CN105218628A - The β-carboline that tryptophan benzyl ester is modified, its synthesis, nanostructure, active and application - Google Patents
The β-carboline that tryptophan benzyl ester is modified, its synthesis, nanostructure, active and application Download PDFInfo
- Publication number
- CN105218628A CN105218628A CN201410260135.1A CN201410260135A CN105218628A CN 105218628 A CN105218628 A CN 105218628A CN 201410260135 A CN201410260135 A CN 201410260135A CN 105218628 A CN105218628 A CN 105218628A
- Authority
- CN
- China
- Prior art keywords
- carboline
- hydroxyl
- benzyl ester
- methoxycarbonyl phenyl
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the β-carboline that the tryptophan benzyl ester shown in following formula is modified, i.e. 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester, disclose its preparation method, disclose its nanostructure, disclose its antitumor action, disclose the effect of its reversing tumor cells resistance.Thus the present invention it preparing antitumor drug and preparing application in reversing tumor medicine-resistant medicine.
Description
Technical field
The present invention relates to the β-carboline that tryptophan benzyl ester is modified, i.e. 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester, relate to its preparation method, relate to its nanostructure, relate to its antitumor action, relate to the effect of its reversing tumor cells resistance.Thus the present invention relates to it preparing antitumor drug and preparing the application in reversing tumor medicine-resistant medicine.The invention belongs to biomedicine field.
Technical background
The health of the malignant tumour serious threat mankind.In clinical cancer therapy, chemotherapy still occupies most important status., tumor multi-medicine drug-resistant and crossing drug resistant make the antitumor drug paying huge work invention lose curative effect very soon.So it is the forward position that antitumor drug is studied with medicine that is reversing tumor resistance that invention has antitumor always.
In antitumor drug research, applicant, once with the β-carboline-3-carboxylic acid that amino-acid benzyl ester modifies tetrahydro-beta-carboline-3-carboxylic acid, β-carboline-3-carboxylic acid and 1-position replace, comprises tetrahydro-beta-carboline-3-carboxylic acid that 1-position replaces or the β-carboline-3-carboxylic acid that 1-position replaces prepares efficient antineoplastic compound.Wherein 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl Nitro-Arginine benzyl ester shows clear and definite antitumor action under 1 μm of ol/kg dosage.Contriver believes, the guanidine radicals of arginine benzyl ester can be affected activity by nitro protection.Under the guiding of this thinking, contriver expects, replaces Nitro-Arginine benzyl ester with other amino-acid benzyl ester, such as, replace Nitro-Arginine benzyl ester with tryptophan benzyl ester, can obtain beyond thought effect.
Summary of the invention
First content of the present invention is to provide 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester of following formula.
Second content of the present invention is to provide the preparation method of 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester, and the method comprises:
(1) under the vitriol oil exists, 5-formylsalicylic acid is 90 DEG C, microwave reaction 2h in methyl alcohol, generates 5-formylsalicylic acid methyl esters;
(2) under the existence of polyphosphoric acid, L-Trp and phenylcarbinol reaction, generate L-Trp benzyl ester;
(3) under trifluoracetic acid exists, in methylene dichloride, 5-formylsalicylic acid methyl esters and the ester condensation of L-Trp benzyl are 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylates;
(4) 2,3-bis-chloro-5,6-dinitrile-1, under the existence of 4-benzoquinones (DDQ), 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate is oxidized to 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-benzyl carboxylate in tetrahydrofuran (THF);
(5) at Pd/C and H
2under existence, in methyl alcohol, the reaction of 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-benzyl carboxylate generates 1-(4-hydroxyl-3-methoxycarbonyl)-β-carboline-3-carboxylic acid;
(6) under DCC and HOBt exists, 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-carboxylic acid is 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester with the ester condensation of L-Trp benzyl in anhydrous methylene chloride.
3rd content of the present invention is the nanostructure measuring 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester.
4th content of the present invention evaluates antitumor tumor activity and the antitumor resistance activity of 1-(4-hydroxyl-3-methoxycarbonyl)-β-carboline-3-formyl tryptophan benzyl ester.
Accompanying drawing explanation
Fig. 1. replace the Nitro-Arginine benzyl ester in 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl Nitro-Arginine benzyl ester with tryptophan benzyl ester, obtain compound of the present invention.
