CN105294833A - Isoquinoline-3-formyl-RI-OBzl, preparation therefor, nanostructure thereof, activity thereof and application thereof - Google Patents
Isoquinoline-3-formyl-RI-OBzl, preparation therefor, nanostructure thereof, activity thereof and application thereof Download PDFInfo
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- CN105294833A CN105294833A CN201410260134.7A CN201410260134A CN105294833A CN 105294833 A CN105294833 A CN 105294833A CN 201410260134 A CN201410260134 A CN 201410260134A CN 105294833 A CN105294833 A CN 105294833A
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- obzl
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Abstract
The present invention discloses Isoquinoline-3-formyl-Arg (NG-NO2)-Ile-OBzl, a preparation method therefor, a nanostructure thereof and activity thereof in inhibiting tumor cell proliferation, and further discloses activity thereof in inhibiting tumor proliferation of S180 solid tumor in a mouse.
Description
Technical field
The present invention relates to isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBz and preparation method thereof, Arg (N
g-NO
2)-Ile is called for short RI.Relate to their tumor cell in vitro proliferation inhibition activity, relate to their restraining effect to mice bearing S180 tumor growth further.Thus the present invention relates to them and prepare the application in antitumor drug.The invention belongs to biomedicine field.
Background technology
Cancer is one group of common name that can affect the various diseases at any position of health.Other term used is malignant tumour and vegetation.According to World Health Organization's statistics, cancer is one of No.1 cause of the death in the world, especially in developing country.And whole world number of cancer deaths estimates continuation to rise, will more than 1,310 ten thousand to the year two thousand thirty.Therefore, develop new efficient, that low toxicity, toxic side effect are little antitumor drug is one of important topic of new drug research always.
Along with the understanding to tumor characteristic and morbidity essence, recent years, antitumor drug was constantly from traditional cell toxicity medicament to the transition of development non-cytotoxic drugs.β-carboline is the cytotoxic anti-tumor compound of natural origin.Contriver recognizes, β-carboline antitumoral cytotoxic essence is the intercalation between DNA of tumor cell.The cuttage of this form can cause cytotoxicity.Contriver once found, β-carboline can insert between the duplex base between DNA of tumor cell.In further studying, contriver recognizes, the anti-tumor activity of β-carboline is from intercalation.Contriver also recognizes, introduces dipeptides generate the effect that β-carboline-3-benzyl carboxylate and derivative can strengthen β-carboline and tumour cell, enhancing anti-tumor activity at 1 of β-carboline.According to these understanding, contriver proposes the isoquinoline 99.9-3-formyl-Arg (N of following formula
g-NO
2)-Ile-OBzl.Compared with the isoquinoline-3-formyl amino acid formyl amino acid benzyl ester of contriver's invention in earlier stage, outstanding creativeness of the present invention is to insert Arg (N between 3-formyl radical and Ile-OBzl base
g-NO
2), remain the intercalation between isoquinoline-3-formyl amino acid formyl amino acid benzyl ester and DNA of tumor cell, again can by inserting Arg (N
g-NO
2) delay metabolism, their effective dose is significantly reduced.In addition, tumour cell autophagy can also be caused.Autophagy is the important channel that tumour cell is bred in the environment of nutritive deficiency, and inducing tumor cell autophagy can injure tumor cells and do not damage non-tumor cell, thus can reduce toxicity.So, isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl can show better anti-tumor activity.
the content of invention
First content of the present invention is to provide the isoquinoline 99.9-3-formyl-Arg (N of following formula
g-NO
2)-Ile-OBzl.
