CN109422799A - Docetaxel anti-liver cancer and anti-targeted prodrug and its pharmaceutical usage - Google Patents

Docetaxel anti-liver cancer and anti-targeted prodrug and its pharmaceutical usage Download PDF

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CN109422799A
CN109422799A CN201710725347.6A CN201710725347A CN109422799A CN 109422799 A CN109422799 A CN 109422799A CN 201710725347 A CN201710725347 A CN 201710725347A CN 109422799 A CN109422799 A CN 109422799A
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gly
gln
liver cancer
prodrug
pro
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CN109422799B (en
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孙逊
郝云鹏
司长梅
王明亮
孟志
彭鹏
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol

Abstract

The invention belongs to biomedicine fields, and in particular to a kind of novel including novel polyenoid taxane targeting anti-liver cancer and anti-prodrug and its pharmaceutical usage representated by general formula (1).The compound of the present invention is worth with pharmaceutical research, can be used as the anticancer prodrug for targeting matrix metalloproteinase MMP-2 or MMP-9.It can be used for treating the cancer of enzyme MMP-2 or MMP-9 specificity overexpression, specifically, the compound of the present invention can be used for treating at least one disease selected from the following: liver cancer, oophoroma, breast cancer, non-small cell lung cancer and colon cancer etc..In formula (1), R1For highly expressed matrix metalloproteinase MMP-2, MMP-9 specific recognition special in liver cancer tissue and the substrate polypeptide sequence of hydrolysis；R2For methyl, trifluoromethyl etc.；R3For hydrogen atom, fluorine atom etc..

Description

Docetaxel anti-liver cancer and anti-targeted prodrug and its pharmaceutical usage
Technical field
The invention belongs to biomedicine fields, and in particular to a kind of novel Docetaxel anti-liver cancer and anti-targeted prodrug and its medicine Purposes.
Background technique
According to data, for liver cancer as most commonly seen one of malignant tumour, the whole world is annual to generate increasing newly more than 700,000 Case and death.China is used as hepatopathy big country, and neopathy number of cases accounts for the 50.5% of global onset of liver cancer sum, death Number accounts for the 51.4% of global PLC mortality number, and is in rise year by year trend.According to liver tumour size and quantity, whether send out Judgment criteria, clinic mainly include for the therapeutic scheme of liver cancer whether raw extrahepatic metastases, liver function grade and vessel invasion etc. Operative treatment (hepatectomy, liver transplant, local ablation therapy etc., suitable for liver cancer initial stage patient), arteria hepatica chemotherapy ( Advanced liver cancer first choice therapeutic scheme) and targeting medicine Sorafenib treatment (mid and late liver cancer adjuvant drug).Due to the hair of liver cancer Disease is invisible, and the patient more than 80% can not carry out operative treatment, therefore the primary treatment scheme of most of liver cancer patient uses The interventional therapy and rope of chemotherapeutics (including 10-hydroxycamptothecine, 5 FU 5 fluorouracil, cis-platinum, adriamycin and methotrexate (MTX) etc.) The adjuvant treatment of La Feini targeting medicine.But the drug-metabolizing function caused by the missing of liver function declines, chemotherapeutics More serious toxic side effect, including cardiac toxic, Toxicity of Kidney, bone marrow suppression, serious gastrointestinal tract can be generated to liver cancer patient Reaction and disease in the urological system etc..And Sorafenib is as by the clinic of U.S. FDA, European Union EMEA and China SFDA approval listing One line medicines resistant to liver cancer, there is also certain clinical shortcomings, including serious gastrointestinal reaction, weakness of limbs and hand-foot syndrome Deng, and the expensive realistic economic problems that is also it and can not ignore.The liver cancer patient group growing in face of China, grinds Fixture has the new high-efficiency medicines resistant to liver cancer of China's independent intellectual property right that will face huge opportunities and challenges, and clinic is very The difficult point urgently solved.
As anti-tumor drug the most successful in mankind's modern medical service history, taxol and second generation taxanes kind anti-cancer drugs Object Docetaxel is widely used in the clinical treatment of the cancers such as oophoroma, breast cancer, non-small cell lung cancer, so far entirely Ball accumulated sales revenue has broken through 30,000,000,000 dollars.Although its clinical efficacy can not be substituted, there are still many very important to lack Point, such as metabolism unstability, poorly water-soluble, Yi Yinqi drug resistance and toxicity.In recent years, for taxanes drug Disadvantages mentioned above, scientists are dedicated to the methods of structure optimization or preparation transformation of a variety of strategies, anti-in taxanes of new generation A series of research achievement is achieved in the research and development of tumour medicine, comprising: (1) kappa he fill in (Cabazitaxel) be directed to Japanese yew The problem of alcohol drug resistance, carries out methylation structure optimization simultaneously in its C-7 hydroxyl and C-10 hydroxyls, in acquisition FDA in 2010 Listing approval；
(2) Oran rope (Orataxel) is optimized for the low disadvantage of paclitaxel oral bioavilability, at present by Spectrum company carries out the clinical trial of II phase, 400 times stronger than taxol to the cancer cell toxicity of multidrug resistance, thin to susceptibility Born of the same parents also show same outstanding inhibitory activity；(3) 2004 years injection Paclitaxel liposome-power simplicities, should in Discussion on Chinese Listed Technology successfully overcomes the technical problem that taxol is insoluble in water and a variety of pharmaceutical medias, fundamentally solves surface-active Adverse reaction caused by agent and super allergic reaction；(4) 005 years first non-solvent nanometer albumin combination chemotherapeutics Abraxane is listed in the U.S., is mainly improved the clinical shortcomings of paclitaxel analog compound poorly water-soluble, is provided simultaneously with and swells The ability that oncocyte surface differential protein combines；(5) the taxol targeted prodrug that Cell Therapeutics company develops Opaxio was ratified to list in the U.S. in 2012 by FDA, and water-soluble and tumor-targeting has larger journey compared to taxol The improvement of degree.Although the research and development of taxane class of anti-cancer agents object of new generation achieve considerable progress, it is directed to taxanes drug This big clinical shortcomings of system toxicity caused by all existing metabolic stability difference and the miscellaneous general property of drug, especially extend its anti-liver In terms of the new indication of cancer, there is not been reported in the drug listed at present.
Prodrug design (prodrug design) strategy obtains depth and is widely applied in taxol new drug development.Before The feature of drug compound maximum is to be effectively improved its specific clinical defect by carrying out specific structural modification to female medicine group； The active configuration of female medicine group is closed using carrier molecule, female medicine bring system toxicity is reduced, improves the generation of drug Thank to stability；By idiosyncratic carrier (monoclonal antibody, polypeptide etc.) by tumor tissues specific recognition, targeting ability of drug etc. is improved.
Matrix metalloproteinase (MMPs) is a kind of restriction enzyme enzyme family with high homology, in healthy body The expression quantity of interior MMPs is very low, and in tumor locus, due to the stimulation of the cell factor by various overexpressions, so that MMPs Expression quantity significantly improves, and wherein MMP-2 and MMP-9 is one the closest with tumor invasion and metabasis relationship found so far Albuminoid hydrolase, the effect in the infiltration, invasion of tumour is very important, is also considered as two most important tumor-markers Object.It has the characteristics that one is common, i.e., can identify the peptide molecule of one section of particular sequence amino acid residue and by its specific water Solution；And there is the high high expression of distribution in malignant tumour oncocyte jointly, and it is low in the certain normal or inflammatory tissues of human body The characteristic of expression.
