tumor tissues homogenates, S2, S3, S4 activates ratio (%),
| Produce blastomogenic cell | S1, | S2 | S3 | S4 | |
| Human fibrosarcoma | HT-1080 | 77.7 | 78.4 | 70.3 | 77.2 |
| Human breast carcinoma | MDA-MB435 | 95.6 | 94.4 | 93.4 | 97.8 |
| HOC | SK-OV-3 | 91.4 | 88.6 | 82.8 | 66.4 |
| Human colon carcinoma | HT-29 | 82.4 | 92.9 | 94.6 | 93.6 |
| People's chronic leukemia | K562 | 67.7 | 76.3 | 73.2 | 77.2 |
| Human pancreas cancer | Panc-1 | 97.8 | 93.8 | 94.5 | 96.1 |
| Non-small cell lung carcinoma | A549 | 89.5 | 92.4 | 84.4 | 86.2 |
| Human prostata cancer | PC-3 | 100.3 | 101.4 | 99.3 | 96.5 |
| Human liver cancer | Hep G2 | 98.3 | 87.6 | 86.5 | 77.0 |
| People's kidney | OS-RC-2 | 89.2 | 94.5 | 89.4 | 93.5 |
| Human heart | Nothing | Nothing | Nothing | Nothing |
Table 3：Influence of the missing of approximate heterogeneity to activation medicine in screening control compounds.S1, S2, S3 and S4
Sample compound (embodiment 10-11 is obtained), using solvent 1, (1%~8% tells for 50% water for injection, 42%~49% alcohol
Temperature 80) unified dissolving, and dilute with water 10 is again to 1 mg/ml.In experiment of the invention, 100 micrograms at a temperature of 37 degree
The sample compound of 1 mg/ml, tumour are added in human breast carcinoma (MDA-MB435) tumor tissues homogenate (pH6.0) of acidifying
Enzyme in tissue homogenate can result in release taxol, the reduction of detection compound and the increase of taxol are capable of by HPLC and
Activation efficiency of the comparison of tumor tissue to medicine.
| Compound | Activation efficiency (%) |
| C1:AAN- group 2- taxols (2 connections) | 64.4 |
| C2:Group 1-AAN- taxols (2 connections) | 51.9 |
| C3:AAN- taxols (2 connections) | 32.7 |
| C4:Group 1-AAN- group 2- taxols (7 connections) | 11.6 |
| C5:Group 1-AANL- group 2- taxols (2 connections) | 54.7.4 |
| C6:Group 1-AANK- group 2- taxols (2 connections) | 43.3 |
| S1:Group 1-AANL- group 2- taxols (2 connections) | 95.1 |
| S2 | 96.3 |
| S3 | 94.5 |
| S4 | 84.3 |
The above results explanation：The not isoplastic connection of paclitaxel derivatives of water solubility targeted activation of the invention and taxol
There is different influences in tumor tissues activation to medicine.Mutual structure-activity relationship between taxol and the compound group being connected
Determine the targeting in tissue site and activation effect.S1, S2, S3, S4 in different tumor types (10 kinds different tumour) swash
Work illustrates the broad spectrum activity (table 2) of drug activation.The specific compound for being produced in comparative compound screening process simultaneously, analysis exists
Activation efficiency in same human breast carcinoma MDA-MB435 tumor tissues, experiment proves S1, each group choosing of S2, S3, S4 compound
It is relative activation collocation in hgher efficiency (table 3) to select
The paclitaxel derivatives of the water-soluble targeted activation that the present invention is provided, experimental design thinking is from by substantial amounts of
Compound experiment design prepares the complex compound of the mode of different connections, then by connecting complex compound to taxol
2 or 7 (on the OH of complex compound is connected in taxane molecule formula respectively the 7th or the 2nd), then by swollen
The size of tumor tissue activation efficiency is screened, and successively screening gained compound in R1, R2, and n when taking different value to swollen
The inhibitory action of knurl.The activation site of tumor tissue specificity is the junction between AAN and group 2, after activation fracture, group
2 from release, and can further discharge taxol.Because the activity center of Aspartase is located at the bottom of ball vesicular invaginations
Portion, cleavage site needs access to activity center, and at this moment whether complex compound has space bit resistive to cleavage site to weigh very much
Will.
