CN102816103B - Vulcanized aspartic acid modified melatonin derivative and application thereof - Google Patents
Vulcanized aspartic acid modified melatonin derivative and application thereof Download PDFInfo
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- CN102816103B CN102816103B CN201210297948.9A CN201210297948A CN102816103B CN 102816103 B CN102816103 B CN 102816103B CN 201210297948 A CN201210297948 A CN 201210297948A CN 102816103 B CN102816103 B CN 102816103B
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- aspartic acid
- melatonin
- sulfuration
- salt
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Images
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Abstract
The invention relates to a tumor drug, and provides a vulcanized aspartic acid modified melatonin derivative shown in the following formula and application thereof, wherein a group R1 is selected from H, C1-C4 alkyl or C2-C4 alkenyl; a group R2 is selected from hydrogen or halogen; and a group R3 is selected from C1-C4 alkyl or C2-C4 alkenyl or a group shown in the description. The derivative can be applied by cancer patients receiving chemotherapy and radiation therapy, and toxic and side effects of chemoradiotherapy of malignant tumors can be reduced. The invention also provides a drug containing the derivative and indomethacin, and the drug has a function of selectively protecting normal cells.
Description
Technical field
The present invention relates to tumour medicine field, more particularly, the invention provides a kind of compound that can reduce concurrent chemoradiotherapy of malignant tumor side effect.
Background technology
Chemotherapy and radiotherapy are the primary treatment methods of cancer patient, but these the two kinds measures for the treatment of are faced with common challenge clinically.The very large difficult problem that people face is the toxic side effect that these therapies are brought, this be due to these two kinds of methods for the treatment of normal tissue cells and cancer cells lack have for selectivity, and there is identical lethality, even more obvious to the damage of the fast medullary cell of multiplication rate, endotheliocyte, epithelial cell, gastrointestinal mucosa cell.Therefore,, when killing and wounding cancer cells, normal cell also usually suffers the calamity of pond Fish widely.Often there is stomatocace, poor appetite in patients receiving treatment, suffer from diarrhoea, shave one's head and white cell, thrombocyte under degradation untoward reaction, even cause the complication that other can be fatal, such as unmanageable infection, multiple organ dysfunction syndrome etc.And most of patient often dies from the complication of caused by radiotherapy and chemotherapy, and also non-constant of survivor's life quality, and easily suffer from secondary tumour; Untoward reaction has often also limited giving of therapeutic dose, and patient is resistance to be can't stand a complete treatment cycle has greatly affected curative effect.Only have few part side effect to be alleviated by changing medication, as disperseed and long-time administration, or in topical mode, as peritonaeum Inner or artery administration, may make within the medicine of high density is only confined to focus, to reduce the untoward reaction of general, or after treating drug treating time, give certain antagonistic, with part, alleviate cancer therapy drug to Normocellular lethality.Yet the indication of topical mode is special few, and very large to patient's wound during administration, take this clinically to reduce the act that toxic side effect belongs to rascal, produce effects atomic; Described agonist drug does not equally possess selectivity yet, when part alleviates the toxic action of medicine normal tissue cell, relatively reduces the anticancer effect of medicine yet.Other solution route is the side effect that rapidly treatment occurs-be symptomatic treatment, as white cell stimulates the application etc. that generates element (G-CSF, GM-CSF) or potent antiemetic (5-HT3 antagonist).But fact proved, this kind of mode also can only alleviate part symptom, do not reduce in essence the degree of injury, more without the effect of preventing.
Another very thorny difficult problem is that tumour cell can produce gradually tolerance in therapeutic process.As everyone knows, after tumour forms, cancer cells constantly grows, via lymphatic vessel and vessel invasion, transfer, and a bunch group becomes increasingly complex, and finally produces and has drug-fast cell mass, and now tumour arrives the stage that cannot effect a radical cure.Therefore the toxicity of anticancer therapy and cannot effectively control tumor-infiltrated and shift, spread and the tolerance of tumour to medicine is the stumbling-block of current oncotherapy.