The synthetic route .i of Fig. 2 .1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester) trifluoracetic acid, 5-formylsalicylic acid methyl esters, L-Trp benzyl ester; Ii) DDQ; Iii) Pd/C, H
2; Iv) DCC, HOBt, Trp-OBzl.
The transmission electron microscope photo of Fig. 3 .1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester.
Embodiment
In order to set forth the present invention further, provide some row embodiments below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares 5-formylsalicylic acid methyl esters
6.64g (40.0mmol) 5-formylsalicylic acid is placed in microwave reactor, after adding 30mL methyl alcohol, slowly adds the dense H of 1mL
2sO
4setting microwave reactor temperature of reaction 95 DEG C, reaction times is 2h, termination reaction after 2h, after temperature is down to room temperature, reaction solution is transferred in 250mL eggplant-shape bottle, with strong aqua adjust pH to 7 under ice bath stirs, reaction solution uses saturated NaHCO after adding a large amount of acetic acid ethyl dissolution after being evaporated to and doing successively
3the aqueous solution and the saturated NaCl aqueous solution wash three times, and ethyl acetate layer is through anhydrous Na
2sO
4dry 3h, filters, and filtrate reduced in volume is to dry, and left at room temperature over night, obtains 6.43g (88.9%) faint yellow needle-like crystal.ESI-MS(m/e)：181[M+H]
+。
Embodiment 2 prepares Trp-OBzl
Get 5.0g (14.8mmol) polyphosphoric acid in 250mL eggplant shaped reaction bottle, add 150mL phenylcarbinol, 3.35g (16.7mmol) L-Trp is added after this mixture is stirred to dissolving in the oil bath of 60 DEG C, prolong reaction 60h, TLC (methylene dichloride: methyl alcohol=5: 1) show raw material point and disappear is installed.Termination reaction, after question response liquid temp is down to room temperature, pours 250mL anhydrous diethyl ether under ice bath stirs in reaction flask, and stir after spending the night and filter with Bu Shi, filter cake anhydrous diethyl ether is washed repeatedly, removing phenylcarbinol.The colorless solid 200mL ethyl acetate obtained suspends, and solution ph to 8 adjusted by triethylamine, and the settled solution obtained uses saturated NaHCO successively
3the aqueous solution and the saturated NaCl aqueous solution wash three times, and ethyl acetate layer is through anhydrous Na
2sO
4after drying, filter, filtrate reduced in volume is to dry, and obtaining 4.26g (86.5%) title compound, is colorless solid.ESI-MS(m/e)：295[M+H]
+。
Embodiment 3 prepares 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylates (1)
15mL anhydrous tetrahydro furan has slowly been joined 150mLCH
2cl
2250mL eggplant shaped reaction bottle in, add 2.7g (15.0mmol) 5-formylsalicylic acid methyl esters and 4.85g (16.5mmol) Trp-OBzl after stirring respectively, reaction solution become safran.After room temperature reaction 96h, under the condition of ice bath, slowly drip saturated NaHCO
3about adjust ph to 8, reaction solution is used saturated NaHCO successively
3, saturated NaCl extracts respectively and washes three times, CH
2cl
2layer anhydrous Na
2sO
4after drying, filter, filtrate reduced in volume is to dry, and obtaining 5.5g (81.5%) title compound, is yellow solid.ESI-MS(m/e)：457[M+H]
+。
Embodiment 4 prepares 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-benzyl carboxylate (2)
Take 6.86g (15.0mmol) 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylates and be placed in 250mL eggplant-shape bottle, dissolve with tetrahydrofuran (THF), ice bath stirs.Take 6.81g (30.0mmol) DDQ in 100mL beaker, slowly add in reaction flask after dissolving with tetrahydrofuran (THF), after several minutes, in reaction solution, have insolubles to separate out.React completely after 8h, reacting liquid filtering, the solid the obtained methylene dichloride of 10/1 and the mixing solutions foam washing of methyl alcohol, filter, obtaining 5.43g (82.7%) target compound, is pale solid.ESI-MS(m/e)：453[M+H]
+；Mp：189-191℃.