By the result of screening experiment, the present invention speculates the connection of group 2, it is possible to prevente effectively from being directly connected to taxol band
The steric hindrance come, without the close of influence Aspartase.And the structure-activity relationship of group 1 can increase the pole of cleavage site
Property, more water miscible protease is easier access to restriction enzyme site, and increase cutting efficiency.Taxol the 2nd is connected to also to show
So reduce steric hindrance and exposed more overall hydrophilic polar group of the taxol to protease, increase cutting efficiency and
It is water-soluble.And reduce activation efficiency if one polar form K of many additions and a polar form L amino acid respectively.
The paclitaxel derivatives by reagent intravenous administration maximum tolerated dose of the present invention water solubility targeted activation of embodiment 5
(MTD) measure.
Test objective：Tested by determining mouse vein medication MTD, understand the acute poison of paclitaxel derivatives of the present invention
Property.
Trial drug：S1, S2, S3 and S4 parenteral solution (S1, S2, S3 and S4 sample compound (embodiment 10-11 is obtained),
Dissolved using the solvent 1 (50% water for injection, 42%~49% alcohol, 1%~8% Tween 80) of solvent 1 is unified, given birth to during experiment
Reason salt solution is diluted to corresponding dosage.
Animal：One-level bar match (BALB/C) mouse (being purchased from Shanghai Slac Experimental Animal Co., Ltd.), body weight
19-21g, is all female.
Method and result：Tested BALB/C mice 36, body weight 19-21g is all female, and 7 groups are randomly divided into by body weight,
Every group 6.As shown in table 1, by 0mg/kg, 25mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 960mg/kg,
Disposable vein injects S1, S2, S3, S4 respectively.And carry out physiological saline group, taxol group parenteral solution (commercially available, Beijing Yue Kang)
Check experiment, each mouse administered volume 0.2ml.Continuous Observation 17 days, daily observation animal whether occur piloerection establish, grain
Disorderly tarnish, lethargic sleep, hunch, radical response etc., records body weight and death condition.Carried out entirely in the 3rd, 5,14 days blood-sample withdrawals
Blood count, animal was dissected at the 14th day and takes heart, liver, kidney, lung, spleen, pancreas HE dyeing observations.
Table 4：Test mice receives the S1 of various dose, S2 and S3 parenteral solutions and physiological saline, paclitaxel injection respectively
Mortality results control
Result and discussion：Present invention injection S1, the mouse group of S2, S3 and S4 solution, in 90mg/kg dosage, animal does not have
Occur that piloerection is established, tousle tarnish, lethargic sleep, hunch, radical response and death condition, S1 as shown in table 4 and S2 are molten
The MTD values (maximum tolerated dose) of liquid liquid are 90mg/kg, and much larger than the MTD value 6mg/kg of taxol, by reagent intravenous administration is most
Big tolerance dose is the important references index of drug toxicity, shows that the toxicity of the taxol of targeted activation release is more notable than taxol
Reduce.
The S1 of the present invention of embodiment 6, drug effect of S2, S3 and the S4 solution (with the sample of embodiment 5) in nude mice (nude mice)
Research
Test objective：By the oncotherapy model of mouse, S1, the antitumor drug effect of S2, S3 and S4 compound are understood.
Trial drug：S1, S2, S3 and S4 solution (with the sample of embodiment 5)；Paclitaxel injection (commercially available, ibid)
With normal saline dilution to respective concentration during experiment.
Control group is physiological saline
Method and result：
1. animal：Nude mice, 6-8 week old is all female.
2. tumor model is produced
1) human prostata cancer PC-3 cells (cell) are from American Type Culture collection warehousing (American type
Culture collection, ATCC) purchase, and the identification of cell is carried out according to the specification that ATCC is provided, cell is using containing
There is 10% hyclone Dulbecco (family name) to improve Iger (family name) culture medium (referred to as, DMEM nutrient solutions) at 37 DEG C, the two of 5%
Cultivated under the conditions of carbonoxide.Once, cell was used within 15 generations for passage in every 3 days.
2) tumour is produced, by 5x 106Panc-1 cell subcutaneous injections treat tumour to nude mice (nude mice) mouse back
It is long to be at least up to 100mm3It is grouped at random during left and right, starts treatment, starts the treatment same day for first day.
3) therapeutic process
According to S1, S2, S3 and S4 clinical application are injected using IV, and S1, S2, S3 and S4 use the metering less than 1/6MTD
24 mgs/kg of dosage, S1, S2, S3 and S4 treatment group uses 8 mgs/kg of dosage of metering of 1/3MTD, control group to use life
Reason salt solution, weekly administration, totally 4 weeks.
