CN105566145A - Amino acid derivative and application thereof - Google Patents

Amino acid derivative and application thereof Download PDF

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Publication number
CN105566145A
CN105566145A CN201510618183.8A CN201510618183A CN105566145A CN 105566145 A CN105566145 A CN 105566145A CN 201510618183 A CN201510618183 A CN 201510618183A CN 105566145 A CN105566145 A CN 105566145A
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amino acid
acid derivative
compound
cancer
carcinoma
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臧仕宁
范恒梅
朱伟
廖瑞斌
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Guangzhou Dehuihang Pharmaceutical Co Ltd
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Guangzhou Dehuihang Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Abstract

The invention discloses an amino acid derivative and application thereof. The amino acid derivative contains an oxalyl group, can interfere energy metabolism of cells and induce cell apoptosis and is widely applicable.

Description

Amino acid derivative and application thereof
Technical field
The present invention relates to amino acid derivative and application thereof.
Background technology
20 th century later since nearly 30 years pathogenesis of cancer always in the trend risen, according to the World Health Organization (WHO) report, nineteen ninety whole world cancer neopathy number of cases about 8,070,000, than 1975 5,170,000 add 37.4%.And the cancer mortality number about 6,200,000 in the whole world in 1997, and by current trend prediction, to the year two thousand twenty along with world population reaches 8,000,000,000,20,000,000 new cancer cases will be had, wherein death toll will reach 1,200 ten thousand, and wherein the overwhelming majority will occur in developing country.
The health of tumour serious harm people, brings huge economical load to patient and society.Effectively carry out Diagnosis and Treat to tumour and have very actual meaning, the Diagnosis and Treat of tumour is the focus of existing medical research.
Tumour of a great variety, characteristic differs, and also differs to the reaction of medicine, and this leads oncogenic treatment is very difficulty.Present stage, the treatment of tumour mainly contains modus operandi and pharmacological agent.Operative treatment is mainly used in the tumour being applicable to not occur to shift, and surgical effect is different according to the difference of tumour, limited more, larger to the infringement of normal human.Pharmacological agent is based on chemotherapy, and known, and Chemotherapeutic Drugs On Normal cell also has stronger lethal effect, and side effect is large, and its use is also restricted.
No matter being operative treatment or pharmacological agent, is all helpless for the malignant tumour occurring to shift.Develop various tumour, particularly to the antitumor drug that the tumour that there occurs transfer all has a better lethal effect, there is very actual meaning.
Summary of the invention
One object of the present invention is to provide class of amino acid derivative.
Another object of the present invention is to provide above-mentioned amino acid derivative preparing the application in antitumor drug.
Another object of the present invention is to provide a kind of antitumor drug.
The technical solution used in the present invention is:
Amino acid derivative, its general structure such as formula shown in I ~ VI,
In formula:
X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof;
R or R' is independently selected from the L-type amino acid of composition human body protein, or the amino acid whose side chain substituents of D-type and simple modifier thereof, or forms the side chain substituents of intermediate of native amino acid metabolic in various human body;
Y, Y 1, Y 2independent is polypeptide;
Described amino acid derivative also comprises its pharmaceutical salts, ester or ether;
Described amino acid derivative does not comprise and other disclosed in meet the compound of above-mentioned general formula.
As the further improvement of above-mentioned amino acid derivative, R, R ' be independently selected from L-glutamic acid, glutamine, citrulline, ornithine, Gelucystine, aspartic acid, l-asparagine, Threonine, Serine, leucine, Isoleucine, glycine, halfcystine, methionine(Met), tryptophane, tyrosine, phenylalanine, α-amino-isovaleric acid, Methionin, hydroxylysine, oxyproline, proline(Pro), Methionin, the side chain substituents of Histidine and simple modifier thereof.
As the further improvement of above-mentioned amino acid derivative, the structural formula of amino acid derivative is and simple modifier.
As the further improvement of above-mentioned amino acid derivative, Y, Y 1, Y 2be independently 2 ~ 12 peptides.Especially, Y, Y 1, Y 2it is independently the cancer target peptide of 2 ~ 12.
As the further improvement of above-mentioned amino acid derivative, the pharmaceutical salts of amino acid derivative is selected from its sodium, potassium, calcium, zinc, lithium, iron, magnesium salts, sulfonate; The medicinal ester of amino acid derivative is selected from the ester between its C2 ~ C4; The medicinal ether of amino acid derivative is selected from the ether between its C2 ~ C4.
Amino acid derivative is preparing the application in antitumor drug, the general structure of amino acid derivative such as formula shown in I ~ VI,
In formula:
X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof;
R or R' is independently selected from the L-type amino acid of composition human body protein, or the amino acid whose side chain substituents of D-type and simple modifier thereof, or forms the side chain substituents of intermediate of native amino acid metabolic in various human body;
Y, Y 1, Y 2independent is polypeptide;
Described amino acid derivative also comprises its pharmaceutical salts, ester or ether;
Or amino acid derivative as above.
Tumour is selected from lung cancer, liver cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, ovarian cancer, nasopharyngeal carcinoma, tongue cancer, skin carcinoma, mammary cancer, prostate cancer, melanoma, skin carcinoma, granulocyte leukemia, Lymphocytic leukemia, osteosarcoma, lymphosarcoma.
A kind of antitumor drug, its activeconstituents is at least one in amino acid derivative as implied above.
Preferably, tumour is selected from lung cancer, liver cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, ovarian cancer, nasopharyngeal carcinoma, tongue cancer, skin carcinoma, mammary cancer, prostate cancer, melanoma, skin carcinoma, granulocyte leukemia, Lymphocytic leukemia, osteosarcoma, lymphosarcoma.
