CN109081789A - The positive positive hexanoyl fatty acid/amino acid of hexanoyl amino first cyclic amide base of amino, synthesis, activity and application - Google Patents
The positive positive hexanoyl fatty acid/amino acid of hexanoyl amino first cyclic amide base of amino, synthesis, activity and application Download PDFInfo
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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Abstract
The invention discloses (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of following formula (AA is L-Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue in formula).It discloses their preparation method, disclose their anti-tumor activity, disclose their activity of resisting tumor metastasis, and their anti-inflammatory activity activity is disclosed, thus anti-tumor drug is being prepared the invention discloses them, the application in medicine for anti transfer of tumor and anti-inflammatory drug.
Description
Technical field
The present invention relates to (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino.It is related to their preparation method, relates to
And their anti-tumor activity, it is related to their activity of resisting tumor metastasis, and be related to their anti-inflammatory activity activity, thus this
Invention is related to them and is preparing anti-tumor drug, the application in medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biologies
Field of medicaments.
Background technique
Invasion and transfer process are the Basic biological characteristics of malignant tumour, are one of the predicaments of tumor research work.Cancer
The main reason for disease transfer is tumor patient morbidity and is dead, accounts for about the 90% of number of cancer deaths.At present to tumor-infiltrated turn
The research of shifting has carried out deep discussion from different aspect.Wherein, plasma urokinase-type plasminogen activator (uPA) series is swollen
Effect in tumor invasion transfer becomes one of the hot spot studied now.Plasma urokinase-type plasminogen activator (uPA) system, this is
A kind of serine stretch protein enzyme family is played a crucial role in the infiltration metastasis of tumour.The system includes urokinase type fibre
Plasminogen activator (uPA), urokinase receptor (uPAR), plasminogen activator inhibitor (PAI), which is related to a variety of
Physiology and pathologic process, including cell migration, angiogenesis, inflammation, embryonic development, growth and metastasis of tumours.
Amino-n-hexanoic acid can generate Reverse transcriptase with activator of plasminogen, and plasminogen is prevented from activating to be fine molten
Enzyme is the fibrinolytic bleeding drug of clinical treatment.Tranexamic acid can equally play anti-fibrinolysis activity in conjunction with plasminogen.Two
Person can reach the dependent interaction for inhibiting uPA system by preventing uPA/uPAR interaction and inhibiting plasmin activation respectively.
It is respectively 3.8mmol/kg and 3.2mmol/kg that Amino-n-hexanoic acid and tranexamic acid, which inhibit the minimum effective dose of uPA system,.Hair
Bright people thinks that their toxic side effect and their minimum effective dose height have direct relation.Inventor recognize first by two kinds
The uPA system inhibitor reasonable combination known, the novel u-PA inhibitor for reconnecting amino acid and constructing should just have under low dosage
There are antitumor, anti-tumor metastasis and anti-inflammatory triple role.It according to this understanding, was explored by 3 years, fatty acid/amino acid is used in discovery
The positive hexanoyl first cyclic amide base n-caproic acid derivative of amino of (L-Ala, L-Gly, L-Ile, L-Leu, L-Pro and L-Val) modification
Not only there is activity of resisting tumor metastasis under 0.5 μm of ol/kg dosage, but also there is antitumor and anti-inflammatory activity simultaneously.Because
The toxic side effect of drug can be reduced with dosage and be disappeared, so effective dose is at least dropped than Amino-n-hexanoic acid and tranexamic acid
Low 6400 times show this structural modification and have technical effect outstanding.According to these discoveries, the present invention is inventors herein proposed.
Summary of the invention
First content of the invention is to provide (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA (formula of-amino of following formula
Middle AA is L-Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue).