4) it is grouped as shown in table 5 below with outcome measurement
Table 5：S1, S2, S3 and S4 medicine, taxol and control group treat the effect of tumour to nude mice
5) result and discussion：As shown in table 5, compare with the taxol drug treatment group control group of equimolar concentration, in S1,
The tumor growth inhibitory effect of S2, S3 and S4 treatment group is greatly improved.
Embodiment 7:S1 of the present invention, drug efficacy study of S2, S3 and the S4 compound in D121 tumour immunity models
Test objective：Model is treated by D121 lung cancer tumors immune model, S1 is understood, S2, S3 and S4 compound it is anti-
Tumour drug effect.
Animal：C57 mouse, 6-8 week old is all female.
Trial drug：S1, S2, S3 and S4 solution (with the sample of embodiment 5)；Paclitaxel injection (commercially available, ibid)
With normal saline dilution to respective concentration during experiment.
Control group is physiological saline
Produce tumor model：
1) D121 lung cancer tumors are bought from American Type Culture Collection ATCC, and cell is used and contains 10% hyclone
DMEM nutrient solutions are cultivated at 37 DEG C under 5% carbon dioxide conditions.Once, cell was used within 15 generations for passage in every 3 days.
2) tumour immunity, mouse peritoneal injection 5x105(trained purchased from US mode by the D121 lung carcinoma cells of radiation death
Support thing preservation institute), inoculation 3 times, every minor tick 2 weeks.Oncocyte is injected after immune end, is then administered again, on every Mondays
Secondary administration, totally 4 weeks.Following table immune group is exactly immune with D121 lung carcinoma cells, and without the dead tumour cell immune group injection lifes of D121
Reason salt solution is control.
3) tumour is produced：After immunologic process terminates (after 4 weeks), by 106D121 lung cancer tumors cell skin bet living
Be mapped to the C57 mouse backs of tumour immunity, whne tumour it is long to 0.3~0.4cm or so when start treatment, recording gauge mouse tumor is big
Small (mm3), and calculate tumour inhibiting rate.
4) tumour CD8+T cells (t lymphocyte subset group) analysis.Tumor tissues by homogenate, in filtering to isolate tumour
Individual cells, are washed twice with buffer solution, and the antibody of LCA CD45-PE and CD8-FITC mark was in room temperature 1 hour
With reference to cell is washed twice with comprising 1% hyclone phosphate buffer PBS, then common with flow cytometry analysis leucocyte
The ratio of T lymphocyte antigens (CD8) positive cell in antigen (CD45) positive cell.
5) packet and outcome measurement
Table 6：The effect of S1, S2, S3 and S4 compound, paclitaxel treatment group and control group tumor suppression and immune activation
6) result and discussion：Compared with immunized controls group and other treatment control group, S1, S2, S3 and S4 compound exist
The therapeutic effect of C57 mouse is greatly improved, and S1 with PDL1- antibody there is the good rush that cooperates with to make through immune and synergistic therapeutic effect
With can be by improving the growth of immunosupress tumour.It is shown in Table 6.
The S1 of the present invention of embodiment 8, drug efficacy study of S2, S3 and the S4 medicine in the metastasis models of BALB/C mice
Test objective：Model is treated by the metastases of BALB/C mice, S1, the antineoplastic of S2 and S3 medicines is understood
Effect.
Trial drug：S1, S2, S3 and S4 solution (with the sample of embodiment 5)；Paclitaxel injection (commercially available, ibid)
With normal saline dilution to respective concentration during experiment.
Control group is physiological saline
1. animal：BALB/C mice, 6-8 week old is all female.
2. tumor model is produced
1) 4T1cells buys from ATCC, and carries out the identification of cell according to the specification that ATCC is provided, and cell is using containing
There are 10% hyclone DMEM nutrient solutions at 37 DEG C, cultivated under 5% carbon dioxide conditions.Once, cell is used for passage in every 3 days
Within 15 generations.
2), the generation of metastases, by 106T1 cells cell subcutaneous injections treat that tumour is long to BALB/C mice back
It is grouped at random during to 1.5cm or so, operation removal hypodermic tumour, and starts medication thing treatment, is put to death after being anaesthetized at the 27th day
Mouse, takes out whole lung, is put into dyeing in Bouin's solution (Bouin ' s solution), is counted under disecting microscope and is transferred to
The tumour quantity of lung.