1HNMR(300MHz，DMSO-d
6)：δ/ppm＝8.87(s，1H)，8.42(m，2H)，8.10(dd，J＝2.1Hz，J＝2.1Hz，1H)，7.69(d，J＝8.1Hz，1H)，7.57(m，3H)，7.37(m，3H)，7.04(d，J＝6.3Hz，1H)，5.46(s，1H)，3.88(s，3H).
13CNMR(75MHz，DMSO-d
6)：δ/ppm＝169.28，165.93，142.35，137.07，135.13，131.75，129.30，128.98，128.47，128.41，122.40，121.73，120.62，116.54，114.71，66.39，52.47。
Embodiment 5 prepares 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-carboxylic acid (3)
Take 2.27g (5.0mmol) 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-benzyl carboxylate 100mL methanol suspension, add 250mgPd/C, the air in reaction flask got rid of by water pump, then pass into hydrogen, room temperature reaction 36h, after reacting completely, reacting liquid filtering, considering liquid is evaporated to dry, and obtaining 1.18g (63.1%) target compound, is yellow solid.ESI-MS(m/e)：361[M-H]
-；Mp：226-227℃。
Embodiment 6 prepares 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester (4)
0.72g (2.0mmol) 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-carboxylic acid is suspended in 1mL dry DMF, 40mL anhydrous methylene chloride is added in reaction flask, add 0.27g (2.0mmol) I-hydroxybenzotriazole (HOBt), ice bath stirs, add 0.45g (2.8mmol) dicyclohexylcarbodiimide (DCC), stir 30 minutes, obtain reaction solution.0.76g (2.2mmol) HClL-Trp-OBzl is suspended in 20mL anhydrous methylene chloride, adjusts pH8 with N-methylmorpholine (NMM), then added in the reaction solution just obtained, regulate pH8 with NMM.Stirring at room temperature 15h, TLC (methylene dichloride: methyl alcohol=150: 1) show reaction and complete, be concentrated into by reaction solution dry, add 50mL ethyl acetate, filtering dicyclohexylurea (DCU) (DCU) precipitates, and filtrate uses saturated NaHCO successively
3the aqueous solution (20mL × 3), the saturated NaCl aqueous solution (20mL × 3), 5%KHSO
4the aqueous solution (20mL × 3), the saturated NaCl aqueous solution (20mL × 3), 5%NaHCO
3the aqueous solution (20mL × 3), the saturated NaCl aqueous solution (20mL × 3) extraction is washed.Ethyl acetate layer anhydrous Na
2sO
4dry, filter, filtrate reduced in volume is to dry, the yellow solid obtained is through reduced pressure chromatography purifying (gradient elution, methylene dichloride: methyl alcohol=200: 1-100: 1), obtaining 0.59g (46.5%) 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester, is colorless solid.ESI
+-MS(m/e)：639[M+H]
+；Mp：165.1-165.7℃；
IR(KBr)：3402.43，3383.14，3234.62，3059.10，2931.80，1751.36，1726.28，1672.85，1656.85，1624.06，1525.69，1492.90，1456.26，1442.75，1354.03，1340.53，1267.23，1232.51，1170.79，1087.85，1010.70，974.05，900.76，835.18，740.67，699.23，605.65，
1H-NMR(300MHz，DMSO-d
6)δ/ppm＝11.91(s，1H)，10.93(s，1H)，10.89(s，1H)，8.79(s，1H)，8.72(d，J＝6Hz，1H)，8.44(m，2H)，8.06(m，1H)，7.67(d，J＝6Hz，1H)，7.60(t，J＝5Hz，1H)，7.56(d，J＝9Hz，1H)，7.21-7.42(m，9H)，7.05(t，J＝6Hz，1H)，6.90(m，J＝6Hz，1H)，5.16(m，2H)，4.95(m，1H)，3.90(s，3H)，3.45(m，2H)。
The cytotoxicity of experimental example 1 assessing compound 4
1. the substratum of compound 4 of the present invention containing 0.1%DMSO is mixed with desired concn.
2. tumour cell is HepG2 (human liver cancer cell), HT-29 (human colon cancer cell), HL60 (human promyelocytic leukemia), S180 (murine sarcoma cells), HeLa (human cervical carcinoma cell), A549 (people lung cancer Fine born of the same parents), MCF-7 (human breast carcinoma Fine born of the same parents) and SH-sy5y (people's neuroblast cancer cells).