Second content of the invention is to provide (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue) synthetic method, this method
Include:
(1) Boc- tranexamic acid and Amino-n-hexanoic acid methyl esters are condensed to obtain N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid first
Ester (1)；
(2) N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters de- Boc in the ethyl acetate solution of hydrogen chloride obtains N-
Ammonia first ring acyl group-Amino-n-hexanoic acid methyl ester hydrochloride (2)；
(3) Boc- Amino-n-hexanoic acid and N- ammonia first ring sulphonyl-amino methyl hexyl are condensed (the positive hexanoyl of N-Boc- amino
Ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters (3)；
(4) compound 3 is saponified demethylation and obtains (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-Amino-n-hexanoic acid (4)；
(5) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 4 obtains (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
N-caproic acid (7)；
(6) (AA is L-Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro by compound 4 and AA-OBzl
Residue and L-Val residue) it is condensed (the positive hexanoyl ammonia first ring acyl of N-Boc- amino) positive caproyl amino-acid benzyl ester (5a- of-amino
f)。
(7) compound 5a-f hydrogenolysis takes off benzyloxycarbonyl group, and Boc is taken off in the ethyl acetate solution of hydrogen chloride and obtains (N- amino
Positive caproyl ammonia first ring acyl) (AA is L-Ala residue, L-Gly residue, L-Ile residue, L-Leu to the positive hexanoyl-AA of-amino (6a-f)
Residue, L-Pro residue and L-Val residue).
Third content of the invention is evaluation (the positive caproyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue) inhibit C57BL/6 mouse anti-
Lung cancer metastasis activity.
4th content of the invention is evaluation (the positive caproyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue) it is raw to S180 mouse tumor
Long inhibition application.
5th content of the invention is evaluation (the positive caproyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue) suppression to ICR mouse inflammation
Production is used.
Detailed description of the invention
AA is L-Ala in the synthetic route .5a and 6a of Fig. 1 (the positive caproyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino
Residue；AA is L-Gly residue in 5b and 6b；AA is L-Ile residue in 5c and 6c；AA is L-Leu residue in 5d and 6d；5e and
AA is L-Pro residue in 6e；AA is L-Val residue in 5f and 6f；I) dicyclohexylcarbodiimide (DCC), 1- hydroxy benzo three
Azoles (HOBt), N-methylmorpholine (NMM), anhydrous tetrahydro furan (THF)；Ii) Hydrochloride/ethyl acetate (4M)；iii)
CH3OH,2MNaOH；iv)Pd/C,H2,CH3OH；Hydrochloride/ethyl acetate (4M).
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares (N-Boc- ammonia first ring acyl)-Amino-n-hexanoic acid methyl esters (1)
0.69g (2.68mmol) Boc- tranexamic acid is suspended in 50mL dry tetrahydrofuran, is sequentially added at 0 DEG C
0.66 g (3.20mmol) dicyclohexylcarbodiimide (DCC) and 0.44g (3.26mmol) I-hydroxybenzotriazole (HOBt), are stirred
Mix 30 min.Then 0.49g (2.70mmol) Amino-n-hexanoic acid methyl esters is added, and adjusts pH value of solution with N-methylmorpholine (NMM)
To 9,6h is stirred at room temperature, TLC (methylene chloride/methanol=30/1) display reaction is completed.It is concentrated under reduced pressure and removes solvent, residue
It is dissolved with 50mL ethyl acetate, filtering.Filtrate is successively saturated NaHCO with 20mL3Solution washs 3 times, and it is molten that 20mL is saturated NaCl
Liquid washs 3 times, and 20mL is saturated KHSO4Solution washs 3 times, and 20mL is saturated NaCl solution and washs 3 times, and 20mL is saturated NaHCO3Solution
Washing 3 times, 20mL are saturated NaCl solution and wash 3 times, the ethyl acetate layer dry 12h of anhydrous sodium sulfate.Filtering, filtrate decompression
It is concentrated to dryness, obtains 0.83g (80%) title compound, be colorless solid.ESI-MS (m/e): 385 [M+H]+。
Embodiment 2 prepares N- ammonia first ring sulphonyl-amino methyl hexyl hydrochloride (2)
By the ethyl acetate solution (4M) of 6.00g (15.62mmol) compound 1 and 60mL hydrogen chloride at -10 DEG C under stirring
It is slowly mixed together, and keeps -10 DEG C of stirring 5h.TLC (methylene chloride/methanol=30/1) display reaction is completed.It is concentrated under reduced pressure and removes
Solvent, residue are dissolved with anhydrous ethyl acetate, and obtained solution is concentrated under reduced pressure.The operation is repeated 3 times.Solid uses anhydrous second again
Ether sufficiently suspends, and removes ether, and obtained colorless solid is directly used in react in next step.ESI-MS(m/e):322[M+H]+。
Embodiment 3 prepares (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-Amino-n-hexanoic acid methyl esters (3)
Using the method for embodiment 1, from 3.36g (14.55mmol) Boc- Amino-n-hexanoic acid and 4.67g (14.57mmol)
Compound 2 obtains faint yellow solid.The solid is sufficiently worn away with ethyl acetate, obtains 6.20g (85%) title compound, is nothing
Color solid.ESI-MS (m/e): 498 [M+H]+。
Embodiment 4 prepares (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-Amino-n-hexanoic acid (4)
6.20g (12.47mmol) compound 3 is dissolved in 20mL methanol, 0 DEG C adjusts pH to 12 with NaOH aqueous solution (2M).
