CN1197847C - Compound N-total trans dimension methanamide derivative and its preparation method and application - Google Patents
Compound N-total trans dimension methanamide derivative and its preparation method and application Download PDFInfo
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Abstract
The present invention particularly relates to a compound N-all trans retinamide derivative, a preparation method thereof and the anti-tumor application thereof. All trans retinoic acid dry powder is used as a raw material to react with phenol and phosphorus trichloride, and the present invention is obtained after the synthesis and purification of stir in nitrogen, ether extraction, laminar analysis, mass spectrometric analysis, etc. The molecules of the derivative of the present invention have the general formula structure. Tests prove that the compound of the present invention has an obvious regulating effect on alpha 1, 6 fucose glycosyltransferase, lower toxicity than retinoic acid, a strong effect on restraining liver cancer cells and an effect on restraining the transferring potentiality of the liver cancer cells in the body of a nude mouse obviously. The present invention can be used to prepare novel anti-tumor medicines, and has high potential social benefits and a bright application prospect.
Description
Technical field
The invention belongs to chemical field, be specifically related to compound N-total trans dimension methanamide derivative and preparation method thereof and its antineoplastic application.
Background technology
Vitamin A acid is applied in the differentiation of inducing of tumour for many years, in tumor treatment such as leukemia, obtained great achievement, single medicine is induced an early young grain leukemia complete remission rate to reach 89%. and is discovered that using vitamin A acid at hepatocarcinoma patient does not reach effective inhibition concentration, but also can produce serious toxic side effect and vitamin A acid syndromes, as liver dysfunction, resistance and inducer remission recurrence later on easily and invalid etc. to recurrent cases, so in fact vitamin A acid has very big restricted to the treatment of hepatocarcinoma patient.The effect of vitamin A acid known in the art comprises that its induction of differentiation and toxic side effect thereof are that special construction by vitamin A acid is determined, the molecule of vitamin A acid contains long unsaturated chain, end is a carboxyl structure, the other end is a white Asia puecon ketone ring structure, whole molecule is hydrophobic property, can pass cytolemma and combine and play a role with acceptor in the cell.For a long time, the researchist imagines the molecular structure of transforming vitamin A acid, hope can obtain low toxicity compound efficiently, the U.S. has the institute of materia medica to filter out the derivative of 4-amino-phenol VAAE, the side chain terminal of this compound is the benzene ring structure with a hydroxyl, and prove that it has stronger tumor inhibition effect, can induce the accent of kinds of tumor cells to die, particularly mammary cancer and melanocyte oncocyte, experimental results show that described derivative induced natural death of cerebral cells effect is not the acceptor that relies on vitamin A acid, but play a role by its side-chain structure transformation, the structural hydroxyl of transforming has replaced original carboxyl, and added a phenyl ring, made molecule have more hydrophobicity.
Summary of the invention
The purpose of this invention is to provide a kind of compound N-total trans dimension methanamide derivative and preparation method thereof with antitumor action.
Another object of the present invention provides the purposes of described compound in the preparation antitumor drug.
The present invention behind synthetic and purifying, is prepared into new N-total trans dimension methanamide derivative by the molecular simulation structure design.Derivative molecular of the present invention still has terminal carboxyl structure, but adds another azepine ring texture, and it has the structure of general formula I.
Wherein R represents proline(Pro), oxyproline, and mode of connection is an amido linkage.
The chemical name of described its molecule of N-total trans dimension methanamide proline(Pro) is: N-total trans dimension methanamide proline(Pro) (N-all-trans-retinylproline), it calculates molecular weight is 398.