3. experimental technique
Tumour cell HL60, HT-29, A549, S180 and MCF-7 select RPMI-1640 substratum; HeLa, HepG2 and SH-sy5y select DMEM to cultivate.Wherein containing 10% through the foetal calf serum and 1 × 10 of deactivation
5u/L penicillin and 100mg/L Streptomycin sulphate.
The cultivation of attached cell
Growth conditions is good, and be in the HepG2 of logarithmic phase, HT-29, HeLa, A549, SH-sy5y and MCF-7 cell is with 3 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L, 37 DEG C, 5%CO
2hatch 4 hours in incubator, by the concentration gradient preset add to be measured, through the sample of sterilising treatment, the solution that every hole 25 μ L compound 4 is mixed with the substratum containing 0.1%DMSO, control group adds the solvent of isopyknic sample dissolution.After continuing to hatch 48 hours, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, and be placed in 37 DEG C and cultivate 4 hours, carefully remove supernatant liquor, every hole adds the DMSO (dimethyl sulfoxide (DMSO)) of 100 μ L, and oscillator plate vibrates about 15min dissolution precipitation.O.D. (absorbancy) value is detected immediately, wavelength 570nm in microplate reader.
The cultivation of suspension cell
Respectively that growth conditions is good, be in HL-60 and the S180 cell of logarithmic phase with 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L, by the concentration gradient preset add to be measured, through the sample of sterilising treatment, the solution that every hole 25 μ L compound 4 is mixed with the substratum containing 0.1%DMSO, control group adds the solvent of isopyknic sample dissolution.Continue cultivation after 48 hours, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, continue to be placed in 37 DEG C and hatch 4 hours, the centrifugal 10min of 3000rpm, careful absorption supernatant liquor, every hole adds the DMSO of 100 μ L, and about 15min that oscillator plate vibrates precipitates and all dissolves, O.D. (absorption value) is measured immediately, wavelength 570nm in microplate reader.
The inhibiting rate of the sample under each sample concentration to tumour cell is obtained with following formula:
Growth inhibition ratio=[(control group average O.D. value-sample sets average O.D. value) the average O.D. value of/control group] × 100%, experiment repetition 3 times, maps to drug level with inhibiting rate, obtains IC by graphing method
50(half effective inhibition concentration) value.
4. experimental result is in table 1 and table 2.Result shows, compound 4a-p of the present invention does not have showed cell toxic action to tumour cell.
4. experimental result is in table 1.Result shows, compound of the present invention 4 pairs of tumour cells do not have showed cell toxic action.
Cytotoxic activity (the IC of table 1 compound 4 pairs of tumour cells
50± SD μM)
The activity of experimental example 3 assessing compound 4a-p Tumor suppression growth
Compound 4a-p of the present invention
Positive control is Zorubicin
Laboratory animal: ICR mouse (cleaning grade), male, body weight 20 ± 2g, is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.;
Animal is divided into blank group, positive controls, compound 4a-p group, often organizes 15;
Knurl liquid is originated: S180 fibrosarcoma mouse is purchased from Department Of Medicine, Peking University's animal experimental center, maintenance of going down to posterity voluntarily;
Solvent is physiological saline tween 80.
2. experimental technique
Dosage is arranged and administering mode
Compound 4a-4p carries out administration by the dosage of 10nmol/kg in the mode of abdominal injection, each administration 0.2ml, administration every day 1 time, successive administration 7 days.
Negative control physiological saline group gives the physiological saline of 0.2ml at every turn, every day 1 time, continuous 7 days.
Positive control Zorubicin group presses 2 μm of ol/kg dosage with the administration of abdominal injection mode, each administration 0.2mL, administration every day 1 time, successive administration 7 days.
Animal model aseptically, by the S180 ascitic tumor sacrifice gone down to posterity voluntarily, takes out inoculation and grows vigorous S180 ascitic tumor knurl liquid after 8 days, add suitable physiological saline, fully mix, the centrifugal 3min of 1000rpm, after removing cell debris.Dye to tumor cell suspension with 0.2% trypan blue prepared in advance, adopt white blood cell count(WBC) method counting, what dye was blue is dead cell, and achromophil is viable cell, the survival rate of swell by following formulae discovery knurl thin born of the same parents Alto concentration and cell.