Present situation based on above-mentioned antitumor drug or field of radiation therapy and current bottleneck, the exploitation of the clinical use of cytoprotective in recent years and angiogenesis inhibitor (anti-angiogenesis) and targeting anticarcinogen, seemingly alleviated to a certain extent the toxic side effect that small part chemicotherapy produces, yet, the data of the clinical cancer therapy by recent years confirms, the anticarcinogen of a new generation, such as angiogenesis inhibitor and targeting anticarcinogen (Humanized monoclonal body, specific proteins enzyme inhibitors is such as Ji Fei is for Buddhist nun, Tarceva etc.) still there is stronger side reaction.Up-to-date clinical study research shows, particularly the medicine of angiogenesis inhibitor (monoclonal antibody of the anti-VEGF of humanized is as rhuMAb-VEGF) promotes the hematogenous metastasis of some tumour on the contrary.Traditional antioxidant, as Triptide (GSH), Vit-E; Vit-C, CoA-Q10, glutamine; methionine(Met), superoxide-dismutase (SOD) etc. does not obtain definite curative effect clinically, and this may be due to protection insufficient strength and lack due to selectivity.For alleviating the medicine of radiotherapy side effect, as amifostine (amifostine), dexrazoxane (Dexrazoxane), all there is following limitation in these protective materials: 1) itself has very strong side effect: the therapeutic dose of amifostine and toxic dose are very approaching, after medication, easily cause ypotension, feel dizzy or confused Halo, these rate of side effects are unexpectedly up to 80%; Dexrazoxane itself causes leukopenia (incidence of leukopenia is up to 78%).2) indication is very narrow: amifostine is mainly only applicable to alleviate the xerostomia symptom in neck cancer patient radiation therapy process; Dexrazoxane be at present clinically approval for preventing anthracyclines to bring out the medicine of cardiac toxic.3) administration is inconvenient, and intravenously administrable is just effective, and costly.Therefore, protectant market outlook of amifostine and dexrazoxane and so on are in fact also pessimistic.
Therefore, to have wide spectrum cytoprotective be optionally to solve the effective way that chemicotherapy causes toxic side effect in research and development.Melatonin is originally the healthcare products of an improvement sleep, but finding melatonin, research recently has the function of stronger anti-oxidative damage, having good oral administration biaavailability, and can promptly be distributed in all histoorgans of whole body, should be a compound that alleviates oxidative damage that has much potentiality.People attempt the toxic side effect of using this type of compounds for reducing chemicotherapy to produce always, show in vitro fruitful in the experimental result in cell strain and animal body.Yet, time cause today, still fail for clinical, its reason is: 1) disturb the result for the treatment of of chemicotherapy to tumour, can not optionally only protect healthy tissues; 2) insufficient strength of protection, can not alleviate the ray of high dosage and the oxidative damage due to high-dose chemotherapy medicine; 3) body easily produces tolerance to melatonin compounds, and protective effect continued less than a complete chemicotherapy cycle; 4) itself have certain side effect, heavy dose of melatonin main manifestations is somnopathy and spirit depressing etc.; 5) protective surface is broad not, and some specific chemicotherapy damage is not had to provide protection.Still nobody develops this type of medicine with satisfactory effect at present.
For above problem, in view of melatonin has the characteristic of many outstanding patent medicine, contriver is using it as there being very much the lead compound (prodrug) of DEVELOPMENT PROSPECT to be optimized, we have carried out a large amount of experiments it have been carried out to structure of modification, by the means with chemical addition, melatonin is modified, finally successfully synthesize a kind of melatonin derivatives with excellent effect, outside keeping the ability of original anti-oxidative damage, increased the function of direct anti-apoptosis.Its anti-apoptosis capacity and scope obtain greatly and promote; the pharmacological action of central is minimized; the toxicity of animal is reduced; protective effect significantly strengthens, and can resist the cell injury that multiple stimulation causes, when with indomethacin combined utilization; greatly; optionally strengthened the susceptibility of tumor tissues to chemicotherapy, significantly improved therapeutic index, and oral administration has been effective.Contriver carries out experimental treatment with new synthetic melatonin derivatives to advanced breast cancer mouse, and result shows that the life-span of advanced breast cancer mouse on average extends 2.75 times.
Summary of the invention
Of the present invention, aspect first, provide a kind of with the compound shown in following formula 1, and pharmacy acceptable salt:
In above structural formula 1, radicals R
1be selected from H, C
1-C
4alkyl, C
2-C
4thiazolinyl, is preferably selected from H and methyl; Radicals R
2be selected from hydrogen or halogen, described halogen is chlorine preferably; Radicals R
3be selected from C
1-C
4alkyl, C
2-C
4thiazolinyl or
be preferably selected from methyl or
in yet another embodiment of the present invention, described salt is the salt forming with the positively charged ion that is selected from following metal: sodium, lithium, potassium, calcium, magnesium, strontium, aluminium, magnesium, manganese, iron, nickel, copper.Preferred described compound is selected from the compound shown in any in following formula 2-5:
In a preferred implementation, preferred described salt is the metal-salt shown in the following structural formula forming with magnesium ion or zine ion:
Second aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises above-described compound of the present invention or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material; Described pharmaceutical composition preferably also comprises indomethacin.