N-total trans dimension methanamide derivative of the present invention prepares by following method:
Synthesis material begins with all-trans-retinoic acid dry powder; elder generation and benzene and phosphorus trichloride effect; and under protection of nitrogen gas, stirred 2-5 hour; present orange-red solution, have a spot of phosphorous acid to separate out on the reaction flask wall, continue under protection of nitrogen gas, to stir 10-30 minute; be transferred to dry layering funnel; isolate the benzole soln that generates the dimension formyl chloride, put in the ice bath and stirred 5-20 minute, be added dropwise to the L-proline(Pro); the latter is dissolved in the basic solution of 2mol/l in advance; continue to stir, and, remain on more than the 9-12 with the pH of the sodium hydroxide solution regulator solution of 2mol/l; deicing is bathed; after the reaction solution stirring reaction spent the night, reaction solution was divided into two-layer, and the upper strata is pale brown look; lower floor's color is darker; with ether extraction three times, the upper strata adds the chromatography pillar, carries out chromatography; the Fractional Collections sample; carry out mass spectroscopy, get the correct part of quality, proceed to analyze.
The present invention transforms on the architecture basics of the all-trans-retinoic acid of formula II and has synthesized N-total trans dimension methanamide proline(Pro).The end of all-trans-retinoic acid side chain is a carboxyl; the present invention adds a prolyl at the end of side chain, keeps original carboxyl and makes it to form amido linkage, also has a carboxyl on the prolyl; the polarity of this molecular side chain end is increased, and wetting ability increases.The constructional feature of the 4-amino-phenol VAAE (4HPR) of the structural formula of N-total trans dimension methanamide proline(Pro) of the present invention and formula III compares; 4HPR has a phenol ring texture at the end of side chain; has stronger hydrophobicity; N-total trans dimension methanamide proline(Pro) of the present invention has added the nitrogen heterocyclic of prolyl; the phenol ring-type similar of this nitrogen heterocyclic and 4HPR; but the nitrogen heterocyclic of prolyl does not have two keys, does not have hydroxyl yet, but has carboxyl.
The compounds of this invention has carried out experimental identification, and the result is as follows:
1. physical property:
The yellow crystal powder
Fusing point is 52 ℃
Efficient thin-layer chromatography (TLC)
The sample applied sample amount is 50ug
The thin-layer chromatography material is a silica gel
Developping agent is chloroform/methanol/water 95: 5: 3
UV detection Rf=0.35
2. ultimate analysis: the numerical value that test determination and this molecular structure of compounds formula are calculated fits like a glove,
Measured value of experiment: C, 64.75% H, 7.66% N, 3.33%
Calculated value: C, 64.83% H, 7.62% N, 3.02%
3. the molecular mass of mass spectroscopy compound: analyze through Mariner ES-Mass analyser, the result shows that a main peak quality is 398.5, numerical value and 398 being consistent of calculating by molecular structural formula, and the peak of significantly not mixing confirms this compound purity height.
4. nuclear magnetic resonance spectroscopy molecular structure: through H
1It is correct that-NMR analyzes this molecular structure of compounds.