The synthesis technique of amino acid derivative, comprises following synthetic route:
In the process of synthesis, p-OH ,-NH as required 2or R group carries out protecting and deprotection;
In formula: X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof.
The invention has the beneficial effects as follows:
Amino acid derivative of the present invention, targeting can suppress lung cancer, liver cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, ovarian cancer, nasopharyngeal carcinoma, tongue cancer, skin carcinoma, mammary cancer, prostate cancer, melanoma, skin carcinoma, granulocyte leukemia, Lymphocytic leukemia, osteosarcoma, the serum lactic dehydrogenase of the malignant tumor tissues such as lymphosarcoma, citrate synthase, ketoglurate dehydrogenase complex protein is active, specificity interference tumour cell produces ATP, destroy its energy metabolism, thus inducing death of neoplastic cells and apoptosis, strengthen cancer cell multiplication, growth, the restraining effect of transfer etc., there is the antitumor pharmacodynamic activity of high-efficiency low-toxicity, all have various malignant tumours such as above-mentioned highly energy-consuming high flow rates and kill and wound preferably or restraining effect.
Amino acid derivative of the present invention, has water-soluble preferably, is easy to make injection formulations.
Partial amino-acid derivative is oral simultaneously still has better, and even better anti-tumor activity, is not available for existing antitumor drug, greatly facilitates the use of patient, overcome the defects such as existing antitumor drug depends on injection, and security is low.
Amino acid derivative of the present invention, synthesis technique is simple, with low cost, is easy to purifying and suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is compound 2 1hNMR spectrogram;
Fig. 2 is compound 2 13cNMR spectrogram;
Fig. 3 is compound 3 1hNMR spectrogram;
Fig. 4 is compound 3 13cNMR spectrogram;
Fig. 5 is compound 4 1hNMR spectrogram;
Fig. 6 is compound 4 13cNMR spectrogram;
Fig. 7 is compound 6 1hNMR spectrogram;
Fig. 8 is compound 6 13cNMR spectrogram;
Fig. 9 is compound 7 1hNMR spectrogram;
Figure 10 is compound 7 13cNMR spectrogram;
Figure 11 is compound 8 1hNMR spectrogram;
Figure 12 is compound 8 13cNMR spectrogram;
Figure 13 ~ 18 are the external antitumor spectra of different compound respectively;
Figure 19 is the impact of different compound on animals tranquillization metabolisable energy;
Figure 20 is the impact of ATP content in different compound on animals transplanted tumor tissue;
The tumour inhibiting rate of different tumor model in the different compound on animals body of Figure 21 ~ 31.
Embodiment
Amino acid derivative, its general structure such as formula shown in I ~ VI,
In formula:
X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof;
R or R' is independently selected from the L-type amino acid of composition human body protein, or the amino acid whose side chain substituents of D-type and simple modifier thereof, or forms the side chain substituents of intermediate of native amino acid metabolic in various human body;
Y, Y 1, Y 2independent is polypeptide;
Described amino acid derivative also comprises its pharmaceutical salts, ester or ether;
Described amino acid derivative does not comprise and other disclosed in meet the compound of above-mentioned general formula.
In the present invention, the simple modifier of group refers to when not changing group agent structure, simply replaces, addition to group, replaces one or more H as used hydroxyl; Halo or with the small molecules esterification of C2 ~ C4, etherificate; When group has carboxyl or amido, carboxyl or amino amide.
Amino acid derivative of the present invention can be L-type, also can be D type.Wherein the structure of L-type and the structure of natural amino acid more close, but it is equally easily by metabolism in vivo, the transformation period is shorter, and onset time is shorter; D type amino acid derivative also can be identified and combine preferably, and be more difficult to by metabolism in vivo, the transformation period is longer, and onset time is longer.Different amino acid derivative can be selected as required as antitumor activity component.
As the further improvement of above-mentioned amino acid derivative, the structural formula of amino acid derivative is and simple modifier.Especially, when amino acid derivative is or when its pharmaceutical salts, ester, ether or acid amides, amino acid derivative can make oral preparations, and there is fine anti-tumor activity.
Tumour cell target polypeptide (2 ~ 10 peptide) has targeting and is distributed in tumor tissues, better can be positioned tumour cell and absorb by tumour cell, be easier to occur pharmaceutical active
Preferably, Y, Y in said structure general formula 1, Y 2be independently 2 ~ 12 peptides, further, Y, Y 1, Y 2be independently 2 ~ 10 peptides, 2 ~ 8 peptides, 2 ~ 7 peptides, 2 ~ 4 peptides.Better, Y, Y 1, Y 2it is independently the cancer target peptide of 2 ~ 12.Further, Y, Y 1, Y 2be independently the cancer target peptide of 2 ~ 10,2 ~ 8,2 ~ 7,2 ~ 4, particularly those be proved be easier to be absorbed by tumour cell and be applied to albumen synthesis polypeptide.
As the further improvement of above-mentioned amino acid derivative, the pharmaceutical salts of amino acid derivative is selected from its sodium, potassium, calcium, zinc, lithium, iron, magnesium salts, sulfonate; The medicinal ester of amino acid derivative is selected from the ester between its C2 ~ C4; The medicinal ether of amino acid derivative is selected from the ether between its C2 ~ C4.
Amino acid derivative is preparing the application in antitumor drug, the general structure of amino acid derivative such as formula shown in I ~ VI,
In formula:
X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof;
R or R' is independently selected from the L-type amino acid of composition human body protein, or the amino acid whose side chain substituents of D-type and simple modifier thereof, or forms the side chain substituents of intermediate of native amino acid metabolic in various human body;
Y, Y 1, Y 2independent is polypeptide;
Described amino acid derivative also comprises its pharmaceutical salts, ester or ether;
Or amino acid derivative as above.