0 DEG C of control and pH 12 stir 4h, and TLC (methylene chloride/methanol=25/1) display reaction is completed.Reaction mixture saturation
KHSO4Solution adjusts pH to 7, is concentrated under reduced pressure.Residue continues with saturation KHSO4Solution adjusts pH to 2, is extracted with ethyl acetate,
Ethyl acetate layer is merged, is washed with saturation NaCl solution to neutrality.The ethyl acetate phase dry 12h of anhydrous sodium sulfate.Filtering,
Filtrate decompression is concentrated to dryness, and obtains 4.60g (76%) title compound, is colorless solid.ESI-MS (m/e): 484 [M+H]+。
Embodiment 5 prepares (the positive hexanoyl ammonia first ring acyl of N- amino)-Amino-n-hexanoic acid (7)
Using the method for embodiment 2,0.87g (84%) title compound is obtained from 1.30g (2.69mmol) compound 4,
For colorless solid.Mp 236-239℃；ESI-MS(m/e):384[M+H]+.IR(cm-1):
3265, 3081,2927,2857,1633,1557,1470,1416,1396,1362,1327,1235,1210,726,697.1H-
NMR (300MHz,D2O): δ/ppm=3.11 (t, J=6.6Hz, 2H), 2.98 (d, J=6.6Hz, 2H), 2.93 (t, J=
7.8Hz, 2 H), 2.20 (t, J=7.2Hz, 2H), 2.12 (t, J=7.2Hz, 2H), 2.09 (m, 1H), 1.76 (m, 4H), 1.67
~1.55 (m, 4 H), 1.52~1.40 (m, 5H), 1.37~1.24 (m, 6H), 0.93 (m, 2H).
Embodiment 6 prepares the positive hexanoyl alanine benzyl ester (5a) of (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-amino
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 1.62g (7.52mmol) HClAla-
OBzl obtains 2.09g (43%) title compound, is colorless solid.ESI-MS (m/e): 645 [M+H]+。
Embodiment 7 prepares the positive hexanoyl glycine benzyl ester (5b) of (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-amino
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 1.52g (7.54mmol) HClGly-
OBzl obtains 2.18g (46%) title compound, is colorless solid.ESI-MS (m/e): 631 [M+H]+。
Embodiment 8 prepares the positive hexanoyl isoleucine benzyl ester (5c) of (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-amino
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 2.96g (7.53mmol) TosIle-
OBzl obtains 3.02g (53%) title compound, is colorless solid.ESI-MS (m/e): 687 [M+H]+。
Embodiment 9 prepares the positive hexanoyl leucine benzyl ester (5d) of (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-amino
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 2.96g (7.53mmol) TosLeu-
OBzl obtains 2.10g (37%) title compound, is colorless solid.ESI-MS (m/e): 687 [M+H]+。
Embodiment 10 prepares the positive hexanoyl proline benzyl ester (5e) of (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-amino
Using the method for embodiment 1, from 3.00g (6.21mmol) compound 4 and 1.50g (6.21mmol) HClPro-
OBzl obtains 1.52g (37%) title compound, is colorless solid.ESI-MS (m/e): 671 [M+H]+。
Embodiment 11 prepares the positive hexanoyl valine benzyl ester (5f) of (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-amino
Using the method for embodiment 1, from 2.20g (4.55mmol) compound 4 and 1.33g (5.46mmol) HClVal-
OBzl obtains 900mg (29%) title compound, is colorless solid.ESI-MS (m/e): 673 [M+H]+。
Embodiment 12 prepares the positive hexanoyl alanine (6a) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
780mg (1.59mmol) compound 5a is dissolved in 20mL methanol, 80mg Pd/C is added, room temperature leads to 10h hydrogen.