" prodrug " layout strategy is to reduce one of most important means of drug toxicity, with special highly expressed in liver cancer tissue Machined metal protease MMPs is identified and the substrate polypeptide that hydrolyzes is as targeting vector group, with the more of preferable anticancer activity Alkene taxane is female medicine, is the chemical combination without report by the bridge chain molecule of self-degradation function by the prodrug of the two connection composition Object.The research and development of this kind of targeted prodrug molecule expand primarily directed to Docetaxel poor selectivity, the big disadvantage of system toxicity Application of such drug in anti-liver cancer and anti-oncotherapy.
Summary of the invention
The object of the present invention is to provide a kind of novel Docetaxel anti-liver cancer and anti-targeted prodrug and its pharmaceutical usages.
The present invention includes novel polyenoid taxane targeting anti-liver cancer and anti-prodrug representated by the following general formula (1).The polyenoid Japanese yew Alkanes targeted prodrug is coupled in bearing taxanes molecule by bridge chain molecule covalent special highly expressed in liver cancer tissue The substrate polypeptide that protease is identified and hydrolyzed can significantly improve drug to the targeting of liver cancer.
In formula (1), R1For the substrate polypeptide sequence including but not limited to matrix metalloproteinase MMP-2 specific recognition and hydrolysis Column such as Gly-Pro-Gln-Gly-Met-Ala-Gly-Gln, Gly-Pro-Gln-Gly-Ile-Ala-Ser-Gln, Gly-Pro- Gln-Gly-Ser-Ala-Gly-Gln、Gly-Pro-Gln-Gln-Ile-Ala-Gly-Gln、Gly-Pro-Gln-Gly-Ile- Trp-Gly-Gln, Gly-Pro-Gln-Gly-Ile-Hyp-Gly-Gln etc., including but not limited to matrix metalloproteinase MMP-9 Specific recognition and substrate polypeptide sequence such as Gly-Pro-Gln-Phe-Ile-Ala-Gly-Gln, the Ala-Ser-Gly- hydrolyzed Pro-Ala-Gly-Pro、Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln、Gly-Pro-Gln-Gly-Tyr-Ala-Gly- Gln, Gly-Asn-Gln-Gly-Ile-Ala-Gly-Gln etc..R2For including but not limited to methyl, trifluoromethyl etc.；R3For comprising But be not limited to hydrogen atom, fluorine atom etc..
The present invention also provides a kind of synthetic methods of above-mentioned novel polyenoid taxane targeting anti-liver cancer and anti-prodrug, including elder generation to exist The position the C-2 ' hydroxyl of polyenoid bearing taxanes introduces corresponding bridge joint group, synthesizes the derivative of polyenoid bearing taxanes Object；Then the derivative for containing bridge joint group is mixed with target polypeptide, is carried out occasionally under the action of condensing agent in 5 DEG C of stirrings Connection, obtains the polyenoid taxanes targeted prodrug.
The compound of the present invention is worth with pharmaceutical research, can be used as targeting matrix metalloproteinase MMP-2 or MMP-9 Anticancer prodrug.It can treat the cancer of enzyme MMP-2 or MMP-9 specificity overexpression, specifically, the compound of the present invention can To treat at least one disease selected from the following: liver cancer, oophoroma, breast cancer, non-small cell lung cancer and colon cancer etc..
The present invention provides the following data of such anti-liver cancer and anti-targeted prodrug: the suppression to HepG2, SMMC-7721 liver cancer cells System activity；To the toxicity of HL7702 normal liver cell and HEK296 kidney cell.
In one embodiment of the present of invention Docetaxel or tetrafluoro Docetaxel by bridge joint group Leu-PABC with Hepatoma-targeting polypeptide A 1-B11 is coupled the synthetic route of prodrug as shown in Scheme 1.
The synthetic route of 1 hepatoma-targeting polypeptide prodrug of Scheme
Compared with prior art, the beneficial effects of the present invention are embodied in:
The present invention is larger for polyenoid taxone system toxicity, lacks the defect of cancer target ability, according to text It offers in report hepatic carcinoma there are highly expressed matrix metalloproteinase MMP-2 and MMP-9, and specific recognition and can hydrolyze by 8 This feature of the polypeptide of a amino acid composition, it is purple with four fluoropolyenes with preferable resisting liver cancer activity using prodrug design strategy The pure and mild Docetaxel of China fir is female medicine, can be carried by MMP-2 or MMP-9 specific recognition and the amino acid sequence of hydrolysis as targeting As bridge chain molecule, design, which has been synthesized, has targeting and suppression to liver cancer for body group, the preferably PABC with self degradation function The prodrug compound of production.Compared with simple polyenoid bearing taxanes, while retaining most of resisting liver cancer activity, The targeting ability of tumour is greatly improved, the toxicity for normal cell can be effectively reduced.In addition prodrug compound of the invention Preparation method is simple, does not need harsh reaction condition, it is easy to accomplish large production reduces drug cost.
Specific embodiment
Below with reference to embodiment, the present invention is further elaborated, but these embodiments are definitely not to any limit of the invention System.
1 Docetaxel of embodiment or tetrafluoro Docetaxel pass through bridge joint group Leu-PABOH and hepatoma-targeting polypeptide The preparation of A1~B11 coupling prodrug
It is purple using taxol (DTX) or the coupling preparation of tetrafluoro Docetaxel (4FDT) and 1~B11 of hepatoma-targeting polypeptide A China fir alkanes targeted prodrug, synthetic route, comprising the following steps:
1) synthesis and activation modification of group Leu-PABOH are bridged
100mL round-bottomed flask is taken, is added Fmoc-L- leucine 800mg (2.27mmol), aminobenzene methanol 300mg is added (2.5mmol) is added anhydrous DCM 50mL, 10min is stirred at room temperature.2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- two is added later Hydrogen quinoline 610mg (2.5mmol), is stirred at room temperature reaction.TLC plate (methylene chloride: methanol=35:1) monitoring reaction feelings after for 24 hours Condition disappears to raw material Fmoc-L- leucine, and water is added to stop reaction, saturated sodium chloride solution washing, and ethyl acetate is extracted twice. Anhydrous sodium sulfate is dry, filters, and organic solvent is spin-dried for obtain crude product, silica gel column chromatography purifying, eluent system uses DCM: MeOH=60:1-40:1 obtains 1 white solid 945mg of compound, yield 91%.
Two neck bottle of 50mL is taken, it is 600mg (1.3mmol) that compound 1, which is added, and two (p-nitrophenyl) carbonic ester 790mg are added (2.6mmol) anhydrous DMF 20ml is added under nitrogen protection, stirs 10min under the conditions of 0 DEG C of ice bath, diisopropyl is slowly added dropwise 664 μ l (3.9mmol) of ethamine, 0 DEG C of stirring 15min after being added dropwise to complete move to room temperature reaction 12h later.TLC plate (n-hexane: third Ketone=4:1) response situation is monitored, to 1 fully reacting of compound, add water to stop reaction, there is solid precipitation, consolidates what suction filtration obtained Body is recrystallized with n-hexane/ethyl acetate, obtains crude product, silica gel column chromatography purifying, eluent system is using n-hexane: acetone= 10:1-6:1 obtains 2 white solid 952mg of compound, yield 84%.