Especially, amino acid derivative is and simple modifier.
Tumour is selected from lung cancer, liver cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, ovarian cancer, nasopharyngeal carcinoma, tongue cancer, skin carcinoma, mammary cancer, prostate cancer, melanoma, skin carcinoma, granulocyte leukemia, Lymphocytic leukemia, osteosarcoma, lymphosarcoma.
A kind of antitumor drug, its activeconstituents is at least one in amino acid derivative as implied above.
Preferably, tumour is selected from lung cancer, liver cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, ovarian cancer, nasopharyngeal carcinoma, tongue cancer, skin carcinoma, mammary cancer, prostate cancer, melanoma, skin carcinoma, granulocyte leukemia, Lymphocytic leukemia, osteosarcoma, lymphosarcoma.
The synthesis technique of amino acid derivative, comprises following synthetic route:
In the process of synthesis, p-OH ,-NH as required 2or R group carries out protecting and deprotection;
In formula: X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof.
For the amino acid derivative that there is polypeptide structure, on the basis of above-mentioned synthesis step, more corresponding solid phase synthesis can be carried out.
Because amino acid derivative structure of the present invention is simple, existing compou nd synthesis company also directly can be entrusted to synthesize and to obtain.
The metabolism of tumour cell is vigorous, a large amount of amino acid is absorbed in its necessary for growth, energy supply small molecules etc., when amino acid derivative of the present invention acts on tumour cell, can assemble by a large amount of targeting Cumulate Sum in tumor tissues and tumour cell, can by the citrate synthase of substrate-level lift mechanism feedback Tumor suppression tissue, ketoglurate dehydrogenase complex protein activity (these two kinds of enzymes are the rate-limiting enzyme that tricarboxylic acid cycle is carried out), simultaneously, also ATP can be produced by specificity interference tumour cell Mitochondria complex IV complex of cytochrome c oxidase, thus inducing death of neoplastic cells and apoptosis, strengthen cancer cell multiplication, growth, the restraining effect of transfer etc., and normal cell metabolism speed is starkly lower than tumour cell, less to amino acid derivative intake of the present invention, the energy metabolism of cell, that material synthesizes the impact be subject to is less equally, does not have obvious lethal effect.Therefore, amino acid derivative of the present invention has the antitumor pharmacodynamic activity of high-efficiency low-toxicity.
Amino acid derivative of the present invention by the impact whether tumour shifts, can be applied to the treatment of each staged tumors on the suppression of tumour, lethal effect, simultaneously also can with existing antitumor drug coupling, play better antitumous effect.Same, also can coupling between amino acid derivative of the present invention, the energy metabolism of blocking-up tumour as much as possible, to play better antitumous effect.
Below in conjunction with concrete synthesis example, the synthesis technique of further exemplary illustration amino acid derivative of the present invention.
The synthesis of amino acid derivative
Oxalic acid acyl L-glutamic acid (compound 4) synthetic route
Overall synthetic route is as follows,
Concrete synthesis technique is as follows:
The synthesis technology route of compound 2
The compound 1 taking 1.0eq is dissolved in the addition of C H 2cl 2in, under agitation condition, add the Et of 2.2eq 3n is in above-mentioned reaction solution.Under ice bath, agitation condition, the EtOOC-COCl of 1.1eq is dropwise added in above-mentioned reaction solution, be added dropwise to complete the bath of recession deicing, stirring at room temperature, and HPLC monitoring is carried out in sampling, the rear stopped reaction until raw material peak disappears.Elimination white insoluble solids, organic phase uses 5%NaHCO respectively 3the aqueous solution, saturated aqueous common salt, 10%KHSO 4the aqueous solution and saturated aqueous common salt respectively wash 1 time, collect organic phase, are spin-dried for concentrated and dry thick compound 2, yield 90%, HPLC purity 95%.
The nuclear magnetic data of compound 2 is:
1hNMR (400Hz, CD 3oD) δ: 4.28-4.38 (m, 2H), 2.31-2.35 (t, 2H), 1.93-2.21 (m, 2H), 1.44-1.47 (d, 18H), 1.32-1.37 (t, 3H), its hydrogen spectrum is as shown in Figure 1;
13cNMR (400Hz, CD 3oD) δ: 173.60,171.38,161.07,159.27,83.41,81.92,63.93,54.22,32.50,28.33,28.21,27.30,14.25, its carbon spectrum as shown in Figure 2;
MS (EI) m/z (100%): 358.1 (M -, 100), theoretical value 359.3;
The synthesis technology route of compound 3
Be dissolved in methyl alcohol by compound 2, and add the appropriate 1mol/LNaOH aqueous solution and regulate its pH8-9, By Hydrolysis At Room Temperature, HPLC monitors reaction.After reaction terminates, adjust pH value of solution 2-3 with hydrochloric acid, concentrated by rotary evaporation removing methyl alcohol, is extracted with ethyl acetate twice, after merging extracted organic phase, with brine It once, be spin-dried for concentrated and dry compound 3, yield 85%, HPLC purity 96%.