TLC (methylene chloride/methanol=5/1) shows that raw material point disappears.It is filtered to remove Pd/C, filtrate decompression is concentrated to dryness.Residue-
10 DEG C slowly mix with 6mL Hydrochloride/ethyl acetate (4M), keep -10 DEG C of stirring 5h.TLC (ethyl acetate/water ice vinegar
Acid=6/1/1) display fully reacting.It is concentrated under reduced pressure, residue is dissolved with anhydrous ethyl acetate, is concentrated under reduced pressure, residue nothing
The dissolution of water ethyl acetate.The operation is repeated 3 times.Obtained solid is sufficiently suspended with anhydrous ether, removes ether, and what is obtained is colourless solid
Body 0 DEG C with saturation NaHCO3Solution adjusts pH to 7 and is obtained 360mg (65%) title compound with C18 column chromatographic purifying, be
Colorless solid.Mp 237-238℃.ESI-MS(m/e):455[M+H]+. IR(cm-1):
3293,3085,2928,2857,1636,1552,1445,1396,1360,1234.1H-NMR(300MHz,D2O): δ/ppm=
4.02 (q, J=7.2Hz, 1H), 3.01 (t, 2H), 2.87 (d, J=6.3Hz, 2H), 2.82 (t, J=7.8Hz, 2H), 2.10
(m, 4H), 2.00 (m, 1H), 1.66 (m, 4H), 1.59~1.41 (m, 6H), 1.35~1.24 (m, 7H), 1.19~1.16 (m,
5H),0.84(m,2H)。
Embodiment 13 prepares the positive hexanoyl glycine (6b) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
Using the method for embodiment 12,443mg (63%) title compound is obtained from 1.00g (1.59mmol) compound 5b
Object is colorless solid.Mp 230-231℃.ESI-MS(m/e):441[M+H]+.IR(cm-1): 3487,3288,3086,2928,2857,1728,1634,1557,1470,1439 1393,1366,1256,1226,
1186,1170, 702.1H-NMR (300MHz, MeOD): δ/ppm=3.97 (s, 2H), 3.17 (t, J=6.6Hz, 2H), 3.03
(d, J=6.6 Hz, 2H), 2.98 (t, J=7.8Hz, 2H), 2.26 (m, 4H), 2.16 (m, 1H), 1.82 (m, 4H), 1.75~
(1.57 m, 6 H), 1.55~1.47 (m, 3H), 1.45~1.31 (m, 6H), 1.00 (m, 2H).
Embodiment 14 prepares the positive hexanoyl isoleucine (6c) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
Using the method for embodiment 12,385mg (45%) title compound is obtained from 1.16g (1.69mmol) compound 5c
Object is colorless solid.Mp 250-251℃.ESI-MS(m/e):497[M+H]+.IR
(cm-1): 3296,3088,2926,2858,1637,1552,1452,1393,1255,1235,1208,699.1H-NMR
(300MHz, MeOD): δ/ppm=4.26 (d, J=5.4Hz, 1H), 3.17 (t, J=6.6Hz, 2H), 3.04 (d, J=
6.9Hz, 2H), 2.93 (t, J=7.5Hz, 2H), 2.25 (m, 4H), 2.15 (m, 1H), 1.89 (m, 4H), 1.81~1.59 (m,
6H), 1.55~1.48 (m, 5H), 1.44~1.29 (m, 6H), 1.17 (m, 1H), 1.01 (m, 2H), 0.91 (m, 6H).