Experimental method reference literature Bakheet Elsadek et al.Development of a novel prodrug of paclitaxel that is cleaved by prostate-specific antigen:An in vitro and in vivo evaluation study.European Journal of Cancer,2010,46(18):3434-3444
2) synthesis of the position Docetaxel C-2 ' intermediate 3a/3b
Two neck bottle of 50mL is taken, it is 710mg (0.81mmol) that tetrafluoro Docetaxel, which is added, and addition compound 20 is 500mg (0.81mmol) is added anhydrous methylene chloride 25mL, 10min is stirred at room temperature.4-dimethylaminopyridine 92mg is added later (0.81mmol), is stirred at room temperature.TLC plate (DCM:MeOH=40:1) monitoring response situation adds water to raw material end of reaction after 8h Quenching reaction, saturated sodium chloride solution washing, ethyl acetate are extracted twice.Anhydrous sodium sulfate is dry, filters, organic solvent is revolved Dry to obtain crude product, silica gel column chromatography purifying, eluent system uses methylene chloride: methanol=100:1-80:1-40:1, obtains Mesosome 3a white solid 662mg, yield 60%.
Compound 3a data are as follows:
mp:172.1-175.3℃；1H NMR (400MHz, Acetone-d6): δ 9.43 (s, 1H), 8.12 (d, J= 7.6Hz, 2H), 7.86 (d, J=7.6Hz, 2H), 7.76-7.64 (m, 5H), 7.58 (t, J=7.6Hz, 2H), 7.51 (d, J= 7.6Hz, 2H), 7.46-7.35 (m, 6H), 7.34-7.25 (m, 3H), 7.04 (d, J=9.6Hz, 1H), 6.83 (d, J= 8.0Hz, 1H), 6.11 (d, J=8.4Hz, 1H), 5.68 (d, J=7.2Hz, 1H), 5.40 (d, J=9.2Hz, 1H), 5.30 (d, J=5.2Hz, 1H), 5.25 (s, 1H), 4.97 (d, J=8.8Hz, 1H), 4.39-4.30 (m, 5H), 4.24 (t, J=7.0HZ, 2H), 4.17 (s, 2H), 3.93 (d, J=6.8Hz, 1H), 3.68 (s, 1H), 2.83 (s, 1H), 2.45 (d, J=17.6Hz, 4H), 2.38-2.28 (m, 1H), 2.12 (d, J=8.4Hz, 1H), 1.93-1.77 (m, 5H), 1.75-1.65 (m, 5H), 1.45- 1.25 (m, 20H), 1.17 (d, J=12.4Hz, 6H), 0.96 (dd, J=10.8,6.6Hz, 6H), 0.88 (t, J=6.6Hz, 1H).ESI-MS:m/z 1292.4[M+H]+,1314.2[M+Na]+；C72H81N3O19:HRMS calcd.1314.5356[M+ Na]+,found 1314.5366.
The synthetic method of compound 3b is similar with 3a, and yield 64%, data are as follows:
mp:167.4-169.8℃；1H NMR (400MHz, Acetone-d6): δ 9.46 (s, 1H), 7.95 (d, J= 7.6Hz, 1H), 7.86 (d, J=7.6Hz, 2H), 7.79 (d, J=9.6Hz, 1H), 7.71 (dd, J=13.2,7.2Hz, 6H), 7.67-7.61 (m, 1H), 7.52 (t, J=13.6Hz, 3H), 7.47-7.35 (m, 7H), 7.30 (dd, J=15.2,7.8Hz, 3H), 6.84 (d, J=8.0Hz, 1H), 6.10 (t, J=9.2Hz, 1H), 5.66 (d, J=6.8Hz, 1H), 5.40-5.34 (m, 1H), 5.32 (d, J=5.6Hz, 1H), 5.24 (s, 1H), 5.20 (d, J=12.0Hz, 1H), 5.12 (d, J=12.0Hz, 1H), 4.98 (d, J=9.2Hz, 1H), 4.41-4.28 (m, 7H), 4.24 (t, J=6.8Hz, 1H), 4.17 (q, J=8.0Hz, 3H), 3.92 (d, J=7.2Hz, 1H), 3.79 (s, 1H), 2.52-2.42 (m, 5H), 2.26 (dd, J=15.6,8.6Hz, 2H), 2.02-1.95 (m, 1H), 1.90-1.75 (m, 7H), 1.73-1.63 (m, 6H), 1.57 (d, J=3.6Hz, 7H), 1.34-1.24 (m, 5H), 1.17 (s, 4H), 0.95 (dd, J=10.4,6.6Hz, 7H) .ESI-MS:m/z 1364.2 [M+H]+, 1386.2 [M+ Na]+；C72H77F4N3O19:HRMS calcd.1386.4980[M+Na]+,found 1386.5001.
3) synthesis of intermediate 4a/4b
Two neck bottle of 10mL is taken, it is 30mg (0.022mmol) that compound 3a, which is added, and addition anhydrous DMF is 3mL, is stirred at room temperature 10min.5.4 μ L (0.055mmol) of piperidines is added dropwise rapidly, 45min is stirred at room temperature.TLC plate (methylene chloride: methanol=20:1) prison Response situation is surveyed, raw material 21a fully reacting adds water to terminate reaction, and methylene chloride extracts 3 times, collects organic phase, and water pump is spin-dried for, Rear pump or output pump take out 30min, the crude product of gained compound 4a, purity is about 80%, be directly used in without further purification in next step react. Compound 4b is similar with the synthetic method of 4a, yield 79%.
4) synthesis of hepatoma-targeting prodrug compound 5a/5b~15a/15b
DTX-PABC-Leu-A1(5a)
Take two neck bottle of 25ml, N2The lower compound 4a that 0.01mmol is added of protection, the targeting vector polypeptide A 1 of 0.015mmol (Gly-Pro-Gln-Gly-Met-Ala-Gly-Gln-Fmoc), the I-hydroxybenzotriazole (HOBt) and 1.5mL of 0.06mmol N,N-Dimethylformamide (DMF) the N- methylmorpholine of 0.04mmol at 0 DEG C after completely dissolution is added, react After 15min, 0.08mmol N is added, N'- diisopropylcarbodiimide (DIC) is warming up to 5 DEG C, and the reaction was continued, and HPLC monitoring is anti- It answers, adds 0.02-0.03mmol targeting vector polypeptide A 1 every other day, add 2 times.About 72h can fully reacting；After reaction, room Solvent n,N-Dimethylformamide (DMF) is removed as far as possible with vacuum oil pump under temperature, and a small amount of dimethyl sulfoxide (DMSO) is added to dissolve, Carry out the standby purifying of compacting in reversed.Mobile phase uses acetonitrile/water system, method particularly includes :+100% water of 0% acetonitrile, 20min (removing DMSO), 0%-40% acetonitrile+100%-60% water, 20min, 40%-65% acetonitrile+60%-35% water, 40min.5a Appearance when 53% acetonitrile gradient collects product peak and is concentrated under reduced pressure into minimum volume, and freeze-drying obtains white solid 5a, yield 35%.Remaining prodrug compound is carried out according to synthetic method.