The nuclear magnetic data of compound 3 is:
1hNMR (400Hz, CD 3oD) δ: 2.31-2.34 (t, 2H), 1.93-2.21 (m, 2H), 1.44-1.47 (d, 18H), its hydrogen spectrum is as shown in Figure 3;
13cNMR (400Hz, CD 3oD) δ: 173.62,171.45,162.20,160.07,83.40,81.93,54.21,32.50,28.33,28.21,27.37, its carbon spectrum as shown in Figure 4;
MS (EI) m/z (100%): 330.2 (M -, 100), theoretical value 331.3;
The synthesis technology route of compound 4
Compound 3 is dissolved in the TFA of 3 times of volumes, HPLC monitors reaction.After reaction terminates, concentrated by rotary evaporation removing TFA.Add suitable quantity of water to dissolve, use CH 2cl 2once, aqueous phase obtains white powder compound 4 through lyophilize, yield 90%, purity 96.8% in washing.
The nuclear magnetic data of compound 4 is: 1hNMR (400Hz, CD 3oD) δ: 4.47-4.54 (m, 1H), 2.39-2.46 (m, 2H), 2.01-2.33 (m, 2H), its hydrogen spectrum is as shown in Figure 5;
13cNMR (400Hz, CD 3oD) δ: 176.31,173.86,162.22,160.09,53.45,30.98,27.37, its carbon spectrum as shown in Figure 6;
MS (EI) m/z (100%): 113 (M --106,100), theoretical value 219;
Oxalic acid acyl glutamine (compound 8) synthetic route
Overall synthetic route is as follows,
Concrete synthesis technique is as follows:
The synthesis technology route of compound 6
The compound 5 taking 1.0eq is dissolved in the addition of C H 2cl 2in, under agitation condition, add the Et of 2.2eq 3n is in above-mentioned reaction solution.Under ice bath, agitation condition, the EtOOC-COCl of 1.1eq is dropwise added in above-mentioned reaction solution, be added dropwise to complete the bath of recession deicing, stirring at room temperature, and HPLC monitoring is carried out in sampling, the rear stopped reaction until raw material peak disappears.Elimination white insoluble solids, organic phase uses 5%NaHCO respectively 3the aqueous solution, saturated aqueous common salt, 10%KHSO 4the aqueous solution and saturated aqueous common salt respectively wash 1 time, collect organic phase, are spin-dried for concentrated and dry thick compound 6, yield 88%, HPLC purity 96%.
The nuclear magnetic data of compound 6 is:
1hNMR (400Hz, CD 3oD) δ: 4.31-4.34 (m, 1H), 3.57-3.62 (m, 2H), 2.29-2.33 (t, 2H), 1.99-2.24 (m, 2H), its hydrogen of 1.50 (s, 9H), 1.15-1.19 (t, 3H) spectrum as shown in Figure 7;
13cNMR (400Hz, CD 3oD) δ: 177.45,171.38,160.12,159.08,83.47,58.32,54.66,32.41,28.18,27.72,18.37, its carbon spectrum as shown in Figure 8;
MS (EI) m/z (100%): 301.2 (M -, 82) and 113.1 (100), theoretical value 302.2;
The synthesis technology route of compound 7
Be dissolved in methyl alcohol by compound 6, and add the appropriate 1mol/LNaOH aqueous solution and regulate its pH8-9, By Hydrolysis At Room Temperature, HPLC monitors reaction.After reaction terminates, adjust pH value of solution 2-3 with hydrochloric acid, concentrated by rotary evaporation removing methyl alcohol, collecting by filtration white insolubles, filter cake cold water washing twice, collect filter cake and dry compound 7, yield 85%, HPLC purity 95%
The nuclear magnetic data of compound 7 is:
1hNMR (400Hz, CD 3oD) δ: 4.31-4.35 (m, 1H), 2.27-2.33 (t, 2H), 1.97-2.24 (m, 2H), 1.47 (s, 9H), its hydrogen spectrum is as shown in Figure 9;
13cNMR (400Hz, CD 3oD) δ: 177.47,171.47,162.35,160.32,83.49,54.57,32.38,28.19,27.83, its carbon spectrum as shown in Figure 10;
MS (EI) m/z (100%): 273.2 (M -, 100), theoretical value 274.2;
The synthesis technology route of compound 8
Compound 7 is dissolved in the TFA of 3 times of volumes, HPLC monitors reaction.After reaction terminates, concentrated by rotary evaporation removing TFA.Add suitable quantity of water to dissolve, use CH 2cl 2once, aqueous phase obtains white powder compound 8 through lyophilize, yield 90%, purity 90% in washing.
The nuclear magnetic data of compound 8 is:
1hNMR (400Hz, CD 3oD) δ: 4.44-4.71 (s, 1H), 2.31-2.35 (m, 2H), 2.05-2.28 (m, 2H), its hydrogen spectrum is as shown in Figure 11;
13cNMR (400Hz, CD 3oD) δ: 177.58,173.79,162.27,160.13,53.71,32.50,28.01, its carbon spectrum as shown in Figure 12;
MS (EI) m/z (100%): 113.1 (M --105,100), theoretical value 218.2.
Use such scheme to synthesize the compound 2,3,4,6,7,8 obtained below to test, to confirm its function.
Safety experiment
1, amino acid derivative is to L929 cytotoxicity experiment
Cell cultures and Cytotoxicity evaluation
L-929 cell 37 ± 1 DEG C 5% ± 1% carbonic acid gas gaseous environment neutralization comprise recommend medium tissue culture flasks moist environment in, add in the cell culture medium (American I nvitrogen company) of 10% foetal calf serum and the microbiotic (American I nvitrogen company) such as penicillin (100units), Streptomycin sulphate (100 μ g) and cultivate, to reach the cell density of requirement of experiment.With PBS rinsing monolayer cell twice, PBS is siphoned away, at 0.25% trypsinase/EDTA, digest in the tissue culture flasks of 37 ± 1 DEG C, until cellular segregation is with floating.