Second content of the present invention is to provide isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) preparation method of-Ile-OBzl, the method comprises the following steps:
(1) L-Phe is carried out Pictet-Spengler condensation with formaldehyde under the catalysis of 35% hydrochloric acid, obtain tetrahydroisoquinoline-3-carboxylic acid;
(2) by tetrahydroisoquinoline-3-carboxylic acid in methanol solution, obtain tetrahydroisoquinoline-3-carboxylate methyl ester with thionyl chloride catalysis under ice bath;
(3) by tetrahydroisoquinoline-3-carboxylate methyl ester in anhydrous DMF (DMF) solution, be that oxygenant obtains isoquinoline 99.9-3-carboxylate methyl ester with potassium permanganate;
(4) under NaOH exists, be isoquinoline 99.9-3-carboxylic acid by the saponification of isoquinoline 99.9-3-carboxylate methyl ester in methyl alcohol;
(5) under dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) exist, Boc-Arg (NO
2) be Boc-Arg (NO with Ile-OBzl condensation in dry DMF
2)-Ile-OBzl;
(6) Boc-Arg (NO in hydrogenchloride-ethyl acetate solution
2)-Ile-OBzl sloughs Boc and generate Arg (NO
2)-Ile-OBzl;
(7) DCC and HOBt exist under, isoquinoline 99.9-3-carboxylic acid in dry DMF with Arg (NO
2)-Ile-OBzl condensation obtains isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl.
3rd content of the present invention evaluates isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl is to the restraining effect of tumor cell proliferation.
4th content of the present invention evaluates isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl suppresses the effect of S180 mice with tumor tumor growth.
5th content of the present invention measures isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) nanostructure of-Ile-OBzl.
6th content of the present invention sets forth isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) impact of-Ile-OBzl cell cycle.
7th content of the present invention sets forth isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) effect of-Ile-OBzl Induces Autophagy.
Accompanying drawing explanation
Fig. 1 chemical combination isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) the synthetic route .i of-Ile-OBzl) HCHO, 35%HCl; Ii) SOCl
2, CH
3oHiii) DMF, KMnO
2; Iv) NaOH, CH
3oH; V) DCC, HOBt, DMF; Vi) 2NHCl/EtOAc.Fig. 2 compound isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl is in pure water environment 10
-5transmission electron microscope photo under M concentration.
Embodiment
In order to set forth the present invention further, provide a series of embodiment 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 tetrahydroisoquinoline-3-carboxylic acid
Take L-Phe 1g, add the formaldehyde of 2.4mL, then add the hydrochloric acid of 8mL35%, solution is first clarified and is separated out white mass afterwards, oil bath 80 DEG C, reacts 8 hours.After reaction terminates, except desolventizing, be placed in eggplant bottle.Add ether ultrasonic agitation 1 hour, repeatedly wear away, filter, obtaining 0.91g (85%) tetrahydroisoquinoline-3-carboxylic acid, is colorless solid.Fusing point 246-247 DEG C.ESI-MS(m/e)：176[M-H]
-。
Embodiment 2 prepares tetrahydroisoquinoline-3-carboxylate methyl ester
In the eggplant type bottle of 50ml, add the methyl alcohol of 6ml, the thionyl chloride of 0.4ml, stir, activation 30min, ice bath.Add tetrahydroisoquinoline-3-carboxylic acid 239mg, react 12 hours under ice bath.Drain solvent, then add methyl alcohol, repeatedly drain 3 times; Add ether 3 times, drain, obtaining 213mg (82.5%) tetrahydroisoquinoline-3-carboxylate methyl ester, is colourless powder.ESI-MS(m/e)：192[M+H]
+。
Embodiment 3 prepares isoquinoline 99.9-3-carboxylate methyl ester
By dry DMF, tetrahydroisoquinoline-3-carboxylate methyl ester 213mg is dissolved, add the water-soluble potassium permanganate solution of distillation, slowly add under ice bath, react 24 hours under room temperature.After reaction terminates, dried up by DMF, filter after being dissolved by black powder with methyl alcohol, filtrate is spin-dried for.Column chromatographic isolation and purification.Obtaining 77mg (37%) isoquinoline 99.9-3-carboxylate methyl ester, is micro-yellow solid.Rf=0.25 (methylene dichloride: methyl alcohol, 20: 1); ESI-MS (m/e): 188 [M+H]
+;
1hNMR (DMSO-d
6, 500MHz) and δ/ppm=9.421 (s, 1H), 8.666 (s, 1H), 8.258 (d, J=4Hz, 1H), 8.22 (d, J=4Hz, 1H), 7.897 (m, 2H), 3.944 (s, 3H).