1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.37-8.04(m,5H),8.04-7.87(m,6H),7.83 (d, J=7.5Hz, 2H), 7.75-7.52 (m, 8H), 7.50-7.15 (m, 14H), 7.10 (t, J=7.1Hz, 1H), 6.94- 6.61 (m, 2H), 5.71 (t, J=8.4Hz, 1H), 5.31 (t, J=17.0Hz, 1H), 5.16-4.89 (m, 7H), 4.84 (d, J =9.8Hz, 1H), 4.33 (m, 4H), 4.20 (m, 6H), 4.12-4.05 (m, 1H), 3.96 (m, 3H), 3.89-3.45 (m, 8H), 3.45-3.37 (m, 1H), 2.33 (t, J=19.7Hz, 2H), 2.19 (m, 5H), 2.06 (m, 5H), 1.93 (t, J=9.6Hz, 5H), 1.90-1.75 (m, 7H), 1.75-1.62 (m, 8H), 1.57 (d, J=11.3Hz, 4H), 1.39 (d, J=44.0Hz, 6H),1.34-1.22(m,10H),1.17(s,9H),0.95(m,7H),0.82(m,8H).ESI-MS:2040.3[M+Na]+； C101H127N13O29S:HRMS calcd.2040.8476[M+Na]+,found 2040.8595.
4FDT-PABC-Leu-A1(5b)
The same 5a of synthetic method, white solid, yield 32%.
1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.50-8.45(m,4H),8.19(s,2H),8.10(d,J =18.1Hz, 8H), 8.02-7.89 (m, 7H), 7.86-7.80 (m, 7H), 7.78-7.74 (m, 2H), 7.65 (t, J=7.3Hz, 9H), 7.59 (d, J=7.9Hz, 11H), 7.44 (s, 1H), 7.36 (t, J=7.5Hz, 14H), 7.24 (d, J=21.9Hz, 29H), 7.11 (s, 2H), 6.93 (d, J=11.8Hz, 0H), 6.77 (d, J=19.2Hz, 4H), 5.13-4.99 (m, 10H), 4.97-4.89 (m, 3H), 4.88-4.83 (m, 1H), 4.48 (d, J=8.5Hz, 0H), 4.17 (d, J=27.1Hz, 13H), 4.07 (d, J=10.2Hz, 1H), 4.02-3.91 (m, 3H), 3.78-3.60 (m, 4H), 3.49 (s, 0H), 2.36 (d, J= 6.1Hz,6H),2.18(m,10H),2.02(br,29H),1.94(br,12H),1.84(brs,17H),1.66(brs,25H), 1.60-1.52(m,10H),1.50-1.41(m,37H),1.17(brs,31H),0.92(brs,19H),0.83(m,24H) .ESI-MS:m/z 2112.3[M+Na]+；C101H123F4N13O29S:HRMS calcd.2112.8099[M+Na]+,found 2112.8194.
DTX-PABC-Leu-A2(6a)
The same 5a of synthetic method, white solid, yield 29%.
1H NMR(400MHz,CDCl3) δ=9.86 (s, 1H), 8.34-8.36 (m, 3H), 8.16-8.18 (m, 2H), 8.09-8.13 (m, 5H), 8.00-8.01 (m, 1H), 7.58-7.70 (m, 5H), 7.24-7.39 (m, 10H), 7.76 (d, J= 2.6Hz,2H),4.84-5.11(m,8H),3.50-4.41(m,12H),2.06-2.19(m,10H),1.82(m,9H),1.67 (m, 12H), 1.46 (m, 6H), 1.29 (m, 11H), 1.18 (d, J=1.7Hz, 5H), 0.93 (s, 1H), 0.76-0.86 (m, 13H).ESI-MS:m/z 1872.7[M+Na]+；C90H123N13O29:HRMS calcd.1872.8506[M+Na]+,found 1872.8587.
4FDT-PABC-Leu-A2(6b)
The same 5a of synthetic method, white solid, yield 37%.
1H NMR(400MHz,DMSO-d6) δ 9.82 (s, 1H), 8.44 (s, 1H), 8.07 (s, 4H), 7.95 (d, J= 2.5Hz,2H),7.86(s,2H),7.73(s,2H),7.56(s,5H),7.24(s,10H),7.08(s,1H),6.72(s,2H), 5.67(s,1H),5.28(s,1H),4.95(m,11H),4.45(m,2H),4.18(m,8H),3.91(m,5H),3.60(m, 9H),2.14(m,5H),2.02(m,6H),1.76(m,12H),1.62(m,12H),1.42(m,18H),1.13(m,10H), 0.79(m,26H).ESI-MS:1944.8[M+Na]+；C90H119F4N13O29:HRMS calcd.1944.8065[M+Na]+, found1944.8081.
DTX-PABC-Leu-A3(7a)
The same 5a of synthetic method, white solid, yield 36%.
1H NMR(400MHz,CDCl3) δ=9.94 (s, 1H), 8.19-8.23 (m, 2H), 8.08-8.09 (m, 2H), 7.90-8.00 (m, 8H), 7.58-7.68 (m, 5H), 7.25-7.39 (m, 8H), 7.10-7.13 (m, 1H), 7.78 (d, J= 3.4Hz, 2H), 5.34-5.36 (m, 1H), 4.95-5.10 (m, 8H), 4.86 (d, J=2.4Hz, 1H), 3.33-4.41 (m, 20H),2.20(m,4H),2.05-2.08(m,5H),1.82(m,8H),1.71(m,6H),1.46(m,5H),1.29(m,9H), 1.18-1.20(m,6H),0.93(m,6H),0.62-0.87(m,7H).ESI-MS:1816.4[M+Na]+；C86H115N13O29: HRMS calcd.1816.7684[M+Na]+,found1816.7702.
4FDT-PABC-Leu-A3(7b)
The same 5a of synthetic method, white solid, yield 30%.
1H NMR(400MHz,DMSO-d6) δ 9.95 (s, 1H), 8.43 (dd, J=45.0,8.5Hz, 1H), 8.30-8.15 (m, 2H), 8.09 (d, J=6.4Hz, 2H), 7.96 (dt, J=15.6,5.5Hz, 4H), 7.77 (d, J=7.8Hz, 1H), 7.60 (d, J=8.2Hz, 5H), 7.44-7.16 (m, 8H), 7.12 (t, J=7.1Hz, 1H), 6.78 (m, 2H), 5.72 (m, 1H), 5.30 (m, 1H), 5.18-4.98 (m, 6H), 4.97 (s, 2H), 4.86 (d, J=9.9Hz, 1H), 4.50 (s, 1H), 4.44- 4.14(m,6H),4.14-4.06(m,1H),3.95(m,4H),3.67(m,5H),3.63-3.51(m,3H),3.51(m,2H), 3.45-3.36(m,2H),2.18(s,4H),2.15-1.95(m,6H),1.81(m,8H),1.68(m,7H),1.63-1.51(m, 4H), 1.51-1.33 (m, 11H), 1.18 (brs, 5H), 0.92 (brs, 7H), 0.86 (m, 4H), 0.82 (d, J=6.1Hz, 3H).ESI-MS:m/z 1888.7[M+Na]+；C86H111F4N13O29:HRMS calcd.1888.7439[M+Na]+,found 1888.7462.
DTX-PABC-Leu-A4(8a)
The same 5a of synthetic method, white solid, yield 32%.
