CN110577552A - Camptothecin-glycine-5, 6-didehydro norcantharidin conjugate and application thereof - Google Patents
Camptothecin-glycine-5, 6-didehydro norcantharidin conjugate and application thereof Download PDFInfo
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Abstract
The invention provides a camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I and a preparation method thereof, wherein R in the formula I is selected from C1-C6 alkyl, substituted alkyl, cycloalkyl, benzyl or substituted benzyl.
Description
Technical Field
The invention belongs to the field of new drug design and synthesis, and particularly relates to a novel camptothecin-glycine-5, 6-didehydro norcantharidin conjugate and an anti-tumor application thereof.
Background
Camptothecin (20- (S) -Camptothecin, abbreviated as CPT) was originally discovered by the american medicinal chemist Wani team in the early 60S of the 20 th century from the extract of the bark of camptotheca acuminata, a broadleaf tree, of the family of the chinese paulownia, which was earlier used in the traditional chinese medicine. Researchers such as vishnujjala and Garzon-Aburbeh have reported that camptothecin cannot be used as an in vivo anti-cancer agent due to high toxicity and low bioavailability. Many attempts have been made by medicinal chemists to obtain camptothecin derivatives with improved biological activity and enhanced stability. Most of these derivatives are directed to products of A, B or C-ring modifications in the chemical structure of camptothecin, however few of these modifications enhance the stability of the camptothecin lactone ring under physiological conditions. Recently, pharmacologists began to focus more on the esterification of the 20-hydroxy group, which itself is believed to increase the rate of hydrolysis of the lactone ring of CPT at neutral pH, by shifting the lactone-carboxylic acid equilibrium towards the carboxylic acid side; esterification of the 20-hydroxy group blocks this process, thereby increasing the stability and water solubility of the parent structure. In general, there may be several cancer genes or pathological pathways for a certain cancer; drug metabolism is still the cause of failure of most tumor therapies, and drug resistance is also a frequently encountered problem. In view of these circumstances, it is desirable to design dual target drugs to achieve optimal therapeutic effects. Camptothecin is a topoisomerase I inhibitor, norcantharidin has the unique characteristic of stimulating bone marrow to produce white blood cells, and in addition, norcantharidin plays a role in inhibiting the growth of cancer cells by inhibiting protein phosphatase. Since glycine molecules contain active NH and OH groups at the same time, glycine is selected as a connecting agent to connect camptothecin and norcantharidin, so that the anticancer double-target drug conjugate is constructed.
In order to find anticancer drug candidates with better drug effect and stronger toxicity, the invention designs camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I with a unique structure, which is formed by connecting 20-hydroxy of camptothecin and 5, 6-didehydro-norcantharidin through glycine, and designs a synthesis method to prepare the target derivative with high yield.
Disclosure of Invention
the invention provides a novel camptothecin-glycine-5, 6-didehydro norcantharidin conjugate; the structural formula is shown as a formula I, wherein R in the formula I is selected from C1-C6 alkyl, substituted alkyl, cycloalkyl, benzyl or substituted benzyl.
In a preferred embodiment, R of formula I is selected from C1-C4 alkyl, substituted alkyl, cycloalkyl or benzyl; more preferably, R of formula I is selected from methyl, ethyl, propyl, butyl, cyclopropyl or benzyl.
In another aspect, the invention provides a method for synthesizing camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I, which comprises the following steps: 1) camptothecin and N-Boc-glycine 1 are subjected to esterification reaction to obtain a compound 2; 2) removing Boc protective group from the compound 2 under the catalysis of trifluoroacetic acid to obtain a compound 3; 3) and 5, 6-didehydro norcantharidin monoester II are subjected to esterification reaction to obtain camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I, and the synthetic route is as follows:
Wherein R in the formula II and the formula I in the synthetic route is consistent and is selected from C1-C6 alkyl, substituted alkyl and cycloalkyl.
In a preferred embodiment, the coupling agent in step 1) is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (abbreviated as EDCI), dicyclohexylcarbodiimide (abbreviated as DCC) or N, N-diisopropylcarbodiimide (abbreviated as DIC); the organic base in step 1) is selected from triethylamine, diisopropylamine, 4-dimethylaminopyridine (abbreviated as DMAP), 1, 4-diazabicyclo [2.2.2] octane (abbreviated as DABCO), etc.; the solvent is selected from halogenated hydrocarbon solvents such as dichloromethane and chloroform.