Experiment shows that the present invention has the effect of regulating α 1,6 Fucose glycosyltransferase (FUT8) in the liver cancer cell, and the core fucosido that FUT8 is responsible for N-type sugar chain (Asn-bound glycan) synthesizes.The structure of N-type sugar chain has important effect to many cell functions as growing, be suppressed and excise as the N-type sugar chain of cell surface, then will cause the death of dying of the poor growth of cell even accent.And that the N-type sugar chain pair cell of cell surface sticks function is particularly important, some N-type sugar chain is participated in contacting of cell and extracellular matrix directly and is sticked effect, and the effect of this cell and extracellular matrix and being attached in the metastases process has great importance.β 1 in the N-type sugar chain, the branched content of 6GlcNAc how much directly influences tumour cell pair cell epimatrix such as fibre connects plain, layer connects plain adherent power, reject the glycosyltransferase mouse afterwards of synthetic this structure, or contain the transgenic animal of this glycosyltransferase, and all can influence tumour significantly at the intravital transfer ability of mouse after rejecting mouse and transgenic animal hybridization.Core Fucose in the structure of N-type sugar chain is relevant with the tumour cell transfer ability, at dried meat breast animal α 1,6 Fucoses are unique core Fucoses (claiming FUTS again), FUT8 has the homology zone that the SH3 homologous sequence has the SH3 part again, the motifs that a plurality of proline rich are arranged, therefore whole molecule forms a stable core texture, also has simultaneously and the conservative catalysis sequence of other fucosyl transferase homologous.Existing being reported in the blood plasma and liver cancer cell of hepatocarcinoma patient, the FUT8 activity is all than the slight rising of normal control, and liver cancer tissue FUT8 activity is 175 ± 78pm01/mg/h, and cancer week is organized as 144 ± 34pm01/mg/h, and normal liver tissue is 79 ± 19pm01/mg/h.The FUT8 activity also differentiation degree with liver cancer tissue is relevant, and well differentiated liver cancer is 384 ± 0.7pmol/mg/h, and the liver cancer of moderate differentiation is 177 ± 182pm01/mg/h, and PD liver cancer is 219 ± 189pm01/mg/h.FUT8 activity change in the liver cancer cell also is because the mRNA of this gene expresses due to the rising, and the FUT8 activity of rising can promote the Fucose glycosylation of alpha-fetoprotein, and is also relevant with the sugar chain processing of integral protein.By the gene transfection technology, make liver cancer cell cross high expression level FUT8, can make integral protein excessively fucosylated, suppress liver cancer cell transfer ability in vivo.Therefore the regulation and control of FUT8 genetic expression are still shifted all the growth of tumour cell and are had great importance, and impel this gene to cross high expression level in liver cancer cell, just may suppress the transfer ability of liver cancer cell.
N-total trans dimension methanamide derivative of the present invention, confirm through test: it is to α 1,6 Fucose glycosyltransferases (FUT8) are regulating effect significantly, and toxicity is lower than vitamin A acid, it is stronger than vitamin A acid to suppress the liver cancer cell effect, and the effect of remarkable inhibition liver cancer cell at the intravital metastatic potential of nude mice arranged, and can prepare new type antineoplastic medicine, especially the high and low liver-cancer medicine of survival rate of anti-grade malignancy has higher, potential social benefit and application prospect.
Description of drawings
Fig. 1 is the molecular mass mass spectroscopy collection of illustrative plates of this compound.
Wherein going up sample sample 100 μ mol N-total trans dimension methanamide proline(Pro) is dissolved in 50% methyl alcohol and the 2mm01/l acetic acid.
Fig. 2 is H
1-NMR analyzes collection of illustrative plates.
Embodiment
With all-trans-retinoic acid dry powder is synthesis material; with benzene and phosphorus trichloride effect; and under protection of nitrogen gas, stirred 2.5 hours; present orange-red solution, have a spot of phosphorous acid to separate out on the reaction flask wall, continue under protection of nitrogen gas, to stir 15 minutes; be transferred to dry layering funnel; isolate the benzole soln that generates the dimension formyl chloride, put in the ice bath and stirred 10 minutes, be added dropwise to ice-cold L-proline(Pro); described L-proline(Pro) is dissolved in earlier in the sodium hydroxide solution of 2m01/l; continue to stir, and, remain on more than 9.0 with the pH of the sodium hydroxide solution regulator solution of 2m01/l; deicing is bathed; after the reaction solution stirring reaction spent the night, reaction solution was divided into two-layer, and the upper strata is pale brown look; lower floor's color is darker; with ether extraction three times, the upper strata adds the silica gel pillar, carries out chromatography; the Fractional Collections sample; carry out mass spectroscopy, get the correct part of quality, proceed to analyze.