Viable count/4 × 10 in the block plaid of cell concn=4
4× extension rate=cell count/mL;
Cell survival rate=viable count/(viable count+dead cell number) × 100%;
The ascitic tumor knurl liquid homogenate method of survival rate more than 90% is prepared into 1.5 × 10
7the cell suspension of individual/mL, is inoculated in healthy mice armpit subcutaneous, and every 0.2mL makes solid tumor animal model.
3. Testing index and method
Measure the knurl weight of S180 mouse and the suppression of tumor growth
S180 mouse successive administration, after 7 days, the 8th day, weighs Mouse Weight, etherization, and disconnected neck is put to death, and cuts off the skin of the right armpit tumor location of mouse, exposes tumour, blunt separation tumour, after weighing, by following formulae discovery tumour inhibiting rate:
The average knurl of tumour inhibiting rate %=(negative control group average knurl weight-compound 4a-p group average knurl weight)/negative control group heavy × 100%
Experimental result is in table 2.Result shows, compound 4b-f when dosage is 10nmol/kg, and the activity of h-k, p suppression S180 tumor-bearing mice tumor growth and dosage are that the Zorubicin of 2 μm of ol/kg is suitable.The effective dose of compound 4a-p once used effective dose 1 μm of ol/kg of disclosed 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl Nitro-Arginine benzyl ester to reduce 100 times than applicant.In addition, because compound 4a-p is to tumour cell not showed cell toxic action, so they suppress the outstanding activity of S180 tumor-bearing mice tumor growth and cell toxicant to have nothing to do.
4. experimental result is in table 2.Result shows, when dosage is 10nmol/kg, compound 4 treats the tumor weight of mouse significantly lower than the tumor weight of saline-treated mice, illustrates that 10nmol/kg is the effective dose of compound 4.Suppress the activity of S180 tumor-bearing mice tumor growth and dosage to be that the Zorubicin of 2 μm of ol/kg is suitable at this dosages for Compound 4, illustrate that its effective dose is than 200 times, Zorubicin ground.In addition, this effective dose of compound 4 once used effective dose 1 μm of ol/kg of disclosed 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl Nitro-Arginine benzyl ester to reduce 100 times than applicant.Because compound 4 pairs of tumour cells not showed cell toxic action, so it suppresses the outstanding activity of S180 tumor-bearing mice tumor growth and cell toxicant to have nothing to do.
Table 2 compound 4 is on the impact of S180 tumor weight
| Compound | Knurl heavy (mean value ± SD g) | Tumour inhibiting rate % |
| Physiological saline | 2.123±0.418 | - |
| Zorubicin | 0.823±0.238 | 61.16％ |
| Compound 4 | 1.104±0.303 a | 47.94％ |
N=12; A) with physiological saline group than p < 0.01, compare p > 0.05 with ADM group.
The activity of experimental example 3 assessing compound 4 reversing drug resistance
The substratum of 1 compound 4 of the present invention containing 0.1%DMSO is mixed with the solution that concentration is 2 μMs.
2 tumour cells are MCF-7/Dox (human breast cancer cell of Adriamycin resistant).
3 experimental techniques
To logarithmic phase, MCF-7/Dox cell in good condition (reagent removal cultivates 3 days) be in 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ l, 37 DEG C, 5%CO
2cultivate 8 hours in incubator, the concentration added through the compound of the present invention 4 of sterilising treatment is the solution of 2 μMs, and negative control group adds the solvent of isopyknic sample dissolution.Cultivate after 2 hours and add Doxorubicin solution 25 μ l by the concentration gradient preset, the blank group of solvent adding isopyknic sample dissolution.Continue cultivation after 48 hours, every hole adds the MTT solution that 25 μ l concentration are 5mg/mL, is placed in 37 DEG C and hatches 4 hours, carefully remove supernatant liquor, and every hole adds 100 μ L dimethyl sulfoxide (DMSO) (DMSO), and vibrate about 10min dissolution precipitation.O.D. (absorbancy) value is detected, wavelength 570nm in microplate reader.
The inhibiting rate of the sample under each sample concentration to tumour cell is obtained with following formula:
Growth inhibition ratio=[(the average O.D. value of the average O.D. value-compound 4 groups of blank group)/average O.D. value of blank group] × 100%
Experiment repetition 3 times, maps to drug level with inhibiting rate, calculates the IC of compound 4 groups of Zorubicins by graphing method respectively
50the IC of (half effective inhibition concentration) value and negative control group Zorubicin
50.