In a preferred embodiment, the solvent used in step 2) is selected from dichloromethane or chloroform.
In a preferred embodiment, the coupling agent in step 3) is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (abbreviated as EDCI), dicyclohexylcarbodiimide (abbreviated as DCC) or N, N-diisopropylcarbodiimide (abbreviated as DIC); the organic base in step 1) is selected from triethylamine, diisopropylamine, 4-dimethylaminopyridine (abbreviated as DMAP), 1, 4-diazabicyclo [2.2.2] octane (abbreviated as DABCO), etc.; the solvent is selected from halogenated hydrocarbon solvents such as dichloromethane or chloroform.
In the above synthetic route, the reaction solvent may be selected from N, N-dimethylformamide (abbreviated as DMF), dimethylsulfoxide (abbreviated as DMSO), dichloromethane, chloroform, tetrahydrofuran or isopropyl ether, depending on the temperature and polarity of the solvent required for the reaction.
The reaction temperature may be appropriately selected depending on the type of the reaction.
The reaction time can be obtained by tracking the reaction condition through monitoring means such as thin layer chromatography TLC, high performance liquid chromatography HPLC or LC-MS liquid mass spectrum combination and the like.
The activity test proves that the camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I designed and synthesized by the invention has good anti-liver cancer effect. Therefore, in a third aspect, the invention provides the use of camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I for preparing an anti-tumor medicament; preferably, the application of the compound in preparing medicines for resisting liver cancer, gastric cancer, colon cancer and pancreatic cancer.
The invention has the advantages that: the invention provides a camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I, which integrates two active drug fragments of camptothecin and norcantharidin derivatives and is a novel double-target tumor inhibitor. The camptothecin-glycine-5, 6-didehydro norcantharidin conjugate has good anti-tumor effect, and especially has high activity on liver cancer, gastric cancer, colon cancer and pancreatic cancer. In addition, the method for preparing the camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I has the advantages of easily available raw materials, low cost and high yield of a target product of the synthetic reaction; is easy to prepare.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Without departing from the inventive concept, a person skilled in the art may make modifications or combinations of the parameters or conditions of the claims, which modifications or combinations shall also be considered as the protective scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims. The solvent and reagent used in the present invention are from Shanghai reagent company, national drug group. The reagents used are all chemically pure, unless otherwise specified.
Example 1 preparation of Compound II
According to the literature, furan reacts with maleic anhydride in tetrahydrofuran to obtain 5, 6-double dehydronorcantharidin 4, 2), and the compound 1 reacts with a corresponding ROH reagent to obtain 5, 6-double dehydronorcantharidin monoester II.
(1) Preparing 5, 6-didehydro norcantharidin 4
12.021g of maleic anhydride was put into a dry mortar, finely ground and dissolved in 90mL of diethyl ether, and 13mL of furan was slowly added dropwise. After the reaction solution was reacted at 38 ℃ for 1 hour, a white solid appeared in the solution, and the white solid increased as the reaction time increased. After 24 hours of reaction, suction filtration was carried out to obtain the objective compound 1(17.459g, 85.75%) as a white solid. Melting point of 122-123 ℃, specific displacement value Rf0.52 (the developing solvent is petroleum ether: ethyl acetate: 3: 1);1HNMR(400MHz,CDCl3):δ3.18(s,2H),5.47(s,2H),6.58(s,2H)。
(2) Preparing 5, 6-didehydro norcantharidin monoester II