Embodiment 4 prepares isoquinoline 99.9-3-carboxylic acid
By 1g isoquinoline 99.9-3-carboxylate methyl ester dissolve with methanol, adjust pH value to be 12, react under room temperature.React after within 4 hours, terminating, adjust pH value to be 7, revolve except methyl alcohol, adjust pH value to be 4, have solid to separate out, filter, obtaining 370mg (40%) isoquinoline 99.9-3-carboxylic acid, is colorless solid.Mp231-232℃；ESI-MS(m/e)：172[M-H]
-。
Embodiment 5 prepares Boc-Arg (NO
2)-Ile-OBzl
By Boc-Arg (NO
2) 3g is dissolved in dry DMF, adds the anhydrous DMF solution of HOBt and DCC under ice bath, ice bath stirs 20min, obtains active ester solution A stand-by.Be dissolved in by Ile-OBzl2.1g in dry DMF, NMM regulates PH to be 8-9, obtains solution B.B is poured in A, room temperature reaction 12 hours.After reaction terminates, reaction solution is evaporated to dry, with acetic acid ethyl dissolution, filtering insolubles.Filtrate respectively washes 3 times with saturated sodium bicarbonate, saturated sodium-chloride water solution successively.Separate ester layer, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, column chromatography purification, obtains 2.8g (57%) Boc-Arg (NO
2)-Ile-OBzl, be colorless solid.Rf=0.25 (methylene dichloride: methyl alcohol, 20: 1); ESI-MS (m/e): 509 [M+H]
+.
Embodiment 6 prepares Arg (NO
2)-Ile-OBzl
Take Boc-Arg (NO
2)-Ile-OBzl1g in eggplant bottle, add 3NHClEtOAc and be about 10mL.TLC monitors extent of reaction, reacts reaction in 4 hours and terminates.Liquid drained by water pump, adds acetic acid ethyl dissolution, 3 times repeatedly; Wear away 3 times with anhydrous diethyl ether again, obtain 0.9mg (99%) Arg (NO
2)-Ile-OBzl, be colourless powder.
Embodiment 7 prepares isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl (1)
Be dissolved in dry DMF by isoquinoline 99.9-3-carboxylic acid 0.37g, add the anhydrous DMF solution of HOBt and DCC under ice bath, ice bath stirs 20min, obtains active ester solution A stand-by.By Arg (NO
2)-Ile-OBzl1g is dissolved in dry DMF, NMM regulates PH to be 8-9, obtains solution B.B is poured in A, room temperature reaction 14 hours.After reaction terminates, reaction solution is evaporated to dry, with acetic acid ethyl dissolution, filtering insolubles.Filtrate respectively washes 3 times with saturated sodium bicarbonate, saturated sodium-chloride water solution successively.Separate ester layer, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, column chromatography purification, obtains 0.36g (27%) isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl, be colorless solid.ESI-MS (m/e): 578 [M+H]
+, mp:78-81 DEG C, [α]
(c=0.48, CH
3oH), IR (KBr): 3305.99,3294.42,2962.66,2935.66,2877.79,1735.93,1654.92,1624.06,1600.92,1516.05,1458.18,1438.90,1388.75,1261.45,1192.01,1145.72,906.54,767.67,748.38,694.37,
1hNMR (DMSO-d
6, 300MHz) δ/ppm=9.4 (s, 1H), 8.845 (d, J=9Hz, 1H), 8.58 (s, 1H), 8.485 (d, J=9Hz, 1H), 8.26 (d, J=6Hz, 1H), 8.205 (d, J=9Hz, 1H), 7.86 (m, 3H), 7.32 (m, 5H), 5.135 (m, 2H), 4.765 (m, 1H), 4.33 (t, J=9Hz, 1H), 3.16 (d, J=9Hz, 2H), 1.78 (m, 3H), 1.57 (d, J=6Hz, 2H), 1.375 (m, 1H), 1.2 (m, 1H), 0.83 (m, 6H), purity: 96.9% moving phase: CH
3oH: H
2o=75: 25, retention time: 11.801min.