The function test of The compounds of this invention
1, to the influence in liver cancer cell cycle:
Adopt different concns effect Hep3B liver cancer cell, detect the cell cycle with flow cytometer then, observe the cycle influence of N-total trans dimension methanamide proline(Pro) (ATRP) to liver cancer cell Hep3B cell, the result as seen, N-total trans dimension methanamide proline(Pro) 1 μ mol/l begins promptly to have effect, and the change that 3 μ mol/l do cell cycle time spent has the significance difference, and the period of effect is mainly in the G2-M phase, the ratio of G2-M phase cell is increased, even liver cancer cell rests on the G2-M phase morely.Table 1 is a cell cycle analysis.
2, to liver cancer cell Surface L ew " antigenic expression influence:
N-total trans dimension methanamide proline(Pro) effect Hep3B liver cancer cell 1-3 days, use a series of specific antibodies (Lewis a then, b, x, y and Sialyl Lewis antibody) detect the Lewis antigen presentation amount on observation of cell surface, the result shows, through the effect of N-total trans dimension methanamide proline(Pro) after 3 days, the Lewis x antigen presentation amount of cell surface significantly reduces P＜0.05.Lewis antigen is the important antigen of cell surface, can be used as the part of adhesion molecule, in the transfer of tumour cell, play an important role, the transfer of known Lewis antigen and colorectal carcinoma and liver cancer has confidential relation, after the effect of N-total trans dimension methanamide proline(Pro), the Lewis x expression amount on liver cancer cell surface reduces, and shows that this compound can influence the antigenic expression of liver cancer cell Lewis.Table 2 is this compound influence to liver cancer cell Surface L ewis antigen presentation.
3, to the influence of the core Fucose structure of liver cancer cell surface sugar chain:
The core Fucose is the core that is in the N-type sugar chain, is unique Fucose glycosyl in the N-type sugar chain core texture, and this glycosyl is connected in glycyl glucose in the core texture with α-1,6 glycosidic link.Described core Fucose structure has and LcA (LCA) bonded characteristic, the present invention utilizes LCA in conjunction with the core Fucose, the AAL lectin is in conjunction with the characteristics of periphery side chain Fucose structure, observe the change of liver cancer cell through 3 days later core Fucoses of N-total trans dimension methanamide proline(Pro) effect of 3 μ M, detect and adopt cells were tested by flow cytometry, the result shows, after the effect of N-total trans dimension methanamide proline(Pro), the LCA binding capacity of Hep3B cell surface significantly increases (P＜0.01), and another derivative 4HPR effect of vitamin A acid is not remarkable.
Table 3 is a cell surface sugar chain fucosyl residues content after the effect of N-total trans dimension methanamide proline(Pro).
4, the fucosyl transferase activity of hepatoma Metastasis kitchen range and normal liver tissue
The core Fucose is with α-1, the 6-glycosidic link is connected in core sugar chain, and the enzyme of this glycosidic link of catalysis is α-1,6 fucosyl transferase (α-1,6FT), contain the Fucose glycosyl in the Lewis antigenic structure, above-mentioned glycosyl is normally so that (α-1,3/4 Fucose glycosidic link is connected in sugar chain, the generation of these glycosidic links of catalysis can be (α-1, (α-1,3/4FT), the present invention directly measures and has compared the fucosyl transferase activity of hepatoma Metastasis kitchen range and normal stem cell to 3/4 fucosyl transferase.Described hepatoma Metastasis kitchen range is tissue-derived in nude mice hepatoma Metastasis model, injection Hep3B cell is in the nude mice spleen tissue earlier, dissect nude mice after 2 months, select liver metastasis tissue and normal liver tissue source as enzyme, measure α-1 wherein, 6FT and α-1, the 3FT activity compares, and the result is, the α of metastasis hepatic tissue-1,6FT specific activity parent cell line significantly reduces, and raises (P＜0.05) α of metastasis tissue-1 than normal liver tissue is active, 3FT is active not to have marked difference with normal liver tissue, but much lower than parent cell line yet.The result shows that the Fucose sugar chain structure of metastasis tissue has unusually.
Table 4 is the mensuration of the Fucose glycosyltransferase enzymic activity of hepatic tissue.