5, 6-bis-dehydronorcantharidin monomethyl ester IIa (R ═ Me)Weighing 4.15g of 5, 6-didehydro norcantharidin 1 and dissolving in 25ml of anhydrous methanol to form a suspension. Then, 0.73ml (0.51g) of triethylamine was added dropwise to the suspension, stirred at room temperature for 24 hours, and the methanol was removed by rotary evaporation to obtain the objective crude product. The crude product obtained is dissolved in 25ml of dichloromethane and extracted once with 7ml of 1mol/L hydrochloric acid, leaving an organic phase, extracted once with 10ml of saturated brine, leaving an organic phase, and the appropriate amount of anhydrous MgSO is added4Drying for 15-30min, suction filtration, washing the filter cake with dichloromethane 2-3 times, leaving a filtrate, and rotary evaporation of the filtrate to give compound IIa (4.50g, 91%) as a white solid.1HNMR(400MHz,DMSO-d6):δ12.45(br,1H),6.41-6.45(m,2H),5.06(s,2H),3.64(s,3H),2.71(s,2H).13CNMR(100MHz,DMSO-d6):δ172.64,172.09,136.71,136.59,80.00,79.67,51.48,46.65,45.94。
5, 6-didehydro norcantharidin ethyl monoacate IIb (R ═ Et)Taking 14.16 g of 5, 6-bis-dehydronorcantharidin, adding 25ml of absolute ethyl alcohol and 0.73ml of triethylamine, stirring for 24 hours at 25 ℃, removing the ethanol by rotary evaporation, dissolving the obtained residue in 25ml of dichloromethane, extracting with 1equ.7ml of hydrochloric acid to leave an organic phase, extracting with 10ml of saturated saline solution to leave the organic phase, adding a proper amount of anhydrous magnesium sulfate, drying for 15-30 minutes, carrying out suction filtration, carrying out rotary evaporation on the filtrate, and drying to obtain 3.95g (74.3%) of the target compound IIb which is a white solid.1HNMR(400MHz,DMSO):δ:6.47(d,J=8Hz,1H),6.44(d,J=8Hz,1H),5.28(d,J=28Hz,2H),4.15(t,J=4Hz,2H),2.86(d,J=8Hz,1H),2.82(d,J=8Hz,1H),1.25(t,J=4Hz,3H).13CNMR(100MHz,DMSO):δ:177.42,171.42,136.85,136.30,80.61,80.32,61.40,47.27,46.77,13.99。
5, 6-bis-dehydronorcantharidin monobasic acid benzyl ester IIc (R ═ Bn)Taking 15.00 g of 5, 6-didehydro norcantharidin into a flask, adding 40ml of dichloromethane, 4.7ml of benzyl alcohol and 0.367g of 4-dimethylaminopyridine into the flask, stirring the mixture for three days at 25 ℃, performing suction filtration, collecting a white solid on a filter cake, and drying the white solid to obtain 4.067g (50%) of a compound IIc as a white solid.1HNMR(DMSO):δ:7.32-7.35(m,5H),6.44(d,J=36Hz,2H),4.95-5.10(m,4H),2.76(t,J=8Hz,2H).13CNMR(100MHz,DMSO):δ:173.07,171.93,137.15,136.97,128.79,128.40,80.49,80.16,66.31,47.14,46.41,40.57,40.36,39.52,39.31.
Example 2 preparation of camptothecin-Glycine-5, 6-didehydro norcantharidin conjugate I
The camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I can be prepared by the following steps: 1) camptothecin and N-Boc-glycine 1 are subjected to esterification reaction to obtain a compound 2; 2) removing the Boc protective group from the compound 2 under the catalysis of trifluoroacetic acid to obtain a compound 3; 3) and carrying out esterification reaction with 5, 6-didehydro norcantharidin monoester II to obtain camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I.
Preparation of Compound 2(BOC-Gly-CPT)
CPT (160mg, 0.46mmol), N-Boc-glycine (1, 160mg, 0.92mmol, 2equ.) and DMAP (0.053g, 0.45mmol, 1.0equ.) were dissolved in CH2Cl2(20 mL). The reaction mixture was cooled to 0 ℃. DIC (0.52mL, 3.35mmol, 1.3equ.) was added dropwise to the reaction mixture. The reaction was kept in an ice bath and stirred continuously for 1h, then at room temperature to avoid side reactions. By TLC (CH)2Cl2:CH3OH ═ 20: 1) the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with water, the organic phase was separated and MgSO4And (5) drying. The solvent was removed under reduced pressure and passed through MeOH/CHCl3The crude product was purified by flash column chromatography with 1/9 as eluent to give the title compound 2BOC-Gly-CPT (200mg, 86.2%) as a yellow solid. Rf=0.68(CH2Cl2:CH3OH=20:1).1H NMR(400MHz,CDCl3)δ=8.33(s,1H),8.18(d,J=4Hz,1H),7.59-7.77(m,3H),7.24(d,J=8Hz,1H),5.63(d,J=8Hz 1H),5.34(d,J=8Hz,2H),5.21(s,2H),4.30(s,3H),4.14(d,J=4Hz,1H),4.01(d,J=8Hz,1H),3.77-3.82(m,3H),2.08-2.25(m,5H),0.94(t,J=8Hz,3H).13C NMR(100MHz,CDCl3)δ=169.54,167.23,167.03,157.30,157.09,155.58,152.15,148.77,146.35,145.57,131.18,130.64,129.63,128.36,128.12,128.03,119.91,96.31,80.17,67.04,49.96,42.37,42.00,31.66,38.33,23.48,7.56.