1H NMR(400MHz,DMSO-d6) δ 9.95 (s, 1H), 8.38-8.02 (m, J=44.2,31.5,13.1Hz, 6H), 8.02-7.88 (m, J=16.9,7.0Hz, 4H), 7.88-7.55 (m, 7H), 7.45-7.16 (m, 9H), 7.11 (t, J= 7.2Hz, 1H), 6.80 (d, J=12.5Hz, 3H), 5.72 (t, J=8.9Hz, 1H), 5.32 (t, J=12.8Hz, 1H), 5.17- 4.91 (m, 7H), 4.86 (d, J=9.7Hz, 1H), 4.38 (m, 2H), 4.19 (m, 4H), 4.13-4.04 (m, 2H), 3.97 (d, J =10.2Hz, 4H), 3.85-3.37 (m, 6H), 2.20 (m, 4H), 2.02 (m, 8H), 1.96-1.77 (m, 10H), 1.77-1.53 (m,13H),1.46(m,6H),1.31(m,10H),1.17(m,8H),0.97(m,8H),0.84(m,7H),0.74(m,7H) .ESI-MS:m/z 1913.8[M+Na]+；C92H126N14O29:HRMS calcd.1913.8707[M+Na]+,found 1913.8703.
4FDT-PABC-Leu-A4(8b)
The same 5a of synthetic method, white solid, yield 29%.
1H NMR(400MHz,CDCl3) δ=10.13 (10.21) (s, 1H), 7.09-8.50 (m, 23H), 5.76 (s, 3H), 5.31 (s, 1H), 5.07 (d, J=2.0Hz, 2H), 4.88-4.92 (m, 2H), 3.94-4.16 (m, 10H), 3.51-3.76 (m, 5H),2.18(s,3H),2.04(bs,7H),1.79(s,9H),1.65(s,8H),1.60(s,6H),1.43-1.48(m,10H), 1.16(s,9H),0.71-1.11(m,20H).ESI-MS:m/z 1985.7[M+Na]+；C92H122F4N14O29:HRMS calcd.1985.9326[M+Na]+,found 1985.9347.
DTX-PABC-Leu-A5(9a)
The same 5a of synthetic method, white solid, yield 15%.
1H NMR(400MHz,CDCl3) δ=10.73 (s, 1H), 9.97 (s, 1H), 8.10-8.13 (m, 4H), 7.99 (s, 2H), 7.89-7.94 (m, 4H), 7.59-7.67 (m, 5H), 7.49 (d, J=2.0Hz, 1H), 6.79-7.38 (m, 15H), 5.71 (d, J=0.4Hz, 1H), 5.34 (d, J=1.6Hz, 1H), 4.84-5.07 (m, 7H), 3.40-4.45 (m, 17H), 3.11 (m, 3H),2.19(m,4H),2.07(m,4H),1.80(m,8H),1.67(m,6H),1.56(m,4H),1.45(m,5H),1.28(m, 10H),1.17(m,2H),0.92(m,7H),0.81-0.86(m,6H),0.68(m,5H).ESI-MS:m/z 1957.5[M+Na ]+；C97H126N14O28:HRMS calcd.1957.8659[M+Na]+,found 1957.8673.
4FDT-PABC-Leu-A5(9b)
The same 5a of synthetic method, white solid, yield 16%.
1H NMR(400MHz,DMSO-d6) δ 10.75 (s, 1H), 9.97 (d, J=17.5Hz, 1H), 8.49 (d, J= 9.1Hz, 1H), 8.37 (d, J=7.9Hz, 0H), 8.26-8.06 (m, 5H), 8.00 (s, 2H), 7.90 (s, 1H), 7.77 (s, 2H), 7.59 (d, J=8.4Hz, 5H), 7.50 (d, J=7.8Hz, 1H), 7.40-7.23 (m, 8H), 7.18 (d, J=9.2Hz, 0H), 7.10 (s, 2H), 6.99 (t, J=7.5Hz, 1H), 6.92-6.86 (m, 1H), 6.80 (s, 2H), 5.72 (t, J= 8.9Hz,1H),5.38-5.23(m,1H),5.13-4.83(m,7H),4.51(m,3H),4.22(m,2H),4.17(m,2H), 3.96(m,4H),3.69(m,5H),3.43(m,2H),3.09(m,1H),2.90(m,1H),2.19(m,4H),2.13-2.01 (m,4H),1.80(m,9H),1.69(m,6H),1.60(m,4H),1.53-1.33(m,11H),1.18(m,5H),0.93(m, 7H), 0.84 (m, 6H), 0.68 (d, J=6.9Hz, 6H) .ESI-MS:1026.3 [M+2Na]2+；C97H122F4N14O28:HRMS calcd.1944.8065[M+Na]+,found 1944.8081.
DTX-PABC-Leu-A6(10a)
The same 5a of synthetic method, white solid, yield 34%.
1H NMR(400MHz,DMSO-d6) δ 9.93 (d, J=12.6Hz, 1H), 8.41 (d, J=13.2Hz, 1H), 8.38- 8.30 (m, -1H), 8.07 (s, 3H), 7.97 (s, 2H), 7.93 (d, J=7.9Hz, 8H), 7.84 (t, J=10.4Hz, 2H), 7.66 (d, J=7.0Hz, 1H), 7.60 (m, 8H), 7.35 (m, 4H), 7.30 (m, 10H), 7.23 (m, 2H), 7.13-7.07 (m, 1H), 6.83 (d, J=12.4Hz, 1H), 6.73 (d, J=8.2Hz, 1H), 5.11 (m, 4H), 5.02 (m, 6H), 4.94 (m, 3H), 4.87-4.81(m,1H),4.41(m,2H),4.29(m,6H),4.21(m,2H),4.09(m,7H),3.95(m,5H), 3.77 (dd, J=15.1,8.5Hz, 1H), 3.59 (m, 10H), 3.11 (m, 15H), 2.19 (m, 6H), 2.05 (m, 7H), 1.95 (m,2H),1.83(m,21H),1.66(m,17H),1.45(m,11H),1.28(m,19H),1.17(m,5H),0.92(m, 14H),0.87-0.76(m,20H),0.73(s,6H).ESI-MS:m/z 1885.8[M+Na]+；C91H122N12O30:HRMS calcd.1026.4137[M+Na]+,found 1026.4145.
4FDT-PABC-Leu-A6(10b)
The same 5a of synthetic method, white solid, yield 31%.
1H NMR(400MHz,DMSO-d6) δ 9.96 (s, 1H), 8.53-8.39 (m, 2H), 8.33 (d, J=8.0Hz, 1H), 8.08 (s, 2H), 8.04-7.91 (m, 2H), 7.86 (dd, J=12.6,6.5Hz, 2H), 7.77 (s, 1H), 7.62 (t, J= 8.4Hz, 5H), 7.41-7.17 (m, 8H), 7.12 (t, J=7.1Hz, 1H), 6.80 (d, J=42.1Hz, 2H), 5.72 (t, J= 8.8Hz, 1H), 5.37-5.24 (m, 1H), 5.18-4.91 (m, 8H), 4.87 (d, J=10.1Hz, 1H), 4.51 (s, 1H), 4.30 (d, J=8.1Hz, 8H), 3.96 (s, 4H), 3.85-3.45 (m, 10H), 3.45-3.38 (m, 1H), 3.11 (t, J= 5.8Hz, 0H), 2.19 (s, 4H), 2.16-2.03 (m, 5H), 1.94 (s, 2H), 1.83 (dd, J=15.3,5.6Hz, 10H), 1.72-1.55 (m, 10H), 1.49 (dd, J=21.0,10.3Hz, 14H), 1.18 (s, 4H), 0.93 (s, 8H), 0.88-0.77 (m, 10H), 0.73 (t, J=7.3Hz, 3H) .ESI-MS:m/z 1957.3 [M+Na]+；C91H118F4N12O30:HRMS calcd.1957.7905[M+Na]+,found 1957.7877.