The 3rd aspect of the present invention provides a kind of compound as shown in following formula 1 and pharmacy acceptable salt thereof for the preparation of the application that reduces the medicine of concurrent chemoradiotherapy of malignant tumor toxic side effects:
In above structural formula 1, radicals R
1be selected from H, C
1-C
4alkyl, C
2-C
4thiazolinyl, is preferably selected from H and methyl; Radicals R
2be selected from hydrogen or halogen, described halogen is chlorine preferably; Radicals R
3be selected from C
1-C
4alkyl, C
2-C
4thiazolinyl or
be preferably selected from methyl or
in yet another embodiment of the present invention, described salt is the salt forming with the positively charged ion that is selected from following metal: sodium, lithium, potassium, calcium, magnesium, strontium, aluminium, magnesium, manganese, iron, nickel, copper.Preferred described compound is selected from the compound shown in any in following formula 2-5:
In a preferred implementation, described salt is the metal-salt shown in the following structural formula forming with magnesium ion or zine ion:
In yet another embodiment of the present invention, the medicine of described reduction concurrent chemoradiotherapy of malignant tumor toxic side effects preferably also comprises indomethacin.
Accompanying drawing explanation
Following specific descriptions combine with accompanying drawing for explaining in more detail technical scheme of the present invention, and accompanying drawing is described as follows:
Fig. 1 shows that compound of the present invention causes the provide protection of people's peripheral leukocytes damage to gamma-rays as protective material;
Fig. 2 shows that compound of the present invention causes the provide protection of people's peripheral leukocytes damage to different types of inducer of apoptosis as protective material;
Fig. 3 shows that compound of the present invention causes the impact of mouse survival rate on gamma-rays as protective material;
Fig. 4 shows that compound of the present invention causes the provide protection of people's peripheral leukocytes damage to gamma-rays as protective material;
Fig. 5 shows that compound of the present invention causes the provide protection of people's peripheral leukocytes damage to taxol as protective material;
Fig. 6 shows that compound of the present invention causes the provide protection of people's peripheral leukocytes damage to cis-platinum as protective material;
Fig. 7 shows that compound of the present invention causes the provide protection of mouse bone marrow cells damage to gamma-rays as protective material;
Fig. 8 shows that compound of the present invention causes the provide protection of mouse bone marrow cells damage to endoxan as protective material;
Fig. 9 shows that compound of the present invention causes the provide protection of mouse platelets damage to carboplatin as protective material;
Figure 10 A and Figure 10 B show that respectively compound of the present invention causes the provide protection of mouse heart damage to Zorubicin as protective material;
Figure 11 A shows that compound of the present invention and indomethacin coupling cause tumor killing effect in nude mice transplanted tumor body to gamma-rays;
Figure 11 B shows that compound of the present invention and indomethacin coupling cause leukocytic impact in nude mice transplanted tumor nude mouse to gamma-rays;
Figure 12 A shows that compound of the present invention and indomethacin coupling cause tumor killing effect in nude mice transplanted tumor body to combined chemotherapy;
Figure 12 B show compound of the present invention and indomethacin coupling on combined chemotherapy on the leukocytic impact of nude mice transplanted tumor;
Figure 13 shows compound of the present invention and the anti-withered experimental result of vulcanizing aspartic acid, melatonin and sulfuration aspartic acid and melatonin mixture.
Embodiment
In following content, will be further described in detail the present invention.But it is pointed out that following embodiment only provides concrete operations example of the present invention in an exemplary fashion, but protection scope of the present invention is not limited only to this.Protection scope of the present invention is only limited by claims.Those skilled in the art can expect apparently; within the protection domain that can limit at the claims in the present invention book, embodiment of the present invention is carried out to various other improvement and replacements; and still can realize identical technique effect, reach final technical purpose of the present invention.
In the present invention, unless indicated to the contrary, all ratios are weight ratio, and all percentage ratios are weight percentage, and the unit of temperature is ℃ that pressure unit of force is handkerchief.Room temperature refers to envrionment temperature conventional in laboratory, with season and change in location, is generally 25 ° of C.In addition, all numerical ranges that the present invention describes include end value and can comprise the new numerical range that the mutual arbitrary combination of the upper and lower bound of scope of disclosure is obtained.For example, if disclosing the weight percentage of certain component is 10 ~ 30 % by weight, preferred 15 ~ 25 % by weight, more preferably 20 ~ 23 % by weight have been equivalent to disclose following numerical range: 10 ~ 15 % by weight, 10 ~ 25 % by weight, 10 ~ 20 % by weight, 10 ~ 23 % by weight, 15 ~ 30 % by weight, 15 ~ 20 % by weight, 15 ~ 23 % by weight, 20 ~ 25 % by weight, 23 ~ 25 % by weight simultaneously.