Preparation of Compound 3(Gly-CPT)
Preparation of Compound 2(150mg, 0.30mmol) from the above procedure in CH 50% TFA2Cl2(20mL) and stirring under reflux for 24h continuously to remove Boc group on amino acid. After removal of the solvent, cold anhydrous ether (20mL) was added and a pale yellow solid precipitated. The precipitate was collected by filtration and washed twice with cold diethyl ether (20 mL. times.3). The crude product is substituted by CH2Cl2Diluted and saturated NaHCO3And (6) washing. The organic phase is MgSO4And (5) drying. After removal of the solvent, by using CH2Cl2:CH3The residue was purified by flash column chromatography with OH 80:1 as eluent to give the title product 3(64mg, 53.4%) as a light yellow solid. Rf=0.32(CH2Cl2:CH3OH=20:1).1H NMR(400MHz,DMSO-d6)δ=8.63(s,1H),8.05-8.15(m,2H),7.87(t,J=8Hz,2H),7.71(t,J=8Hz,2H),7.43(s,1H),5.47-5.66(m,2H),5.32(s,2H),4.12-4.28(m,2H),2.20-2.32(m,2H),1.08(t,J=8Hz,3H).13C NMR(100MHz,DMSO-d6)δ=169.56,167.21,157.28,155.60,152.14,148.72,146.32,145.57,131.15,130.60,129.62,128.37,128.10,127.98,119.93,96.31,67.02,49.95,42.38,31.66,25.82,7.56.
Preparation of camptothecin-glycine-5, 6-bis-dehydronorcantharidin conjugate Ia (R ═ Me)
Compound 3(100mg, 0.25mmol), compound IIa (107mg, 0.54mmol), EDCI (124.0mg, 1.29mmol) and DMAP (27.40mg, 0.17mmol) were suspended in CH2Cl2(15ml), the resulting reaction mixture was stirred at room temperature for 48 hours. Adding CH2Cl2(40ml) to dilute the reaction mixture, then with H2O (20 mL. times.3) washed the mixture, separated, and the organic layer was MgSO4And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using CH2Cl2:CH3OH 97: 3) to afford the title compound Ia (102mg, 69%) as a pale yellow solid.1H NMR(400MHz,DMSO-d6)δ=8.67(s,1H),8.18(d,J=8Hz,1H),8.11(d,J=8Hz,1H),7.88(t,J=8Hz,1H),7.71(t,J=8Hz,1H),7.09(s,1H),6.62(d,J=4Hz,1H),6.56(d,J=4Hz,1H),5.52(s,1H),5.46(s,2H),5.23(d,J=8Hz,1H),5.16(d,J=8Hz,1H),4.55(d,J=16Hz,1H),4.22(d,J=16Hz,1H),3.06(s,3H),2.11(s,2H),1.17-1.21(m,1H),0.86(t,J=4Hz,3H).13C NMR(100MHz,DMSO-d6)δ=176.09,175.75,167.06,166.22,156.82,152.73,146.46,144.79,137.14,136.99,131.97,128.95,128.48,128.16,119.44,95.44,95.00,80.92,77.33,76.98,66.90,50.46,47.94,47.59,41.16,39.31,30.96,23.80,23.63,7.76.IR(KBr)ν(cm-1)=3421,2921,2851,1754,1720,1666,1620,1428,1384,1130,801.