DTX-PABC-Leu-B7(11a)
The same 5a of synthetic method, white solid, yield 11%.
1H NMR(400MHz,DMSO-d6) δ 10.02-9.91 (s, 1H), 8.32-8.22 (s, 1H), 8.10 (d, J= 6.0Hz, 11H), 8.03-7.87 (m, 17H), 7.83 (t, J=10.4Hz, 1H), 7.73 (t, J=7.2Hz, 1H), 7.66 (d, J =7.1Hz, 2H), 7.60 (d, J=7.5Hz, 12H), 7.35 (d, J=7.2Hz, 5H), 7.32-7.24 (m, 16H), 7.22 (s, 3H),7.12(m,18H),6.86-6.71(m,3H),5.02(m,16H),4.40(m,2H),4.33(m,2H),4.20(m,9H), 3.95 (m, 8H), 3.87-3.77 (m, 2H), 3.65 (m, 3H), 3.57 (m, 1H), 3.41 (d, J=7.0Hz, 1H), 2.44 (m, 9H), 2.18 (m, 10H), 2.05 (m, 9H), 1.94 (d, J=7.1Hz, 3H), 1.76 (m, 24H), 1.68 (m, 24H), 1.59 (m,10H),1.45(m,16H),1.37(m,2H),1.27(m,29H),1.17(m,16H),1.01(m,2H),0.92(m, 19H),0.84(m,9H),0.81-0.57(m,27H).ESI-MS:m/z 1932.8[M+Na]+；C96H127N13O28:HRMS calcd.1932.8806[M+Na]+,found 1932.8842.
4FDT-PABC-Leu-B7(11b)
The same 5a of synthetic method, white solid, yield 12%.
1H NMR(400MHz,DMSO-d6) δ 9.96 (s, 1H), 8.48 (d, J=9.0Hz, 1H), 8.32-8.03 (m, 5H), 7.98 (d, J=4.3Hz, 3H), 7.88-7.72 (m, 3H), 7.72-7.52 (m, 5H), 7.32 (ddd, J=22.8,14.9, 7.7Hz, 7H), 7.22 (s, 1H), 7.16-7.04 (m, 6H), 6.78 (d, J=16.2Hz, 2H), 5.72 (m, 1H), 5.35- 5.23 (m, 1H), 5.17-4.89 (m, 7H), 4.86 (d, J=9.6Hz, 1H), 4.56-4.41 (m, 2H), 4.36 (s, 1H), 4.25-4.09 (m, 4H), 4.05-3.90 (m, 4H), 3.90-3.77 (m, 2H), 3.71 (m, 2H), 3.58 (d, J=6.9Hz, 1H),3.49(s,1H),3.46-3.35(m,1H),2.96(m,1H),2.81-2.66(m,1H),2.29-2.13(m,4H), 2.13-1.98(m,4H),1.94(m,3H),1.87-1.75(m,6H),1.75-1.53(m,13H),1.53-1.34(m,14H), 1.18(m,11H),1.01(m,2H),0.92(s,6H),0.79(m,14H).ESI-MS:2004.5[M+Na]+； C96H123F4N13O28:HRMS calcd.2004.8429[M+Na]+,found 2004.8456.
DTX-PABC-Leu-B8(12a)
The same 5a of synthetic method, white solid, yield 30%.
1H NMR(400MHz,DMSO-d6) δ 10.20 (d, J=3.9Hz, 0H), 9.80 (d, J=10.5Hz, 1H), 8.43 (d, J=14.9Hz, -1H), 8.35 (d, J=13.9Hz, -1H), 8.06 (dd, J=22.9,10.9Hz, 4H), 7.95 (d, J= 11.3Hz, 3H), 7.91 (t, J=8.6Hz, 12H), 7.81 (t, J=15.7Hz, 13H), 7.66 (t, J=7.4Hz, 11H), 7.59(m,14H),7.50(m,2H),7.35(m,16H),7.28(m,23H),7.08(m,2H),5.36-5.29(m,1H), 5.08 (s, 3H), 5.00 (m, 10H), 4.96-4.87 (m, 8H), 4.87-4.80 (m, 2H), 4.38 (d, J=9.1Hz, 2H), 4.35-4.12(m,19H),4.07(m,2H),3.94(m,11H),3.89-3.78(m,2H),3.55(m,3H),3.43(m, 8H),2.18(m,15H),2.01(m,16H),1.79(m,17H),1.65(m,21H),1.44(m,17H),1.27(m,35H), 1.17(m,32H),0.91(m,22H),0.85(m,12H),0.80(m,11H).ESI-MS:m/z 1851.4[M+Na]+； C95H116N10O27:HRMS calcd.1851.7904[M+Na]+,found 1851.7979.
4FDT-PABC-Leu-B8(12b)
The same 5a of synthetic method, white solid, yield 25%.
1H NMR(400MHz,DMSO-d6) δ 9.87 (d, J=7.3Hz, 1H), 8.48 (d, J=9.1Hz, 3H), 8.10 (m, 5H), 8.00 (d, J=10.3Hz, 1H), 7.83 (m, 18H), 7.77 (m, 3H), 7.68 (m, 11H), 7.64-7.50 (m, 20H), 7.36 (m, 20H), 7.29 (m, 24H), 7.14-7.08 (m, 2H), 6.98 (m, 3H), 5.34-5.30 (m, 2H), 5.25 (d, J= 5.5Hz,1H),5.13-5.01(m,15H),4.93(m,9H),4.85m,2H),4.27(m,7H),4.17(m,9H),4.10(m, 4H),3.96(m,12H),3.83(m,1H),3.57(m,4H),3.51(m,24H),2.99(m,3H),2.92(m,9H),2.67- 2.61(m,2H),2.41-2.38(m,5H),2.32-2.21(m,8H),2.18(m,15H),2.03(m,2H),1.94(m,8H), 1.81(m,14H),1.70(m,4H),1.66(m,10H),1.60(m,20H),1.51-1.42(m,51H),1.41-1.36(m, 4H),1.18(m,75H),0.92(m,24H),0.83(m,27H).ESI-MS:m/z 1923.7[M+Na]+；C95H112F4N10O27: HRMS calcd.1923.7527[M+Na]+,found 1923.7520.
DTX-PABC-Leu-B9(13a)
The same 5a of synthetic method, white solid, yield 24%.
1H NMR(400MHz,DMSO-d6) δ 9.96 (d, J=9.5Hz, 1H), 8.33 (d, J=7.8Hz, 0H), 8.28- 8.24 (m, 0H), 8.21-8.01 (m, 10H), 7.92 (m, 14H), 7.84 (m, 6H), 7.77 (d, J=8.2Hz, 1H), 7.67 (m, 8H), 7.60 (m, 11H), 7.43 (d, J=6.2Hz, 2H), 7.35 (m, 13H), 7.28 (m, 21H), 7.21 (s, 1H), 7.16-7.09 (m, 5H), 6.76 (m, 3H), 5.70 (d, J=8.4Hz, 2H), 5.37-5.32 (m, 1H), 5.09 (m, 3H), 5.02 (m, 8H), 4.93 (m, 3H), 4.85 (t, J=6.9Hz, 1H), 4.44-4.31 (m, 2H), 4.29-4.09 (m, 18H), 3.93(m,5H),3.72(m,8H),2.19(m,9H),2.09-2.02(m,9H),1.83(m,10H),1.67(m,20H),1.58 (m, 8H), 1.46 (m, 13H), 1.28 (m, 27H), 1.17 (m, 16H), 0.99 (d, J=6.2Hz, 1H), 0.92 (m, 17H), 0.84(m,18H),0.78-0.69(m,17H).ESI-MS:m/z 2022.9[M+Na]+；C102H129N13O29:HRMS calcd.2022.8911[M+Na]+,found 2022.8878.