Embodiment 15 prepares the positive hexanoyl leucine (6d) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
Using the method for embodiment 12,480mg (65%) title compound is obtained from 1.01g (1.47mmol) compound 5d
Object is colorless solid.Mp 223-225℃.ESI-MS(m/e):497[M+H]+.IR
(cm-1): 3297,3084,2926,2858,1633,1552,1446,1376,1257,1234,1207,686.1H-NMR
(300MHz,D2O): δ/ppm=4.05 (dd, J1=7.8Hz, J2=6.0Hz, 1H), 3.03 (t, J=6.3Hz, 2H), 2.91
(d, J=6.6Hz, 2H), 2.85 (t, J=7.5Hz, 2H), 2.13 (m, 4H), 2.04 (m, 1H), 1.68 (m, 4H), 1.60~
1.47 (m, 9H), 1.40~1.29 (m, 3H), 1.27~1.17 (m, 6H), 0.85 (m, 2H), 0.77 (m, 6H).
Embodiment 16 prepares the positive hexanoyl proline (6e) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
Using the method for embodiment 12,286mg (62%) title compound is obtained from 0.64g (0.96mmol) compound 5e
Object is colorless solid.Mp 221-222℃.ESI-MS(m/e):481[M+H]+.IR
(cm-1): 3278,3084,2928,1633,1557,1448,1386,1343,1293,1261,1235,1208,698.1H-NMR
(300MHz, D2O): δ/ppm=4.20 (m, 1H), 3.46 (m, 2H), 3.08 (m, 2H), 2.97 (d, J=6.6Hz, 2H),
2.91 (t, J=7.8Hz, 2H), 2.31 (m, 1H), 2.17 (m, 4H), 1.98 (m, 1H), 1.84 (m, 2H), 1,74 (m, 4H),
1.65~1.47 (m, 6H), 1.44~1.36 (m, 3H), 1.32~1.25 (m, 6H), 0.91 (m, 2H).
Embodiment 17 prepares the positive hexanoyl valine (6f) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
Using the method for embodiment 12,380mg (59%) title compound is obtained from 900mg (1.34mmol) compound 6f
Object is colorless solid.Mp 245-246℃.ESI-MS(m/e):483[M+H]+.IR
(cm-1): 3295,3085,2929,2858,1633,1552,144386,1385,1253,1235,1207.1H-NMR
(300MHz,D2O): δ/ppm=3.94 (d, J=5.7Hz, 1H), 3.04 (t, J=6.6Hz, 2H), 2.90 (d, J=6.6Hz,
2H), 2.85 (t, J=7.8Hz, 2H), 2.13 (m, 4H), 2.00 (m, 1H), 1.68 (m, 4H), 1.60~1.44 (m, 6H),
1.41~1.30 (m, 3H), 1.27~1.18 (m, 6H), 0.85 (m, 2H), 0.77 (m, 2H).
The activity of resisting tumor metastasis of the measurement of embodiment 18 compound 6a-f
Lewis murine lung cancer cell (LLC the is purchased from ATCC) inoculation of this rating model, selects DMEM culture medium (to contain 10%
Fetal calf serum through inactivating, 1 × 105U/L penicillin and 100mg/L streptomysin), it was passed according to attached cell cultural method every two days
In generation, is primary, enrichment of cell.Vitellophag when cell growth state is good and is in logarithmic growth phase, is adjusted thin with physiological saline
Born of the same parents' density is to 1 × 107A/mL.The dyeing of placenta indigo plant, makes viable count > 95%.Take inbred strais C57BL/6 male mice (SPF
Grade, 20 ± 2g of weight), the fixed mouse of left hand.It is sterilized with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa.It is sterile that the right hand holds 1mL
LLC tumor cell suspension is subcutaneously injected toward mouse armpit in syringe, and every mouse injects 0.2mL.After mouse inoculation 10 days, grow
The tumour of diameter about 4-5mm is knurl source.The Lewis lung cancer tumor-bearing mice etherization of inoculation 10 days, cervical dislocation are put to death.With
75% ethyl alcohol impregnates 10min, and knurl is removed in disinfection on superclean bench.Select well-grown tumor tissues sterile flat
It shreds, is placed in the tissue homogenizer of glass manufacture in ware.The ratio for being again 1 to 3 (g ratio mL) than physiological saline volume in tumor mass
The physiological saline that heating degree is 4 DEG C, is lightly ground and cell suspension is made.Cell suspension crosses 200 mesh cell sieve single cell suspensions.
With the cell density of physiological saline tune single cell suspension to 1.5 × 107A/mL.The dyeing of placenta indigo plant, makes viable count > 95%.