The IC of reversal index=negative control group Zorubicin
50the IC of/compound 4 groups of Zorubicins
50
4 experimental results are in table 3.Result shows that compound 4 of the present invention can reverse the resistance of the human breast cancer cell to Adriamycin resistant effectively.
Table 3 compound 4 reversing drug resistance is active
| Compound | IC 50 | Reversal index |
| Contrast | 83.33±17.63 | - |
| 4 | 19.33±4.33 | 4.31 |
Experimental example 4 measures the transmission electron microscope photo of compound 4
Compound 4 being configured to concentration is 1 × 10
-8the pure water solution of M, is layered on copper mesh uniformly, under transmission electron microscope (TEM, JEM-1230, JEOL), observe nanostructure.Fig. 3 is shown in by the photo obtained.Result shows, compound 4 can form nano particle in water, and diameter is 43-214nm.When this nanoparticle is transported in vivo, can not be engulfed by macrophage, outstanding drug effect can be played.
Claims (5)
1. the β-carboline that the tryptophan benzyl ester shown in following formula is modified, i.e. 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester.
2. the preparation method of 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester of claim 1, the method comprises:
(1) under the vitriol oil exists, 5-formylsalicylic acid is 90 DEG C, microwave reaction 2h in methyl alcohol, generates 5-formylsalicylic acid methyl esters;
(2) under the existence of polyphosphoric acid, L-Trp and phenylcarbinol reaction, generate L-Trp benzyl ester;
(3) under trifluoracetic acid exists, in methylene dichloride, 5-formylsalicylic acid methyl esters and the ester condensation of L-Trp benzyl are 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylates;
(4) 2,3-bis-chloro-5,6-dinitrile-1, under the existence of 4-benzoquinones (DDQ), 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate is oxidized to 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-benzyl carboxylate in tetrahydrofuran (THF);
(5) at Pd/C and H
2under existence, in methyl alcohol, the reaction of 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-benzyl carboxylate generates 1-(4-hydroxyl-3-methoxycarbonyl)-β-carboline-3-carboxylic acid;
(6) under DCC and HOBt exists, 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-carboxylic acid is 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester with the ester condensation of L-Trp benzyl in anhydrous methylene chloride.
3. the nanostructure of 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester of claim 1.
4. 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester of claim 1 is preparing the application in antitumor drug.
5. the application of 1-(4-hydroxyl-3-methoxycarbonyl phenyl)-β-carboline-3-formyl tryptophan benzyl ester in the antitumor medicine-resistant medicine of preparation of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410260135.1A CN105218628A (en) | 2014-06-10 | 2014-06-10 | The β-carboline that tryptophan benzyl ester is modified, its synthesis, nanostructure, active and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410260135.1A CN105218628A (en) | 2014-06-10 | 2014-06-10 | The β-carboline that tryptophan benzyl ester is modified, its synthesis, nanostructure, active and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105218628A true CN105218628A (en) | 2016-01-06 |
Family
ID=54987957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410260135.1A Pending CN105218628A (en) | 2014-06-10 | 2014-06-10 | The β-carboline that tryptophan benzyl ester is modified, its synthesis, nanostructure, active and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105218628A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1552727A (en) * | 2003-12-19 | 2004-12-08 | 复旦大学附属中山医院 | Targetted polypeptide for specificity of liver cancer blood vessel |
| CN101906102A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | Beta-carboline alkaloid derivative, preparation method and application thereof |
| CN102241674A (en) * | 2010-05-12 | 2011-11-16 | 首都医科大学 | Synthesis method and antitumor activity evaluation of 1,1-dimethyl-beta-carboline-3-formacyl amino acid benzyl ester |
| CN103159828A (en) * | 2011-12-14 | 2013-06-19 | 首都医科大学 | 1-(4-hydroxy-3-methoxycarbonyl)-beta-carboline-3-formyl tryptophyl amino acid benzyl ester, and synthesis and application thereof |
| CN103450340A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | Heterocyclic carboxylic acid-modified anti-tumor oligopeptides and their synthesis, anti-tumor effects and application |