N-total trans dimension methanamide proline(Pro) of the present invention and all-trans-retinoic acid (ATRA) and-4-amino-phenol VAAE (4HPR) compares.All-trans-retinoic acid 10 μ M mass actions were in Hep3B cell 3 days, 4-amino-phenol VAAE and N-total trans dimension methanamide proline(Pro) all are that 3 μ M acted on the Hep3B cell 3 days, collecting cell, carry out the mensuration of enzymic activity, the result is that the Hep3B liver cancer cell passed through the effect of N-total trans dimension methanamide proline(Pro) after 3 days, α-1, the 6FT activity rises to 266.47 ± 11.91pmol/hr.mg from 150.51 ± 68.94 of contrast, and two groups of difference have significance (P=0.0007).And all-trans-retinoic acid and the effect of 4-amino-phenol VAAE there are no significant difference, show that The compounds of this invention has liver cancer cell α-1, the active stronger regulating effect of 6FT, and activity is lower 3.3 times than ATRA, and all-trans-retinoic acid and 4-amino-phenol VAAE all do not have tangible regulating effect.
Table 5 be three kinds of compounds to liver cancer cell α-1, the effect of 6FT is (pmol/hr.mg) relatively.
Influence to transfer ability in the liver cancer cell nude mouse:
N-total trans dimension methanamide proline(Pro) and 4-amino-phenol VAAE acted on liver cancer cell Hep3B respectively after 3 days, respectively treated injection cell is observed the formation of metastasis in the nude mouse, relatively N-total trans dimension methanamide proline(Pro) and amino-phenol VAAE are to the influence of the transferance of liver cancer cell.The result shows that after 4-amino-phenol VAAE (4HPR) the effect liver cancer cell, the formation and the control group of metastasis are basic identical, therefore think that the 4HPR pre-treatment can not suppress the transfer of liver cancer cell; And after N-total trans dimension methanamide proline(Pro) of the present invention (ATRP) effect and the processing liver cancer cell, it is obviously low than control group that the transfer of nude mouse inner cell forms, and two groups of difference have significance (P＜0.05).Illustrate that N-total trans dimension methanamide proline(Pro) of the present invention has the effect that liver cancer cell shifts that suppresses, and effect is stronger than vitamin A acid and compound 4-amino-phenol VAAE.
Table 6 is hepatoma Metastasis tests in the nude mouse.
Table 1.
N-total trans dimension methanamide proline(Pro) effect Hep3B cell 4 days
Average
G0-G1 G2-M S G2/G1 transfers the cell of dying
Standard deviation
Contrast 60.11 4.21 35.68 2.08 0.29
±3.93 ±0.87 ±3.06 ±0.03 ±0.03
1uM 60.82 16.59 22.70 2.01 1.05
±9.2 ±5.98 ±3.21 ±0.01 ±0.35
3μM 63.66 16.05
* 20.30 2.00 2.42
±7.88 ±2.94 ±4.9 0.00 ±0.4
6μM 58.04 17.87
* 24.10 2.00 2.77
±11.07 ±5.01 ±6.1 0.00 ±1.37
9μM 53.84 17.6
* 28.56 2.04 4.09
±7.84 ±2.4 ±4 ±0.01 ±1.3
n＝3
*P＜0.01
Table 2.