Left hand fixes inbred strais C57BL/6 male mice, is sterilized with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa.The right hand holds 1mL
Tumor cell suspension, every injection 0.2mL is subcutaneously injected in mouse armpit in asepsis injector.Mouse grows diameter after inoculation 10 days
Mice Inoculated is grouped by the tumour of 4-5mm at random by the gross tumor volume measured.Every group of 12 mouse.The 11st day of inoculated tumour
Mouse or the normal saline solution (dosage be 20 μm ol/kg/ days) or oral chemical combination for taking orally generally acknowledged anti tumor translocation peptide RGDS
The normal saline solution (dosage be 0.5 μm ol/kg/ days) of object 6a-f or the normal saline solution (dosage 5 of oral administration of compound 7
μm ol/kg/ days) or oral normal saline (dosage is 10mL/kg/ days), daily to 1 medicine, successive administration 12 days, every three days
Measure and record gross tumor volume.The next day measurement knurl product of last time administration, etherization cervical dislocation are put to death, and the swollen of mouse is taken
Tumor weighing takes the lung of mouse and calculates the burrknot number of tumour lung transfer.It is examined with t for statistical analysis to data.As a result see
Table 1.Not only effectively inhibit neoplasm lung metastasis in 0.5 μm of ol/kg dosages for Compound 6a-f, and activity and dose ratio they
High 400 times of RGDS and their high 10 times compounds 7 of dose ratio do not have significant difference.These statistics indicate that, the present invention has
Significant technical effect.
The activity of resisting tumor metastasis of 1 compound 6a-f of table
And physiological saline ratio p<0.01, a) with RGDS and compound 7 than p>0.05；N=12.
Embodiment 19 measures the neoplasm growth activity of compound 6a-f
Adriamycin, compound 7 and compound 6a-f are used into physiological saline solution before measurement, are administered for S180 mouse.
Taken in gnotobasis and be inoculated in male ICR mouse 10 days eugonic S180 ascitic tumor fluids, with normal saline dilution at (1:
2) liquid is sufficiently mixed, and by 0.2% Trypan Blue of tumor cell suspension Fresh, white blood cell count(WBC) is pressed after mixing
Method counts, and dye blue person is dead cell, and tinter is not living cells.By viable count/4 in cell concentration=4 block plaids ×
104× extension rate=cell number/mL calculates cell density, by cell survival rate=viable count/(viable count+dead cell
Number) × 100% calculating cell survival rate.It is 2.0 × 10 that density, which is made, with homogenate method in tumor liquid by survival rate greater than 90%7A/
The cell suspension of mL.The cell suspension inoculation is subcutaneous (0.2mL/ is only) in mouse right axillary, manufactures S180 tumor-bearing mice.Inoculation is for 24 hours
The normal saline solution (dosage is 2 μm of ol/kg/ days g) or daily oral of adriamycin is injected intraperitoneally in S180 tumor-bearing mice daily afterwards
The normal saline solution (dosage be 5 μm ol/kg/ days) of compound 7 or the daily normal saline solution (agent of oral administration of compound 6a-f
Amount for 0.5 μm ol/kg/ days).It is administered once a day, successive administration 12 days.The next day measurement knurl product of last time administration, second
Ehterization cervical dislocation is put to death, and is then fixed mouse right axillary tumor location with tweezers, is cut off skin blunt separation tumour and claim
Weight.Curative effect is indicated with knurl weight (mean value ± SD g), and data are examined with t and variance analysis.It the results are shown in Table 2.In 0.5 μm of ol/kg agent
It measures lower compound 6a-e and not only effectively inhibits tumour growth, but also their high 10 times compounds 7 do not have activity with dose ratio
Significant difference.These statistics indicate that, the present invention has significant technical effect.
Influence of the 2 compound 6a-f of table to S180 mice tumors grew
And physiological saline ratio p<0.01, a) with compound 7 than p>0.05；N=12.