Experimental example 1 evaluates isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) effect of-Ile-OBzl (be called for short compound 1) inhibition tumor cell propagation
Compound isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl 0.5%DMSO1640 substratum is mixed with desired concn.Respectively by A549 that is good for growth conditions, that be in logarithmic phase, S180, MCF-7 cell is according to 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.At 37 DEG C, 5%CO
2cultivate 4 hours in incubator, by the concentration gradient 100 μMs, 50 μMs, 25 μMs and the 12.5 μMs compound isoquinoline 99.9-3-formyl-Arg (N added through sterilising treatment that preset
g-NO
2) solution of-Ile-OBzl, control group adds 1640 substratum containing 0.5%DMSO of equal-volume 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, and after careful removing supernatant liquor, every hole adds 100 μ lDMSO, and vibrate about 15min dissolution precipitation.OD (absorbancy) value is measured under 570nm wavelength immediately in microplate reader.By inhibiting rate=[(containing the OD mean value-compound isoquinoline 99.9-3-formyl-Arg (N of the 1640 substratum groups of 0.4%DMSO
g-NO
2) the OD mean value of-Ile-OBzl)/containing the OD value of the 1640 substratum groups of 0.4%DMSO] × 100% " calculate inhibiting rate.Test parallel repetition 3 times, with inhibiting rate to compound isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) the concentration mapping of-Ile-OBzl, calculate the IC of the compounds of this invention
50(half effective inhibition concentration) value.
Compound isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl is mixed with desired concn with containing the DMEM substratum of 0.4%DMSO.Respectively by good for growth conditions, be in U2OS, SH-sy5y and HacaT cell of logarithmic phase according to 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.At 37 DEG C, 5%CO
2cultivate 4 hours in incubator, by the concentration gradient 100 μMs, 50 μMs, 25 μMs and the 12.5 μMs compound isoquinoline 99.9-3-formyl-Arg (N added through sterilising treatment that preset
g-NO
2) solution of-Ile-OBzl, control group adds the DMEM substratum containing 0.5%DMSO of equal-volume 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, and after careful removing supernatant liquor, every hole adds 100 μ lDMSO, and vibrate about 15min dissolution precipitation.OD (absorbancy) value is measured under 570nm wavelength immediately in microplate reader.By inhibiting rate=[(containing the OD mean value-compound isoquinoline 99.9-3-formyl-Arg (N of the DMEM substratum group of 0.4%DMSO
g-NO
2) the OD mean value of-Ile-OBzl group)/containing the OD mean value of the DMEM substratum group of 0.5%DMSO] × 100% calculate inhibiting rate.Test parallel repetition 3 times, with inhibiting rate to compound isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) the concentration mapping of-Ile-OBzl, calculate the IC of the compounds of this invention
50(half effective inhibition concentration) value.
Result lists table 1 and table 2 in.Can find out the present invention from result, compound isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) the IC50 value of-Ile-OBzl to MCF-7 cell, A549 cell, S180 cell, SH-Sy5y cell, HacaT cell be all greater than 100, U2OS cell is had to the effect of certain inhibition tumor cell propagation, IC50 value is 55.6 ± 3.7 μMs.
The effect of table 1 compound 1 inhibition tumor cell propagation
n＝18.
The effect of table 2 compound 1 inhibition tumor cell propagation
n＝18.