4FDT-PABC-Leu-B9(13b)
The same 5a of synthetic method, white solid, yield 29%.
1H NMR(400MHz,DMSO-d6) δ 9.97 (s, 1H), 8.49 (d, J=9.2Hz, 1H), 8.34 (d, J=7.3Hz, 1H), 8.25-8.03 (m, 5H), 7.93 (dd, J=11.4,4.9Hz, 2H), 7.85 (d, J=7.5Hz, 2H), 7.78 (d, J= 7.1Hz,2H),7.73-7.52(m,7H),7.48-7.24(m,12H),7.21(s,1H),6.82-6.73(m,2H),5.37- 5.22 (m, 1H), 5.18-4.98 (m, 5H), 4.98-4.92 (m, 2H), 4.87 (d, J=9.8Hz, 1H), 4.49 (d, J= 14.0Hz,1H),4.20(m,8H),3.97(m,3H),3.89-3.54(m,7H),3.49(s,1H),3.47-3.37(m,2H), 2.19 (m, 4H), 2.08 (m, 4H), 1.90 (t, J=70.8,25.4Hz, 7H), 1.69 (d, J=14.3Hz, 11H), 1.52- 1.26 (m, 13H), 1.17 (d, J=6.9Hz, 8H), 0.93 (m, 7H), 0.84 (m, 7H), 0.80-0.64 (m, 7H) .ESI-MS: m/z 2094.3[M+Na]+；C102H125F4N13O29:HRMS calcd.2094.6817[M+Na]+,found 2094.6863
DTX-PABC-Leu-B10(14a)
The same 5a of synthetic method, white solid, yield 17%.
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.15(s,1H),8.37-8.17(m,2H),8.10(d,J =6.3Hz, 2H), 8.06-7.77 (m, 8H), 7.69-7.51 (m, 5H), 7.32 (m, 8H), 7.12 (t, J=7.0Hz, 1H), 6.98 (d, J=8.1Hz, 2H), 6.79 (m, 2H), 6.58 (d, J=8.0Hz, 2H), 5.73 (t, J=8.6Hz, 1H), 5.35 (d, J=6.8Hz, 1H), 5.13-4.91 (m, 7H), 4.86 (d, J=9.8Hz, 1H), 4.41 (d, J=9.0Hz, 3H), 4.18 (m, 4H), 3.94 (m, 3H), 3.86-3.74 (m, 1H), 3.68 (m, 3H), 3.61-3.36 (m, 4H), 2.86 (d, J= 17.1Hz, 1H), 2.68 (s, 1H), 2.57 (t, J=11.5Hz, 1H), 2.20 (m, 4H), 2.11-1.98 (m, 4H), 1.92- 1.75(m,9H),1.65(m,10H),1.46(m,5H),1.31(m,9H),1.18(m,7H),0.97(m,7H),0.84(m, 7H).ESI-MS:m/z 1892.8[M+Na]+；C92H119N13O29:HRMS calcd.1892.8129[M+Na]+,found 1892.8114.
4FDT-PABC-Leu-B10(14b)
The same 5a of synthetic method, white solid, yield 12%.
1H NMR(400MHz,DMSO-d6) δ 10.03-9.94 (m, 1H), 9.14 (s, 2H), 8.47 (t, J=7.8Hz, 1H), 8.33-8.19 (m, 1H), 8.09 (d, J=7.2Hz, 3H), 7.98 (br, 8H), 7.84 (s, 1H), 7.76 (t, J= 6.5Hz, 1H), 7.60 (m, 9H), 7.35 (m, 4H), 7.29 (m, 10H), 7.20 (d, J=17.7Hz, 2H), 7.11 (m, 1H), 6.97 (m, 3H), 6.81 (d, J=8.2Hz, 1H), 6.73 (d, J=12.3Hz, 1H), 6.58 (m, 4H), 5.70 (d, J= 16.0Hz, 1H), 5.32 (t, J=7.9Hz, 1H), 5.10 (m, 2H), 5.05 (m, 6H), 4.97 (m, 3H), 4.85 (t, J= 8.8Hz,1H),4.50(s,1H),4.35(m,3H),4.18(m,4H),3.95(m,5H),3.67(m,4H),3.58(m,2H), 3.47 (m, 1H), 2.84 (s, 2H), 2.68 (s, 1H), 2.19 (m, 6H), 2.14 (s, 1H), 2.05 (m, 8H), 1.95 (t, J= 10.0Hz,1H),1.83(m,5H),1.80(m,10H),1.68(m,13H),1.62-1.52(m,6H),1.50-1.41(m, 21H),1.40(m,2H),1.17(m,8H),0.93(m,12H),0.83(m,13H).ESI-MS:m/z 1964.3[M+Na]+； C92H115F4N13O29:HRMS calcd.1964.7752[M+Na]+,found 1964.7779.
DTX-PABC-Leu-B11(15a)
The same 5a of synthetic method, white solid, yield 31%.
1H NMR(400MHz,DMSO-d6) δ 9.97 (s, 1H), 8.31-7.99 (m, 8H), 7.94 (dd, J=16.6, 8.4Hz, 4H), 7.68 (t, J=8.1Hz, 2H), 7.60 (m, 4H), 7.48-7.32 (m, 3H), 7.29 (m, 5H), 7.20 (s, 1H), 7.12 (t, J=7.3Hz, 1H), 6.96 (d, J=19.0Hz, 1H), 6.74 (t, J=19.9Hz, 2H), 5.73 (t, J= 8.8Hz, 1H), 5.30 (dd, J=35.8,9.0Hz, 1H), 5.10 (m, 2H), 5.08-4.91 (m, 5H), 4.86 (d, J= 10.2Hz,1H),4.52-4.43(m,1H),4.39(m,2H),4.27-4.04(m,4H),3.98(m,3H),3.78-3.51(m, 7H), 3.12 (d, J=5.2Hz, 1H), 2.84 (s, 1H), 2.68 (m, 1H), 2.57-2.47 (m, 1H), 2.43-2.35 (m, 1H),2.20(m,4H),2.14-1.98(m,5H),1.98-1.83(m,3H),1.81(m,4H),1.78-1.52(m,11H), 1.46(m,5H),1.31(m,10H),1.18(m,7H),1.07-0.90(m,7H),0.85(m,6H),0.75(m,6H).ESI- MS:m/z 1859.8[M+Na]+；C88H120N14O29:HRMS calcd.1859.8238[M+Na]+,found 1859.8199.
4FDT-PABC-Leu-B11(15b)
The same 5a of synthetic method, white solid, yield 27%.