By the Vitro Cytotoxicity of compound 2,3,4,6,7,8 pairs of L929 cells of our design and synthesis, and perform according to the morphological analysis of the cell strain of ISO10993-part5.
The qualitative appearance classification of table 1 toxicity of compound
Test event, observes the Vitro Cytotoxicity of compound 2,3,4,6,7 and 8 pairs of L929 cells.Various compound all adopts the DMEM of 5% to dilute, compound concentration to 100 μM, and is diluted to 50 μMs respectively, 25 μMs, 12.5 μMs, 6.25 μMs 5% DMEM diluent, add 5%CO respectively 2in the confluent monolayer cell of the L-929 mouse fibroblast cultivated.Independently three parts of test fluid are respectively positive control (cis-platinum, positive control) in addition, negative control (physiological saline) and Vehicle controls (5%DMEM).All test fluid are all the 5% ± 1%CO of 37 ± 1 DEG C in temperature 2middle cultivation 24 hours.Monolayer cell is aobvious positive in testing, and reagent controls test solution, after cultivating, is detected any change going for 24 ± 1 hours to judge cellular form under the microscope.
Result
Under the condition of this research, compound 2,3,4,6,7,8 is under the concentration of 100 μMs, and the observation of 24 ± 1 hours, finds lower to L-929 cytotoxicity or do not have obvious cytotoxicity.
After 24 hours after incubation, morphologic observation and biological respinse, the results are shown in Table 2.
The qualitative appearance classification of the tested drug compound toxicity of table 2
By reagent Interflow individual layer Per-cent Intracellular granular Dissolve Rank Reaction
100 μMs of compounds 2 Nothing <50％ Have Nothing 2 Gentle
100 μMs of compounds 3 Nothing <50％ Have Nothing 2 Gentle
100 μMs of compounds 4 Have <20％ Have Nothing 1 Slightly
100 μMs of compounds 6 Have 0％ Have Nothing 0 No reaction
100 μMs of compounds 7 Have 0％ Have Nothing 0 No reaction
100 μMs of compounds 8 Have 0％ Have Nothing 0 No reaction
Cis-platinum Nothing >70％ Nothing Nothing 4 Acutely
Negative control (NS) Have 0％ Have Nothing 0 No reaction
Blank (solvent) Have 0％ Have Nothing 0 No reaction
。
Conclusion
The toxicity data of compound 2,3,4,6,7,8 pairs of L929 cells shows, at 100 μMs, 50 μMs, and 25 μMs, 12.5 μMs, 6.25 μMs 5% DMEM diluent act on L929 cell, through 24 hours observe, when peak concentration 100 μMs find there is no obvious cytotoxicity.
2, the killing experiments (IC of the cancer cell in vitro of amino acid derivative 50)
Experiment material and instrument
Medicine 2,3,4,6,7,8, reference substance cis-platinum, people lung cancer H460, H1650, SPC-A-1, A549 cell strain, HepG2 cell, breast cancer cell line MCF-7, colon cancer cell line HT-29 strain, prostate cancer PC-3, DU145 cell strain, s strain, gastric cancer cell line MGC-803 strain, DMEM substratum, 10%FBS calf serum, MTT reagent, DMSO, 96 orifice plates, microplate reader etc.Compound 2 (20140701), compound 3 (20140506), compound 4 (20140305), compound 6 (20140508), compound 7 (20140602), compound 8 (20140304) are from the synthesis in applicant laboratory.
Experimental technique and step
1) logarithmic phase cell is collected;
2) cell count is adjusted to be 4 × 10 3individual/L, every hole adds 100uL;
3) cultivate 12 hours;
4) interpolation is respectively the medicine of 0.5,2.5,5.0,10,25,50,100 μM of concentration and the positive control medicine cis-platinum of 0.5,2.5,5.0,10,25,50,100 μM of concentration by reagent and positive control drug concentration gradient; Establish Vehicle controls group in addition
5), after cultivating 24, every hole adds MTT (5mg/ml) solution 20 μ l;
6) hatch 4h, stop cultivating, inhale and abandon supernatant liquor;
7) DMSO100ul/ hole is added, vibration 10min;
8) put microplate reader to measure, λ=490nm;
9) record result, draw a diagram.
By following formulae discovery medicine to the growth inhibition ratio of cell and IC50:
IR%=(1-experimental group OD value/control group OD value) × 100%
Result: compound 2,3,4,6,7,8 0.5,2.5,5.0,10,25,50,100 μM 5% DMEM diluent, act on external lung cancer H460, H1650, SPC-A-1, A549 cell, hepatoma Hep G 2 cells, MCF-7 Breast Cancer Cell, colon cancer cell line HT-29, prostate cancer PC-3, DU145 cell, s, gastric cancer cell line MGC-803 respectively, observed through 24 hours, observe compound 2,3,4,6,7,8 to 50% inhibiting rate (IC of above-mentioned cell 50).
Compound 2,3,4,6,7,8 acts on lung cancer H460, H1650, SPC-A-1, A549 cell, hepatoma Hep G 2 cells, MCF-7 Breast Cancer Cell, colon cancer cell line HT-29, prostate cancer PC-3, DU145 cell, s, gastric cancer cell line MGC-803 respectively, after 24 hours hatch, adopt MTT method to detect anti-tumor activity find, compound 2,3,4,6,7,8 has certain antitumor action (seeing Figure 13 ~ 18 respectively), but compared with positive controls cis-platinum, its Anti-tumor angiogenesis external of amino acid derivative is not high.