Lewis?a Lewis?b Lewis?y Lewis?x Sialyl?Lewis?x
Fate contrast ATRP contrast ATRP contrast ATRP contrast ATRP contrast ATRP
3 days 0.056 0.0579 0.0457 0.0497 0.1093 0.1181 0.1721 0.01586
*0.0706 0.0699
±0.0129 ±0.014 ±0.014 ±0.014 ±0.0172 ±0.0121 ±0.0243 ±0.02 ±0.0217 ±0.0202
P?value 0.4227 0.0523 0.1317 0.0465 0.3917
2 days 0.065 0.0477 0.0307 0.036 0.0923 0.1077 0.15 0.138 0.0457 0.0477
±0.0174 ±0.0142 ±0.0023 ±0.0044 ±0.0114 ±0.0084 ±0.0225 ±0.0151 ±0.004 ±0.0025
P?value 0.1609 0.1499 0.1532 0.14997 0.21902
1 day 0.0133 0.012 0.014 0.0123 0.038 0.0323 0.051 0.051 0.012 0.013
±0.0042 ±0.001 ±0.0025 ±0.0004 ±0.0056 ±0.0022 ±0.0078 ±0.0091 ±0.0017 ±0.0025
P?value 0.3127 0.128 0.0947 0.4736 0.2114
Table 3.
Average Hep3B LCA LCA
SD Control 4HPR ATRP sticks the weak strong cell of cell adhesion
LCA 137.72 156.26 186.61
* 160.23 171.39
±12.7 ±30.65 ±13.95 ±7.79 ±18.86
AAL 760.34 717.65 755.11 356.56 227.13
±12.17 ±7.89 ±41.43 ±62.52 ±74.51
N＝4
*P＜0.01
Table 4.
The normal Hep3B that shifts
Hepatic tissue cancerous tissue lymph-node cell
α-1，6FT 6.35 13.82 26.07 177.4
±1.69 ±3.64 ±10.03 ±5.04
P value 0.0222
*
α-1，3FT 11.68 9.62 8.74 47.17
±0.93 ±4.81 ±0.58 ±4.12
P value 0.2175
*
*Compared?with?normal?liver?tissues?and?parent?Hep3B?cells.
n＝4
Table 5.
Cell contrast 4HPR ATRP HPR+ATRP ATRA
Average SD Average SD Average SD Average SD Average SD
Hep3B 150.51 68.94 139.64 14.18 266.47 11.91 ND 223.77 73.66
P?value 0.7496 0.0007 0.3109
sub-Hep3B
LCA
Adherent cell 227.39 64.07 287.58 72.12 359.84 19.54 414.05 65.55 199.65 24.23
P?value 0.3163 0.0034 0.075 0.4424
LCA
Adherent cell 201.09 57.45 255.57 90.03 261.15 13.84 200.03 45.2 130.67 11.7
P?value 0.3027 0.0063 0.9236 0.0062
F1 melanochrome
Oncocyte 79.58 13.27 100.27 28.2 125.37 93.48 ND ND
P?value 0.4165 0.5057
n＝4
ND＝not?done
Table 6
Because metastases is dead
The nude mice that cell grouping nude mice shifts
The nude mice that dies
Hep3B 4HPR 8 8 1
ATRP 8 1
* 0
*P＜0.05
Claims (7)
1, N-total trans dimension methanamide derivative is characterized in that having the structure of general formula I:
Wherein R represents proline(Pro).
2, by the described N-total trans dimension methanamide derivative of claim 1, it is characterized in that described derivative is a N-total trans dimension methanamide L-proline(Pro), has following structural formula:
It calculates molecular weight is 398.
3, a kind of preparation method of N-total trans dimension methanamide derivative of claim 1 is characterized in that being undertaken by following step:
1) gets all-trans-retinoic acid dry powder and benzene and phosphorus trichloride effect;
2) nitrogen stirs down, isolates the benzole soln that generates the dimension formyl chloride, adds proline(Pro);
3) basic solution is regulated pH value 9-12, spends the night;
4) with carrying out chromatography after the ether extraction, the correct part of quality is got in mass spectroscopy.
4, by the preparation method of claim 3, it is characterized in that described basic solution is a sodium hydroxide solution.
5, by the preparation method of claim 3, it is characterized in that churning time is 2-5 hour under the described nitrogen.
6, the application of the described N-total trans dimension methanamide derivative of claim 2 in the preparation antitumor drug.
7, the application of the described N-total trans dimension methanamide derivative of claim 1 in the preparation medicines resistant to liver cancer.
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