3) therapeutic process：Injected using IV, S1, S2, S3 and S4 all using 1/6MTD metering, 12 mgs/kg of dosage,
Taxol drug treatment group uses 4 mgs/kg of dosage of metering of 1/6MTD, control group to use physiological saline, once every three days
Administration (amount /), totally 4 times.
4) it is grouped as shown in table 7 with outcome measurement
Table 6：The effect of S1, S2, S3 and S4 medicine, paclitaxel treatment group and control group for nude mouse tumor metastasis suppressor
4) it is grouped as shown in table 7 with outcome measurement
Table 7：The effect of S1, S2, S3 and S4 medicine, paclitaxel treatment group and control group for nude mouse tumor metastasis suppressor
| Group | Animal | Metastatic tumour quantity | Suppress the rate of transform |
| S1 groups | 10 | 3±4 | 97.95918 |
| S2 groups | 10 | 9±5 | 93.87755 |
| S3 groups | 10 | 16±9 | 89.11565 |
| S4 groups | 10 | 12±18 | 91.83673 |
| Paclitaxel treatment group | 10 | 137±32 | 6.802721 |
| Model control group | 10 | 147.0±46 | — |
5) result and discussion：As shown in table 7, compare with paclitaxel treatment group control group, in S1, S2, S3 and S4 group abdominal cavity
After administration, it is greatly improved in the metastases inhibition of BALB/C mice, illustrates that such medicine has good antitumor
Transfer drug effect.
Drug efficacy study of the embodiment 9S1 compounds in many tumor models
Test objective：By many tumor models of mouse, the broad spectrum activity of the antineoplastic of S1 is understood.
Medicine：S1 solution (with the sample of embodiment 5), with normal saline dilution to respective concentration during experiment.
Method and result：
1. animal：Nude mice, 6-8 week old is all female.
2. tumor model is produced
1) corresponding cell from American Type Culture collection warehousing (American type culture collection,
ATCC) buy, and the identification of cell is carried out according to the specification that ATCC is provided, cell is used and contains 10% hyclone Da Erbai
Gram (family name) improvement Iger (family name) culture medium (referred to as, DMEM nutrient solutions), at 37 DEG C, is cultivated under 5% carbon dioxide conditions.Every 3
Once, cell was used within 15 generations for its passage.
2) tumour is produced, by 5x106Correspondence cell subcutaneous injection treats that tumour is long to nude mice (nude mice) mouse back
At least up to 100mm3It is grouped at random during left and right, starts treatment, starts the treatment same day for first day.
3) therapeutic process
Injected using IV according to S1 solution, S uses the micro-/kilogram dosage control group use life that rubs of metering 17.6 of 1/6MTD
Reason salt solution, weekly administration, totally 3 weeks.
4) it is grouped as shown in table 2 below with outcome measurement
Table 9：Therapeutic effects of the S1 in many tumor models
5) result and discussion：As shown in table 9, S1 has good drug effect in kinds of tumors model, illustrates that medicine can be with
As an anti-tumor medicine for broad spectrum activity.
In other embodiments (embodiment 10~24, synthetic method is close with embodiment S1) of the invention, for difference
The activation characteristic of the taxol of the water-soluble targeted activation of amino acid structure, tumour inhibiting rate and suppress the rate of transform and surveyed respectively
Examination, method of testing and above-described embodiment 4,6,8 is identical, and test result is as shown in table 9：
Table 9：The activation characteristic of the taxol of the water-soluble targeted activation of embodiment 10~24, tumour inhibiting rate and suppress the rate of transform
As a result.
Result and discussion：As shown in table 9, the compound of embodiment 10~24 have certain Activation Activity and tumour growth and
Metastasis suppressor effect, illustrates that we screen individual process and have the practical significance of optimization activation and curative effect, by above-mentioned preferredization
The embodiment of compound, it should be appreciated that the description above is not considered as limitation of the present invention.In those skilled in the art
After having read the above, for R of the invention1And R2The amino acid substitution of position and change all will be apparent.