3, Mouse Acute Toxicity experiment
SPF level KM kind mouse, independent ventilation systems (IVC) facility of animal rearing in SPF level laboratory animal room.Group support, freely drinks water, takes food, and laboratory temperature is 20 ~ 25 DEG C, and humidity is 40 ~ 70%.Animal housing's condition remains stable, with the reliability of warranty test result.Feed and drinking-water: feed is SPF level particle mouse material, purchased from Guangdong Medical Lab Animal Center, nutrition and health meet the requirement of SPF level laboratory animal.Drinking-water freely absorbs.
Clinical plan approach: oral administration.
Prerun data: the compound 8 (20140304) that applicant synthesizes voluntarily is with maximal dose, and namely after the administration of 1800.mg/kgbw peak concentration maximum volume single oral, the mortality ratio of mouse is 0%.
Animal divides into groups: get qualified, the satisfactory animal of body weight 140 of quarantine, be divided into 14 groups at random by body weight and sex, often organize 10, male and female half and half.Test medicine is prepared: Weigh Compound 8 lyophilized injectable powder, and physiological saline solution is prepared.Route of administration and number of times: single oral administration.Administration volume: 10ml/kg.Animal on an empty stomach between: fasting 6 ~ 12 hours before administration, fasting 4 hours after administration.
O&E: overview: the response situation of observing animal after administration immediately, and continuous observation 4 hours, later every morning respectively observes 1 time, Continuous Observation 14 days, record animal poisoning manifestations and feature, toxic reaction time of occurrence, extinction time and death time of animal.
Body weight determination: difference (d before administration 1), 24 hours (d after administration 2), the 4th day (d 4), the 8th day (d 8), the 11st day (d 11) and the 15th day (d 15) weigh the weight of animals.
Pathological examination: to be poisoned to death or moribund animals carries out cuing open inspection in time, other animals carry out cuing open inspection after the observation period terminates, and when finding that histoorgan occurs that volume, color, quality etc. change, then carry out histopathologic examination to the histoorgan changed.The histoorgan cuing open inspection comprises thymus gland, the heart, lung, liver, spleen, pancreas, kidney, suprarenal gland, stomach, intestines (duodenum, jejunum, ileum, caecum, colon, rectum), lymphoglandula, bladder, prostate gland, testis (attached testis), uterus, ovary.
Observation index: in detail record reaction of animals situation, comprises outward appearance, behavioral activity, the mental status, appetite, stool and urine and color thereof, fur, the colour of skin, breathing, nose, eye, oral cavity with or without abnormal secretion thing, the situation such as body weight change and death.
Experimental result: in 14 days, mouse is without death, and after gavage, mouse rolls up, and does not like activity, and analysis is because drug level is too high, and gavage volume is excessive to be caused.Show that compound 8 toxicity is lower, mouse maximum tolerated dose is about 1800mg/kg, is equivalent to 512 times of the clinical plan dosage of people.
Amino acid derivative is on the impact of cellular energy metabolism
1. the antitumor energy metabolism effect of amino acid derivative
Method: the CCM metabolism car adopting MEDGRAPHIC company of the U.S. to produce, allows nude mice tranquillization non-stimulated before test, (index of measurement is air-breathing and the O in exhaling to accept measurement after tranquil 30 minutes 2, CO 2and expiratory gas volume, according to the principle that nitrogen gas concn in air-breathing and expiration is constant, calculate inspiratory capacity.Draw oxygen depletion amount (VO thus 2) and carbonic acid gas generation (VCO 2), in conjunction with the total nitrogen output of twenty-four-hour urine (N).Ambient moisture during test is 50-65%, and temperature is 18-24 DEG C, and normal atmosphere is 101 ~ 102.4kPa (758-768mmHg), and by these data input computer, for instrumental correction.
Again according to formula 3.94 × VO 2+ 1.11 × VCO 2-2.17 × N, calculates energy expenditure.Respiratory quotient is according to RQ=VCO 2/ VO 2calculate, nonprotein respiratory quotient is according to NRQ=(VCO 2-4.754 × N)=(VO 2-5.293 × N) calculate.Obtain amino acid derivative to nude mice lotus knurl A549 animal model Resting energy expenditure REE (RestingEnergyExpenditure, every day energy expenditure total amount: kJ/d) impact, the results are shown in Figure 19:
Compound 2 (20140701), compound 3 (20140506), compound 4 (20140305), compound 6 (20140508), compound 7 (20140602), compound 8 (20140304) are from the synthesis in applicant laboratory.As can be seen from Figure 19, the 10th day and the 14th day upon administration, model group and cis-platinum group and compound 2,3,4,6,7,8 groups significantly can reduce the energy metabolism of tumor tissues.
2.ATP nucleus formation
ATP detection kit (ATPAssayKit) is utilized to detect ATP (adenosine5'-triphosphate) level in tumor bearing nude mice tumor tissues.Changing when fluorescein produces fluorescence according to Photinus pyralis LUC (fireflyluciferase) needs ATP to provide energy to develop.When Photinus pyralis LUC and fluorescein are all excessive, in certain concentration range, the generation of fluorescence and the concentration of ATP are directly proportional.So just can detect the ATP concentration in solution with sensitivity.Detection kit used can the low ATP reaching 5nmol/L of detectable level.And the concentration of ATP is only 0.1-1 μm of ol/L in the cell or tissue lysate of routine, the intracellular ATP levels of some usual cell is about 10nmol/mg albumen.When detecting ATP concentration in cell or tissue, after the lysate cracking provided with this test kit, namely can measure ATP concentration.