-
2014
- 2014-06-10 CN CN201410260135.1A patent/CN105218628A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1552727A (en) * | 2003-12-19 | 2004-12-08 | 复旦大学附属中山医院 | Targetted polypeptide for specificity of liver cancer blood vessel |
| CN101906102A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | Beta-carboline alkaloid derivative, preparation method and application thereof |
| CN102241674A (en) * | 2010-05-12 | 2011-11-16 | 首都医科大学 | Synthesis method and antitumor activity evaluation of 1,1-dimethyl-beta-carboline-3-formacyl amino acid benzyl ester |
| CN103159828A (en) * | 2011-12-14 | 2013-06-19 | 首都医科大学 | 1-(4-hydroxy-3-methoxycarbonyl)-beta-carboline-3-formyl tryptophyl amino acid benzyl ester, and synthesis and application thereof |
| CN103450340A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | Heterocyclic carboxylic acid-modified anti-tumor oligopeptides and their synthesis, anti-tumor effects and application |
Non-Patent Citations (1)
| Title |
|---|
| 彭师奇: "6-取代吲哚喹嗪酮的1H NMR", 《波谱学杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103450335B (en) | β-carboline acyl tryptophyl tryptophyl amino-acid benzyl ester, its synthesis, antitumor action and application | |
| CN105218634A (en) | The indoles quinolizine that YIGSR modifies, its preparation, nanostructure, active and application | |
| CN103450329A (en) | 3H-imidazo[4,5-c]pyridine-6-formyl-amido acid benzyl esters and their synthesis, anti-tumor activity and use | |
| CN105315338A (en) | LDV-modified [beta]-carboline, and preparation, nano structure, activity and application thereof | |
| CN107400146A (en) | A kind of antitumor metal iridium (III) complex and its preparation method and application | |
| CN105218638A (en) | The indoles quinolizine that RGDS modifies, its preparation, nanostructure, active and application | |
| CN105218637A (en) | The indoles quinolizine that LPNISKP modifies, its preparation, nanostructure, active and application | |
| CN103864890B (en) | Imidazoles isopropyl acetyl theanine benzyl ester pyrido indole, its prepare, nanostructured and application | |
| CN105273047A (en) | Amino-acid benzyl ester modified beta-carboline, activity, nanometer structure, synthesis and application | |
| CN102631683A (en) | Application of functionalized nano-selenium in tumor angiogenesis inhibiting and antitumor drugs | |
| CN105237618A (en) | Amino acid benzyl ester-modified beta-carbolines, synthesis, nanostructures, activities, and applications | |
| CN106188209B (en) | A kind of melbine conjugate for having antitumor and activity of resisting tumor metastasis concurrently and its application | |
| CN105218628A (en) | The β-carboline that tryptophan benzyl ester is modified, its synthesis, nanostructure, active and application | |
| CN104003966B (en) | 5,7,2,, 4,-tetrahydroxy-3-ylflavone analogs and their preparation method and application | |
| CN105153277A (en) | Beta-carboline modified by KE as well as preparation, nanostructure, activity and application of the same | |
| CN105218635A (en) | The β-carboline that Trp-Trp-Trp pentapeptide is modified, its preparation, nanostructure, active and application | |
| CN105294835A (en) | LDV modified 5-fluorouracil, preparation therefor, nanostructure thereof, vigor thereof and application thereof | |
| CN104072443B (en) | N-substituted-piperazinyl dithiocarbamic acid bismuth (III) coordination compound and preparation method thereof and the application in preparing antitumor drug | |
| CN103860564B (en) | Pyridine ruthenium (II) coordination compound is as the application of antitumor drug | |
| CN103483187B (en) | 4-ethyoxyl-2-hydroxyl-6-methyl benzoic acid and Pharmaceutical composition thereof and application | |
| CN105273053A (en) | Trp-Trp-Trp decapeptide modified beta-carboline, and preparation, nanometer structure, activity and application thereof | |
| CN108484661B (en) | Hexavanadic acid- β -alanine tert-butyl ester derivative and preparation method and application thereof | |
| CN101967163B (en) | Platinum (II) anti-cancer compound with selectivity for cancer cells | |
| CN105273044A (en) | 1-(ethylamino acid benzyl ester)-beta-carboline-3-benzyl carboxylate, preparation, nano-structure, activity and application | |
| CN105218636A (en) | The β-carboline that LPNISKP modifies, its preparation, nanostructure, active and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160106 |