Preparation of camptothecin-glycine-5, 6-didehydro norcantharidin conjugate Ib (R ═ Et)
(20S) -camptothecin aminoacetate (120mg,0.30mmol) and compound IIb (130mg,0.61mmol) were placed in a 100mL round-bottomed flask, 15mL of dichloromethane was added, the reaction was stirred in ice bath, then EDCI (0.15g,0.74mmol) and DMAP (0.037g,0.31mmol) were added dropwise, reacted in ice bath for 2h, room temperature for 56 h. Extracting with water, adding anhydrous magnesium sulfate into organic phase, drying, rotary drying under reduced pressure, and separating by flash column chromatography (eluent is CH)2Cl2:CH3OH 50:1) to give target compound Ib (151mg, 84.0%) as a yellow solid. m.p.151-152 deg.C, Rf0.63 (developing solvent CH)2Cl2:CH3OH 20:1, observed at 254nm uv).1H NMR(400MHz,DMSO-d6)δ=8.58(d,J=8Hz,1H),8.00-8.24(m,3H),7.77-7.83(m,1H),7.61-7.66(m,1H),7.12(d,J=4Hz,1H),6.38(d,J=4Hz,2H),5.48(s,2H),5.06-5.18(m,3H),4.86(d,J=12Hz,1H),4.18-4.28(m,1H),4.04(t,J=16Hz,1H),3.91-3.99(m,1H),3.75-3.89(m,1H),2.68-2.71(m,1H),2.57-2.60(m,1H),2.16(d,J=4Hz,2H),0.85-1.05(m,6H).13C NMR(100MHz,DMSO-d6)δ=171.66,171.61,171.42,171.36,169.54,167.51,167.48,156.87,156.83,152.58,152.55,148.23,148.17,146.33,146.29,145.53,145.49,137.16,137.10,136.94,136.88,132.05,131.97,130.83,130.77,129.97,129.21,128.86,128.29,128.27,128.06,128.00,119.34,95.63,81.31,81.26,79.28,76.72,66.73,60.41,60.22,50.50,47.09,47.03,46.34,46.26,30.85,30.80,23.73,14.33,14.10,8.01.IR(KBr)ν(cm-1)=3433,3133,1751,1662,1617,1401,1234,1107,1052,763,592.
Preparation of camptothecin-glycine-5, 6-didehydro norcantharidin conjugate Ic (R ═ Bn)
In a 100mL round bottom flask, (20S) -camptothecin aminoacetate (110mg,0.27mmol), compound IIc (150mg,0.52mmol), DMAP (0.028g,0.22mmol), and dichloromethane (15mL) were added sequentially; the reaction was stirred in an ice bath for 2h and then at room temperature for 36 h. Extracting with water, adding anhydrous magnesium sulfate to the organic phase, drying, and reducingpressure spin-drying, and fast column separation (eluent CH)2Cl2:CH3OH 50:1) to give the title compound Ic (152mg, 83.2%) as a yellow solid. m.p.236-237 deg.C, Rf0.63 (developing solvent CH)2Cl2:CH3OH 20:1, color development observed under uv 254 nm).1H NMR(400MHz,DMSO-d6)δ=8.66(s,1H),8.09-8.19(m,2H),7.88(t,J=8Hz,1H),7.71(t,J=8Hz,1H),7.31(d,J=8Hz,5H),7.09(s,1H),6.59(d,J=16Hz,2H),5.49(d,J=12Hz,3H),5.21(d,J=16Hz,3H),4.55(d,J=12Hz,1H),4.22(d,J=12Hz,2H),3.06(s,2H),2.11(s,2H),1.05-1.12(m,2H),0.86(t,J=8Hz,3H).13C NMR(100MHz,DMSO-d6)δ=176.08,175.74,167.00,166.21,156.84,152.77,148.32,146.49,144.78,137.14,136.99,131.99,130.92,130.21,129.39,128.98,128.84,128.74,128.61,128.47,128.41,128.34,128.17,127.05,126.84,119.57,95.45,80.92,77.04,66.91,63.32,50.66,47.83,47.67,30.97,7.82.IR(KBr)ν(cm-1)=3474,3414,3138,1753,1713,1618,1400,1153,1085,997,697,618,477.