The anti-inflammatory activity of the measurement of embodiment 20 compound 6a-f
Because mouse ear swelling caused by dimethylbenzene is acknowledged as acute inflammation model, the present invention causes in dimethylbenzene
Mouse ear swelling model on measure compound 6a-f therapeutic effect.Because aspirin is the positive for treating acute inflammation
Medicine, so the present invention selects aspirin for positive control drug.The ring that ICR male mice (42 ± 3g of weight) is 22 DEG C in temperature
Border tranquillization 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), aspirin group are randomly divided into
(dosage is 1.11 mmol/kg), (dosage is 0.5 μm of ol/ for 7 groups of compound (dosage is 5 μm of ol/kg) and compound 6a-f group
Kg), every group of 12 mouse.Mouse is by place group or oral normal saline or oral aspirin or oral administration of compound when measurement
7 or oral administration of compound 6a-f.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, and mouse receives after 2h
Etherization, the neck that breaks are put to death, and are cut two ears of left and right, are taken round auricle in the same position of two ears with the punch of 7mm, weigh,
Two ear swelling differences are found out as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 3.?
0.5 μm of ol/kg dosages for Compound 6a-f not only effectively inhibits mouse ear swelling caused by dimethylbenzene, but also activity and agent
Amount does not have significant difference than their high 10 times compounds 7.These statistics indicate that, the present invention has significant technical effect.
The influence of mouse ear swelling caused by 3 compound 6a-f paraxylene of table
And physiological saline ratio p<0.01, a) with compound 7 than p>0.05；N=12.
Claims (5)
1. following (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino of general structure,
AA is L-Ala residue, L-Gly residue, L-Ile residue, L-Leu residue, L-Pro residue and L-Val residue in formula.
2. the preparation method of (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of claim 1, this method comprises:
(1) Boc- tranexamic acid and Amino-n-hexanoic acid methyl esters are condensed to obtain N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters
(1)；
(2) N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters de- Boc in the ethyl acetate solution of hydrogen chloride obtains N- ammonia first
Ring sulphonyl-amino methyl hexyl hydrochloride (2)；
(3) Boc- Amino-n-hexanoic acid and N- ammonia first ring sulphonyl-amino methyl hexyl are condensed (the positive hexanoyl ammonia first of N-Boc- amino
Ring acyl group)-Amino-n-hexanoic acid methyl esters (3)；
(4) compound 3 is saponified demethylation and obtains (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino)-Amino-n-hexanoic acid (4)；
(5) compound 4 in the ethyl acetate solution of hydrogen chloride take off Boc obtain (the positive hexanoyl ammonia first ring acyl of N- amino)-amino just oneself
Sour (7)；
(6) compound 4 and AA-OBzl are condensed (the positive hexanoyl ammonia first ring acyl of N-Boc- amino) positive caproyl amino-acid benzyl of-amino
Ester (5a-f)；
(7) compound 5a-f hydrogenolysis take off benzyloxycarbonyl group, in the ethyl acetate solution of hydrogen chloride take off Boc obtain (N- amino just oneself
Acyl group ammonia first ring acyl) the positive hexanoyl-AA of-amino (6a-f).
3. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of claim 1 is in preparing medicine for anti transfer of tumor
Using.
4. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of claim 1 answering in the preparation of antitumor drugs
With.
5. (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino application in preparing anti-inflammatory drugs of claim 1.
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| CN1246069A (en) * | 1997-01-31 | 2000-03-01 | 奥姆里克斯生物化学品公司 | A stabilized mixture comprising fibrinogen |
| WO2012126833A1 (en) * | 2011-03-18 | 2012-09-27 | Institut Pasteur | New conjugated molecules comprising a peptide derived from the cd4 receptor coupled to a polyanionic polypeptide for the treatment of aids |
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| WO2013172954A1 (en) * | 2012-05-17 | 2013-11-21 | Ra Pharmaceuticals, Inc | Peptide and peptidomimetic inhibitors |
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2017
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| CN1246069A (en) * | 1997-01-31 | 2000-03-01 | 奥姆里克斯生物化学品公司 | A stabilized mixture comprising fibrinogen |
| CN103313720A (en) * | 2010-11-08 | 2013-09-18 | 辛索尼克斯公司 | Bismuth-containing compounds for modulating properties of biologically active agents |
| WO2012126833A1 (en) * | 2011-03-18 | 2012-09-27 | Institut Pasteur | New conjugated molecules comprising a peptide derived from the cd4 receptor coupled to a polyanionic polypeptide for the treatment of aids |
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