Compound 2 (20140701), compound 3 (20140506), compound 4 (20140305), compound 6 (20140508), compound 7 (20140602), compound 8 (20140304) are from the synthesis in applicant laboratory.Compound 2,3,4,6,7,8, on the impact of ATP content in tumor bearing nude mice A549 transplanted tumor tissue, is shown in Figure 20.
As can be seen from Figure 20, the 14th day upon administration, model group and cis-platinum group and compound 2,3,4,6,7,8 groups significantly can reduce the ATP content of tumor tissues, but compared with cis-platinum group, the effect that compound 2,4 and 6 suppresses ATP to generate has significant difference.
The antitumor pharmacodynamic experiment of amino acid derivative
Laboratory animal:
Healthy Balb-c nude mice, male female half and half, about 4 week age, body weight 18-22g, purchased from Guangdong Medical Lab Animal Center.Get Tumor diameter after inoculation 2-3 week and be about the nude mice of 0.5-1.0cm for experiment.
Clone:
Human malignant lesion's cell strain H460, H1650, SPC-A-1, A549, HepG2, MCF-7, HT-29, PC-3, DU145, Hela, MGC-803.
The foundation of SPCA model of nude mice bearing tumor:
Healthy Balb-c nude mice 70, male, 4 ~ 5 week age, body weight 18-22g.Non-small cell lung carcinoma cell strain H460, H1650, SPC-A-1, A549, HepG2, MCF-7, HT-29, PC-3, DU145, Hela, MGC-803, adjustment cell density is about 1 × 10 7individual/ml, in nude mice front right oxter subcutaneous vaccination 0.2ml/ only, treat that tumour grows to about 1.0 × 1.0cm after 2-3 week, put to death, get tumor tissues evenly to shred, it is subcutaneous that sleeve pipe is seeded to tested nude mice front right oxter, observes after inoculation 1-2 week, tumor formation rate reaches 98.6%, and the nude mice selecting tumor growth about 0.5 × 0.5cm is used for experiment.
Amino acid derivative is to the tumor-inhibiting action of H460 cell strain tumor bearing nude mice
Animal divides into groups:
Select the model tumor bearing nude mice that gross tumor volume is about 0.5 × 0.5cm and carry out random packet, compound 2 (20140701), compound 3 (20140506), compound 4 (20140305), compound 6 (20140508), compound 7 (20140602), compound 8 (20140304) are from the synthesis in contriver laboratory.Therefore, tumor animal is divided into eight groups, model group, positive controls, compound 2 groups, compound 3 groups, compound 4 groups, compound 6 groups, compound 7 groups, compound 8 groups, often organizes 8 animals.
Dosage is arranged:
Model group: equal-volume physiological saline; Positive controls: 10 μMs/kg (cisplatin solution); Compound 2 groups: 50 μMs/kg; Compound 3 groups: 50 μMs/kg; Compound 4 groups: 50 μMs/kg; Compound 6 groups: 50 μMs/kg; Compound 7 groups: 50 μMs/kg; Compound 8 groups: 50 μMs/kg; Often group all carrys out abdominal injection (ip) administration according to 0.1ml/10g.
Medication:
Administration every day in continuous 14 day.All adopt abdominal injection (ip) administering mode, daily before weigh, determine each dosage according to every daily weight.The next day, weighs, and amount calculates gross tumor volume.Within 15th day, by sacrifice of animal, take out the heart, liver, spleen, lung, kidney, tumour, after weighing respectively, preserve in 10% formaldehyde.
Testing index:
(1) calculation formula of gross tumor volume (tumorvolume, TV) is:
V=1/2 × a × b 2(a, b represent respectively the length of tumour and wide)
(a, b unit is mm, and gross tumor volume V unit is mm 3)
(2) tumor weight inhibiting rate=(the average knurl weight of 1-administration group average knurl weight/control group) × 100%
(3) gross tumor volume inhibiting rate=(1-(after administration group administration front volume-administration volume)/(after control group administration front volume-administration volume)) × 100%.
Amino acid derivative pharmacodynamic experiment result
1. amino acid derivative amino acid oxamide to the tumour inhibiting rate of lung cancer H1650 model in nude mouse as shown in figure 21.
As can be seen from Figure 21, compound 3 and compound 8 are compared with positive control drug cis-platinum, and P>0.05, namely the drug effect of compound 8 and compound 2 anti-lung cancer H1650 propagation is suitable with cis-platinum.
2. amino acid derivative amino acid oxamide to the tumour inhibiting rate of lung cancer H460 model in nude mouse as shown in figure 22.
As can be seen from Figure 22, compound 2 is with 6 compared with positive control drug cis-platinum, and P>0.05, namely the drug effect of compound 2 and 6 anti-lung cancer H460 propagation is suitable with cis-platinum.
3. amino acid derivative amino acid oxamide to the tumour inhibiting rate of lung cancer SPC-A-1 model in nude mouse as shown in figure 23.
As can be seen from Figure 23, compound 2,3,4 is with 7 compared with positive control drug cis-platinum, and P>0.05, namely the drug effect of the anti-lung cancer SPC-A-1 propagation of compound 2,3,4 and 7 is suitable with cis-platinum.
4. amino acid derivative amino acid oxamide to the tumour inhibiting rate of lung cancer A549 model in nude mouse as shown in figure 24.
As can be seen from Figure 24, compound 2,3 is with 7 compared with positive control drug cis-platinum, and P>0.05, namely the drug effect of compound 2,3 and 7 suppressing lung cancer A 549 propagation is suitable with cis-platinum.
5. amino acid derivative amino acid oxamide is to liver cancer HepG in nude mouse 2the tumour inhibiting rate of model as shown in figure 25.