Experimental example 2 evaluates isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl (be called for short compound 1) suppresses the activity of S180 mice tumors grew
Derivative of the present invention is added tween 80 hydrotropy, with physiological saline by sample dissolution before measuring; Zorubicin is dissolved in physiological saline.Get under aseptic condition and be inoculated in the ICR mouse S180 sarcoma of 7-10 days, add appropriate normal saline tumor cells suspension, cell count is 1 × 10
7individual/mL, is inoculated in healthy male ICR mouse forelimb armpit subcutaneous, every injected in mice 0.2mL.After tumor inoculation 24h, the aqueous solution for the treatment of group mouse abdominal injection every day 0.2mL the compounds of this invention, successive administration 9 days, dosage is 5 μm of ol/kg.Naive mice abdominal injection every day 0.2mL physiological saline.Positive control is made with Zorubicin (dosage is 2 μm of ol/kg).Experiment proceeds to the 10th day, claim Mouse Weight, and the tumour taking each group of mouse is weighed, and finally adds up the tumour inhibiting rate of each treated animal.The curative effect of solid tumor represents with the heavy inhibition percentage of knurl, is calculated as follows: tumor-like hyperplasia %=[1-(administration group knurl heavy/blank group knurl weight)] × 100%.Result lists table 3 in.Table 3 result shows this isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl treats the knurl weight that the knurl of mouse is heavily significantly less than saline-treated mice, illustrates that its effective dose (5 μm of ol/kg) is lower 20 times than the effective dose (100 μm of ol/kg) of isoquinoline 99.9-3-formyl-AA-OBzl disclosed in contriver.
Table 3 compound 1 is on the impact of S180 tumor-bearing mice tumor growth
N=12; A) with physiological saline group than p < 0.01.
Experimental example 3 measures isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) transmission electron microscope photo of-Ile-OBzl
By isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl is according to 1 × 10
-5the aqueous solution of the concentration configuration compound of M, is layered on uniformly on copper mesh, observes the self-assembly property of compound under transmission electron microscope (TEM, JEM-1230, JEOL).Fig. 2 is shown in by the photo obtained.Result shows, compound all can form nano particle in water, and diameter major part is between 130-170nm.
Experimental example 4 measures isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl (the being called for short compound 1) impact on the U2OS cell cycle
The U2OS cell dissociation that growth conditions is good, be in logarithmic phase is made single cell suspension, with 4.5 × 10
5the density of individual/mL is inoculated in 6 orifice plates, every hole 2mL, at 37 DEG C, 5%CO
2attach overnight in incubator, adds the 60 μMs of isoquinoline 99.9-3-formyl-Arg (N prepared
g-NO
2)-Ile-OBzl, Zorubicin and blank solution, every hole 500 μ L.Take out 6 orifice plates after 24h, collected by trypsinisation cell, centrifugal, go supernatant to stay cell precipitation, with 1mL ice PBS by resuspended for cell one-tenth single cell suspension, be transferred in 1.5mL centrifuge tube, recentrifuge precipitates, and carefully absorbs supernatant.Add 70% ethanol of 1mL ice bath precooling, blow fast and evenly avoid the formation of cell mass, spend the night in 4 DEG C of fixed cells.After using RNaseA37 DEG C of process cell half an hour every other day, lucifuge propidium iodide stain.The every porocyte of flow cytomery is used to be in the quantity in each cycle.Result Wincycle software analysis.Result is as table 4.It is as shown in the table, isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl is to after U2OS cytosis 48h, there is obvious change G0, the G1 phase relative to blank group.
Table 4 compound 1 is on the impact of U2OS cell cycle
Experimental example 5 measures isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) effect of-Ile-OBzl (be called for short compound 1) induction U2OS cell autophagy.