Example 3 solubility test
The compound Ia obtained by the synthesis and the parent compound camptothecin CPT were selected, dissolved in chloroform at 25 ℃ and the solubility results are shown in Table 1.
TABLE 1 solubility of Compounds Ia and CPT in chloroform at 25 ℃
Compound Ia has many times the solubility of CPT in chloroform. As we expected, the solubility of the synthesis product I in organic solvents was much better than that of CPT.
example 4 bioactivity test experiment
Cell line and solvent
Tumor cell lines:
Human liver cancer cell HEPG2, human stomach cancer cell BGC803, human colon cancer cell SW480, human pancreatic cancer cell PANC-1
Cell culture in RPMI1640 containing 10% fetal bovine serum
Solvent: dimethylsulfoxide (abbreviated as DMSO).
embodiment for detecting cell anti-tumor activity by MTT method
In the test, cantharidin is taken as a positive control, DMSO solvent is taken as a blank control, and the inhibitory activity test of camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate with the concentration of 50 mu mol/mL on four tumor cells, namely liver cancer cell HEPG2, human gastric cancer cell BGC803, colon cancer cell SW480 and pancreatic cancer PANC-1, is carried out. The inhibition using camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I was evaluated after 48 or 72h of drug treatment using a standard MTT assay.
TABLE 3 inhibitory Activity of camptothecin-Glycine-5, 6-didehydro norcantharidin conjugate I on four tumor cells
atest solvent is DMSO.
Camptothecin, glycine and functionalized norcantharidin are constructed into conjugates through two coupling reactions, and a series of novel camptothecin-glycine-5, 6-didehydro norcantharidin conjugates I are obtained with better yield. The synthesized conjugate I is tested to have strong inhibitory activity on cancer cells in vitro, in particular to four cancer cell lines of human liver cancer cell HEPG2, gastric cancer cell BGC803, colon cancer cell SW480 and pancreatic cancer PANC-1; can be used for preparing corresponding anti-tumor candidate drugs.
Claims (9)
1. Camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I:
Wherein R in the formula I is selected from C1-C6 alkyl, substituted alkyl, cycloalkyl, benzyl or substituted benzyl.
2. The camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to claim 1, wherein R in formula I is selected from C1-C4 alkyl, cycloalkyl or benzyl.
3. The camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to claim 2, wherein R of formula I is selected from methyl, ethyl, propyl, butyl, cyclopropyl or benzyl.
4. The method for synthesizing camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to any one of claims 1 to 3, comprising the following steps:
1) Camptothecin and N-Boc-glycine 1 are subjected to esterification reaction to obtain a compound 2; 2) removing Boc protective group from the compound 2 under the catalysis of trifluoroacetic acid to obtain a compound 3; 3) and 5, 6-didehydro norcantharidin monoester II are subjected to esterification reaction to obtain camptothecin-glycine-5, 6-didehydro norcantharidin conjugate I, and the synthetic route is as follows:
R is selected from C1-C6alkyl, substituted alkyl, cycloalkyl, benzyl, substituted benzyl of
Wherein R in the formula II and the formula I in the synthetic route is consistent and is selected from C1-C6 alkyl, substituted alkyl and cycloalkyl.
5. The method for synthesizing camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to claim 4, wherein the coupling agent in step 1) is selected from EDCI, DCC or DIC; the organic base in the step 1) is selected from triethylamine, diisopropylamine, DMAP or DABCO; the solvent is selected from dichloromethane or chloroform.
6. The method for synthesizing camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to claim 4, wherein the solvent used in step 2) is selected from dichloromethane or chloroform.
7. The method for synthesizing camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to claim 4, wherein the coupling agent in step 3) is selected from EDCI, DCC or DIC; the organic base in the step 1) is selected from triethylamine, diisopropylamine, DMAP or DABCO; the solvent is selected from dichloromethane or chloroform.
8. The use of camptothecin-glycine-5, 6-didehydro-norcantharidin conjugate I according to any of claims 1 to 3 for the preparation of an antitumor medicament.
9. The use according to claim 7, wherein the tumor is selected from liver cancer, stomach cancer, colon cancer or pancreatic cancer.
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