As can be seen from Figure 25, compound 4 with 6 compared with positive control drug cis-platinum, the anti-liver cancer HepG of compound 4 and 6 2the drug effect of propagation is suitable with cis-platinum, but the drug effect of the anti-liver cancer of compound 2,3 and 7 is higher than cis-platinum (P<0.05).
6. amino acid derivative amino acid oxamide to the tumour inhibiting rate of mammary cancer MCF-7 model in nude mouse as shown in figure 26.
As can be seen from Figure 26, compound 2,3 is with 7 compared with positive control drug cis-platinum, and the drug effect that anti-breast cancer MCF-7 breeds is suitable with cis-platinum.
7. amino acid derivative amino acid oxamide to the tumour inhibiting rate of colorectal carcinoma HT-29 model in nude mouse as shown in figure 27.
As can be seen from Figure 27, compound 2,3,4 is with 7 compared with positive control drug cis-platinum, and the drug effect that anti-breast cancer MCF-7 breeds is suitable with cis-platinum.
8. amino acid derivative amino acid oxamide to the tumour inhibiting rate of prostate cancer PC-3 model in nude mouse as shown in figure 28.
As can be seen from Figure 28, compound 2,3 is with 7 compared with positive control drug cis-platinum, and the drug effect that its anti-prostate cancer PC-3 breeds is suitable with cis-platinum.
9. amino acid derivative amino acid oxamide to the tumour inhibiting rate of prostate cancer DU145 model in nude mouse as shown in figure 29.
As can be seen from Figure 29, compound 2,3,4 is with 7 compared with positive control drug cis-platinum, and the drug effect that anti-prostate cancer DU145 breeds is suitable with cis-platinum.
10. amino acid derivative amino acid oxamide to the tumour inhibiting rate of cervical cancer Hela cells model in nude mouse as shown in figure 30.
As can be seen from Figure 30, compound 2,3 is with 4 compared with positive control drug cis-platinum group, and the drug effect of anti-Hela propagation is suitable with cis-platinum, but compound 7 is compared with cis-platinum group, and the drug effect of anti-Hela propagation is higher than cis-platinum.
11. amino acid derivative amino acid oxamide to the tumour inhibiting rate of Gastric Cancer MGC in nude mouse-803 model as shown in figure 31.
As can be seen from Figure 31, compound 2,3,7 is with 8 compared with positive control drug cis-platinum group, and the drug effect that anti-Gastric Cancer MGC-803 is bred is suitable with cis-platinum.

Claims (10)

1. amino acid derivative, its general structure such as formula shown in I ~ VI,
In formula:
X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof;
R or R' is independently selected from the L-type amino acid of composition human body protein, or the amino acid whose side chain substituents of D-type and simple modifier thereof, or forms the side chain substituents of intermediate of native amino acid metabolic in various human body;
Y, Y 1, Y 2independent is polypeptide;
Described amino acid derivative also comprises its pharmaceutical salts, ester or ether;
Described amino acid derivative does not comprise
2. amino acid derivative according to claim 1, is characterized in that: R, R ' be independently selected from L-glutamic acid, glutamine, citrulline, ornithine, Gelucystine, aspartic acid, l-asparagine, Threonine, Serine, leucine, Isoleucine, glycine, halfcystine, methionine(Met), tryptophane, tyrosine, phenylalanine, α-amino-isovaleric acid, Methionin, hydroxylysine, oxyproline, proline(Pro), Methionin, the side chain substituents of Histidine and simple modifier thereof.
3. amino acid derivative according to claim 1, is characterized in that: the structural formula of amino acid derivative is
and simple modifier.
4. amino acid derivative according to claims 1 to 3, is characterized in that: Y, Y 1, Y 2be independently 2 ~ 12 peptides.
5. amino acid derivative according to claim 4, is characterized in that: Y, Y 1, Y 2it is independently the cancer target peptide of 2 ~ 12.
6. amino acid derivative according to claims 1 to 3, is characterized in that: the pharmaceutical salts of amino acid derivative is selected from its sodium, potassium, calcium, zinc, lithium, iron, magnesium salts, sulfonate; The medicinal ester of amino acid derivative is selected from the ester between its C2 ~ C4; The medicinal ether of amino acid derivative is selected from the ether between its C2 ~ C4.
7. amino acid derivative is preparing the application in antitumor drug, the general structure of described amino acid derivative such as formula shown in I ~ VI,
In formula:
X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof;
R or R' is independently selected from the L-type amino acid of composition human body protein, or the amino acid whose side chain substituents of D-type and simple modifier thereof, or forms the side chain substituents of intermediate of native amino acid metabolic in various human body;
Y, Y 1, Y 2independent is polypeptide;
Described amino acid derivative also comprises its pharmaceutical salts, ester or ether;
Or as shown in claim 2 ~ 6 any one.
8. application according to claim 7, is characterized in that: tumour is selected from lung cancer, liver cancer, colorectal carcinoma, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, ovarian cancer, nasopharyngeal carcinoma, tongue cancer, skin carcinoma, mammary cancer, prostate cancer, melanoma, skin carcinoma, granulocyte leukemia, Lymphocytic leukemia, osteosarcoma, lymphosarcoma.
9. an antitumor drug, its activeconstituents is at least one in the amino acid derivative shown in claim 1 ~ 6 any one.
10. the synthesis technique of amino acid derivative, comprises following synthetic route:
In the process of synthesis, p-OH ,-NH as required 2or R group carries out protecting and deprotection;
In formula: X is selected from oxalyl group and simple modifier thereof, or compound containing oxalyl group and the reacted residue of amino acid couplings and simple modifier thereof.
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