The U2OS cell dissociation that growth conditions is good, be in logarithmic phase is made single cell suspension, with 5 × 10
5the density of individual/mL is inoculated in 6 orifice plates, every hole 2mL, at 37 DEG C, 5%CO
2attach overnight in incubator, adds the isoquinoline 99.9-3-formyl-Arg (N of 60 μMs that prepare
g-NO
2)-Ile-OBzl, the rapamycin of 10 μMs and blank solution, every hole 500 μ L.6 orifice plates are taken out, collected by trypsinisation cell after 24h, centrifugal, go supernatant to stay cell precipitation, with 1mL ice PBS by resuspended for cell one-tenth single cell suspension, centrifugal, using PBS re-suspended cell after removing supernatant liquor, centrifugal, go supernatant to stay cell precipitation, with 250 μ L's
greenDetectionReagent staining fluid, evenly, 37 DEG C of lucifuges hatch 30min in piping and druming.Centrifugal, go supernatant to stay cell precipitation, wash twice with PBS.Centrifugal, go supernatant to stay cell precipitation, fix 20min with the paraformaldehyde of 4%.Centrifugal, go supernatant to stay cell precipitation, wash twice with PBS.Add the PBS re-suspended cell of 500 μ L, lucifuge 4 DEG C preservation, spends the night.Next day, upper machine testing after re-suspended cell, flow cytometer 488nm wavelength detecting, result Wincycle software analysis.Do not have part sample detection 10,000 cells.Result is as table 5.Fluorescence intensity data as can be seen from table, isoquinoline 99.9-3-formyl-Arg (N
g-NO
2) after-Ile-OBzl acts on U2OS cell, Induces Autophagy.
The fluorescence intensity of the compound 1 of table 5 flow cytometer record
Claims (4)
1. isoquinoline 99.9-3-formyl-Arg (the N of following formula
g-NO
2)-Ile-OBzl.
2. isoquinoline 99.9-3-formyl-Arg (the N of claim 1
g-NO
2) preparation method of-Ile-OBzl, the method comprises:
(1) L-Phe is carried out Pictet-Spengler condensation with formaldehyde under the catalysis of 35% hydrochloric acid, obtain tetrahydroisoquinoline-3-carboxylic acid;
(2) by tetrahydroisoquinoline-3-carboxylic acid in methanol solution, obtain tetrahydroisoquinoline-3-carboxylate methyl ester with thionyl chloride catalysis under ice bath;
(3) by tetrahydroisoquinoline-3-carboxylate methyl ester in anhydrous DMF (DMF) solution, be that oxygenant obtains isoquinoline 99.9-3-carboxylate methyl ester with potassium permanganate;
(4) under NaOH exists, be isoquinoline 99.9-3-carboxylic acid by the saponification of isoquinoline 99.9-3-carboxylate methyl ester in methyl alcohol;
(5) under dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) exist, Boc-Arg (NO
2) be Boc-Arg (NO with Ile-OBzl condensation in dry DMF
2)-Ile-OBzl;
(6) Boc-Arg (NO in hydrogenchloride-ethyl acetate solution
2)-Ile-OBzl sloughs Boc and generate Arg (NO
2)-Ile-OBzl;
(7) DCC and HOBt exist under, isoquinoline 99.9-3-carboxylic acid in dry DMF with Arg (NO
2)-Ile-OBzl condensation obtains isoquinoline 99.9-3-formyl-Arg (N
g-NO
2)-Ile-OBzl.
3. isoquinoline 99.9-3-formyl-Arg (the N of claim 1
g-NO
2)-Ile-OBzl nanostructure.
4. isoquinoline 99.9-3-formyl-Arg (the N of claim 1
g-NO
2)-Ile-OBzl preparing the application in antitumor drug.
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|---|---|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101497584A (en) * | 2008-01-29 | 2009-08-05 | 首都医科大学 | Isoquinoline-3-formyl amino acid formyl amino acid benzyl ester, as well as preparation and use thereof |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101497584A (en) * | 2008-01-29 | 2009-08-05 | 首都医科大学 | Isoquinoline-3-formyl amino acid formyl amino acid benzyl ester, as well as preparation and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| ZHENG MQ等: "A class of novel N-isoquinoline-3-carbonyl-L-amino acid benzylesters: Synthesis, anti-tumor evaluation and 3D QSAR analysis", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 蔡青等: "伪肽策略在DNA嵌插剂设计中的应用", 《转化医学研究》 * |
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