1H NMR(400MHz,dmso)δ10.17(s,1H),8.71-8.36(m,5H),8.36-8.08(m,5H),7.93- 7.70 (m, 3H), 7.70-7.46 (m, 5H), 7.46-7.22 (m, 7H), 7.20-7.05 (m, 0H), 6.92 (d, J=15.2Hz, 1H), 6.72 (t, J=16.0Hz, 2H), 5.70 (t, J=8.5Hz, 1H), 5.36-5.22 (m, 1H), 5.18-4.99 (m, 5H), 4.96-4.79(m,2H),4.45(m,2H),4.32(s,1H),4.11(m,5H),4.01-3.86(m,3H),3.73-3.53(m, 7H), 3.07 (d, J=17.3Hz, 1H), 2.29-2.09 (m, 4H), 1.98 (m, 4H), 1.86 (m, 2H), 1.76 (m, 3H), 1.74-1.51(m,13H),1.51-1.40(m,8H),1.31(m,3H),1.16(m,6H),1.05-0.87(m,7H),0.77 (m,12H).ESI-MS:m/z 1931.7[M+Na]+；C88H116F4N14O29:HRMS calcd.1931.7861[M+Na]+, found 1931.7872.。
Embodiment 2:(tetrafluoro) Docetaxel anti-liver cancer and anti-targeted prodrug is in vitro to HepG2 cell lines and SMMC- 7721 proliferation inhibition activity and toxicity to normal liver cell strain HL7702 and normal kidney cell line HEK293
Experimental method: cell in vitro measurement is carried out using mtt assay.Using Sorafenib and 10-hydroxycamptothecine as the positive Control is observed drug and is grown under various concentration to cell using Docetaxel and tetrafluoro Docetaxel as female medicine control Inhibition situation, calculate its half inhibiting rate (IC50Value) with evaluate its in vitro anti-liver tumour activity and to normal cell Toxicity.
HepG2 cell is cultivated in the DMEM culture medium containing 10% fetal calf serum with HEK293 cell, SMMC- 7721 are cultivated in 1640 culture mediums containing 10% fetal calf serum with HL-7702 cell.When cell is in division stage, Collected by trypsinisation cell, adjustment cell density to 5 × 10 is added4A/mL is inoculated with 100 μ L cell suspensions into 96 holes, every hole 5000 cells.96 orifice plates are placed in CO2It is cultivated in cell incubator, condition of culture: 37 DEG C of constant temperature, 5%CO2, humidity is big In 95%.After for 24 hours, microscopically observation confirms the adherent situation of cell, discards culture medium, be added 200 μ L contain various concentration by The culture medium of reagent object, concentration setting: for hepatoma cell line HepG2 and SMMC-7721, it is 5 that test drug concentrations, which are arranged, ×10-6、1×10-6、2×10-7、4×10-8、8×10-9、1.6×10-9、3.2×10-10mol/L.For normal liver cell HL- 7702 with normal nephrocyte setting test drug concentrations be 3.2 × 10-4、1.6×10-4、8×10-5、4×10-5、2×10-5、1 ×10-5、5×10-6mol/L.Not celliferous blank cultures are as blank control, the culture containing cell and 0.2%DMSO Base is as cell controls.3 multiple holes of every group of setting are as parallel control.96 orifice plates are placed in CO2It is trained in cell incubator It supports.After 72h, MTT the solution 20 μ L (5mg/mL), 37 DEG C of incubation 4h of Fresh is added in every hole.Liquid in hole is discarded, every hole adds Enter the DMSO of 150 μ L, shake 5min, OD value is measured with 490nm Detection wavelength.Each acute drug is to the inhibiting rate of cell according to such as Lower formula calculates:
Inhibiting rate=[1- (medicine group OD value-blank control group 0D value)/(cell controls group OD value-blank control group 0D Value)] × 100%
IC50 value is calculated using SPSS software.The above experiment calculates IC in triplicate50Value and standard deviation.
Experimental result shows that all prodrug compounds all have certain difference for tumour cell and normal tissue cell Selectivity.While retaining most of resisting liver cancer activity, the toxicity of normal cell is significantly reduced, it was demonstrated that prodrug design The feasibility of strategy: active female medicine is modified, while there is lethal effect to liver cancer cells, to the poison of normal cell Property is smaller, has reached the target of prodrug design.
Table 1 shows anti-liver cancer and anti-targeted prodrug In vitro cell experiment data.
Table 1

Claims (10)

1. the polyenoid taxane as shown in formula (1) targets anti-liver cancer and anti-prodrug
Wherein, R1For highly expressed matrix metalloproteinase MMPs specific recognition special in liver cancer tissue and the substrate polypeptide of hydrolysis Sequence；R2For methyl, trifluoromethyl；R3For hydrogen atom, fluorine atom.
2. polyenoid taxane as described in claim 1 targets anti-liver cancer and anti-prodrug, which is characterized in that the substrate polypeptide sequence is base Matter metalloproteinases MMP-2 or matrix metalloproteinase MMP-9 specific recognition and the substrate polypeptide sequence hydrolyzed.
3. polyenoid taxane as claimed in claim 2 targets anti-liver cancer and anti-prodrug, the matrix metalloproteinase MMP-2 specific recognition And the substrate polypeptide sequence hydrolyzed is Gly-Pro-Gln-Gly-Met-Ala-Gly-Gln, Gly-Pro-Gln-Gly-Ile- Ala-Ser-Gln、Gly-Pro-Gln-Gly-Ser-Ala-Gly-Gln、Gly-Pro-Gln-Gln-Ile-Ala-Gly-Gln、 Gly-Pro-Gln-Gly-Ile-Trp-Gly-Gln、Gly-Pro-Gln-Gly-Ile-Hyp-Gly-Gln。
4. polyenoid taxane as claimed in claim 2 targets anti-liver cancer and anti-prodrug, the matrix metalloproteinase MMP-9 specific recognition And substrate polypeptide sequence Gly-Pro-Gln-Phe-Ile-Ala-Gly-Gln, Ala-Ser-Gly-Pro-Ala-Gly- hydrolyzed Pro、Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln、Gly-Pro-Gln-Gly-Tyr-Ala-Gly-Gln、Gly-Asn- Gln-Gly-Ile-Ala-Gly-Gln。
5. matrix metalloproteinase MMP-2 specific recognition as claimed in claim 3 and the polyenoid taxane hydrolyzed targeting anti-liver cancer and anti- Prodrug, structure are as follows:
6. matrix metalloproteinase MMP-9 specific recognition as claimed in claim 4 and the polyenoid taxane hydrolyzed targeting anti-liver cancer and anti- Prodrug, structure are as follows:
7. the synthetic method of compound as described in claim any one of 1-6, which is characterized in that first in polyenoid taxanes chemical combination The position the C-2 ' hydroxyl of object introduces corresponding bridge joint group, synthesizes the derivative of polyenoid bearing taxanes；Then this is contained The derivative of bridge joint group is mixed with target polypeptide, is coupled under the action of condensing agent in 5 DEG C of stirrings, obtains the polyenoid Taxanes targeted prodrug.
8. polyenoid taxane targeting anti-liver cancer and anti-prodrug as claimed in any one of claims 1 to 6 is in preparation treatment liver-cancer medicine Purposes.
9. purposes as claimed in claim 8, special high expression matrix metalloproteinase MMP-2 in the liver cancer tissue.
10. purposes as claimed in claim 8, special high expression matrix metalloproteinase MMP-9 in the liver cancer tissue.
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