In some embodiments of the invention, the taxol compound of other water-soluble targeted activations has also been synthesized, its
In, the arbitrary integer in n=1-150, R1It is Ala, any one amino acid in Thr, Val or Ile；R2It is Ala, Thr, Val
Or any one amino acid in Asn；And done above-mentioned activation test (method is with embodiment 2), the effectiveness study to tumour
(method is with embodiment 6,7), transfer curative effect (method is with embodiment 8) and the experiment of many tumor efficiencies (method is with embodiment 9), and
Achieve the experimental result similar to S1-S4.The experiment proved that, in the range of n=1-300, as n increases, under tumour inhibiting rate is slight
Drop.As n values increase, Activation Activity is slightly decreased, and the drug quality number of equimolar metering increases, but because n values increase
It is big also to increase drug metabolism half-life period, therefore overall drug effect is to slightly decrease, and is selected from the range of 1~150 in n, equal energy
Reach the close technique effects of embodiment of the present invention S1-S4.
In sum, the present invention has synthesized the antineoplastic of the taxol of water-soluble targeted activation, and by toxicity and
The test of pesticide effectiveness proves that compound has lower toxicity than taxol, more preferable formulation method, while medicine, immunization therapy and
Directly treatment all drug effects are greatly improved, and are expanded and to the specific notable feature of metastases with treatment indication, are had
Good actual therapeutic application value.
Although present disclosure is discussed in detail by above preferred embodiment, but it should be appreciated that above-mentioned
Description is not considered as limitation of the present invention.After those skilled in the art have read the above, for of the invention
Various modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited to the appended claims.
Claims (7)
1. paclitaxel derivatives of water-soluble targeted activation, it is characterised in that the paclitaxel derivatives are compound S1, below
Following formula is represented:
2. paclitaxel derivatives of water-soluble targeted activation, it is characterised in that the paclitaxel derivatives are compound S2, below
Following formula is represented:
3. the paclitaxel derivatives of water solubility targeted activation as claimed in claim 1 or 2 are used to prepare the use of antineoplastic
On the way.
4. the paclitaxel derivatives of water-soluble targeted activation according to claim 3 are used to prepare the use of antineoplastic
On the way, it is characterised in that described purposes is for preparing anti-bladder cancer, the cancer of the brain, breast/breast cancer, cervical carcinoma, colon/rectum
Cancer, the cancer of the esophagus, kidney, liver cancer, lung cancer, nasopharyngeal carcinoma, cancer of pancreas, prostate cancer, cutaneum carcinoma, stomach cancer, the cancer of the uterus, oophoroma, testis
The purposes of ball cancer or leukemia medicine.
5. the paclitaxel derivatives of water-soluble targeted activation according to claim 4 are used to prepare the use of antineoplastic
On the way, it is characterised in that described purposes is the purposes for preparing the antineoplastic for aiding in using in radiation treatment.
6. the paclitaxel derivatives of water-soluble targeted activation according to claim 4 are used to prepare the use of antineoplastic
On the way, it is characterised in that described purposes is the purposes for preparing the synergistic treatment medicine in immunization therapy and immunization therapy.
7. the paclitaxel derivatives of water-soluble targeted activation are used to prepare antineoplastic according to any one of claim 3-6
The purposes of thing, it is characterised in that the medicine is to be made up of with pharmaceutic adjuvant the paclitaxel derivatives of water-soluble targeted activation
Pharmaceutical composition.
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| JP2017529129A JP6854759B2 (en) | 2014-08-22 | 2015-08-21 | Small molecule target conjugates specifically activated by the tumor microenvironment and their use |
| AU2015306574A AU2015306574B2 (en) | 2014-08-22 | 2015-08-21 | Specifically activated micromolecular target coupling body in tumor microenvironment and use thereof |
| CN201580044392.4A CN106715457B (en) | 2014-08-22 | 2015-08-21 | Small molecule targeting couplet specifically activated by tumor microenvironment and application thereof |
| CA2958495A CA2958495C (en) | 2014-08-22 | 2015-08-21 | Small molecule conjugates specifically activated in tumor microenvironment for targeting and use thereof |
| PCT/CN2015/087746 WO2016026458A1 (en) | 2014-08-22 | 2015-08-21 | Specifically activated micromolecular target coupling body in tumor microenvironment and use thereof |
| US15/505,861 US10682371B2 (en) | 2014-08-22 | 2015-08-21 | Small molecule conjugates specifically activated in tumor microenvironment for targeting and use thereof |
| EP15833275.9A EP3184540A4 (en) | 2014-08-22 | 2015-08-21 | Specifically activated micromolecular target coupling body in tumor microenvironment and use thereof |
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