The inventor has carried out extensive and deep research, has developed with the melatonin derivatives of modifying with sulfuration aspartic acid shown in following formula 1:
Radicals R
1be selected from H, C
1-C
4alkyl, C
2-C
4thiazolinyl, is preferably selected from H and methyl; Radicals R
2be selected from hydrogen or halogen, described halogen is chlorine preferably; Radicals R
3be selected from C
1-C
4alkyl, C
2-C
4thiazolinyl or
be preferably selected from methyl or
in a preferred embodiment of the present invention, compound of the present invention is selected from the compound shown in following formula 2-5:
Because the compound shown in formula 1-5 comprises carboxyl, therefore can form pharmacy acceptable salt with metallic cation.Those skilled in the art can require to select suitable metallic cation according to concrete administration.Described pharmacy acceptable salt is the zinc salt shown in following formula or magnesium salts preferably:
Can in carcinosis radiotherapy and chemotherapy process, by compound of the present invention, give patient, thereby the in addition optionally protection of normal tissue and cell alleviates the side effect that chemicotherapy brings, and suppresses the formation of tumor tissues tolerance simultaneously.In general, compound of the present invention can be for the cancer patients of any kind, the example of described cancer comprises: liver cancer, cancer of the stomach, esophagus cancer, intestinal cancer, nasopharyngeal carcinoma, mammary cancer, lymphatic cancer, kidney, carcinoma of the pancreas, bladder cancer, ovarian cancer, uterus carcinoma, osteocarcinoma, carcinoma of gallbladder, lip cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, vascular tumor etc., but be not limited to this.In fact, any patient who accepts chemicotherapy all can obtain the effect that alleviates chemicotherapy side effect by absorbing compound of the present invention.
Compound of the present invention can be made any formulation, gives to carry out the object of chemicotherapy treatment with suitable administering mode.For example, compound of the present invention can be made to the formulations such as solution, suspension, emulsion, tablet, pill, implant, before chemicotherapy operation, in process or afterwards, by oral, intravenous injection, through modes such as skin absorption, mucosal absorption, body are implanted into, by compound of the present invention, give patient.Those skilled in the art can, according to factors such as patient's symptom kind, healthy situation, concrete chemicotherapy schemes, suitably select the protectant consumption of the present invention.The dosage of every day can disposablely give, and also can be divided into repeatedly and giving.In a preferred embodiment of the present invention, protective material of the present invention is by oral way administration.For example, in a specific embodiment of the present invention, melatonin zinc salt and indomethacin coupling that sulfuration aspartic acid of the present invention is modified, every day twice oral administration, the effective dose of the two be respectively 5-12 mg/kg body weight/time with 0.5-1 mg/kg body weight/time.
In a preferred embodiment of the present invention, the inventor also finds, in the time of compound of the present invention and indomethacin coupling, the selective protection effect of its normal tissue and the effect of inhibition tumor cell tolerance can obtain further raising.
Below in conjunction with embodiment, specifically describe technical scheme of the present invention.
Embodiment
The chemical reagent that following synthetic example is used is the analytical grade reagent purchased from strange (Sigma-Aldrich) company in SIGMA-Ai Er Delhi.The water using is deionization bi-distilled water.Reaction is carried out under normal temperature and pressure conditions.
Embodiment 1: distinguish in this embodiment compound and the metal-salt thereof shown in synthesis type 2-5.
A. synthesizing of melatonin magnesium salts/zinc salt that the sulfuration aspartic acid of formula 2 is modified
In this embodiment, according to the compound of course synthesis type 2 shown below:
Synthesizing of step 1. sulfuration aspartic acid: (1) is suspended in 60% NaH (1.8mmol) in THF (5ml) at 0-4 ° of C, adds the methyl sulfurous phosphoric acid (CH of 1 equivalent
3-SO
2-H
2pO
3), by the asparagus fern ammonium aldehyde (commerical prod of the carboxyl of 1 equivalent (with t-Bu (tertiary butyl) protection) and amido (with Fmoc (fluorenes methoxy carbonyl acyl group) protection) protection, be purchased from the strange company in SIGMA-Ai Er Delhi, compound 1a) add wherein, stirring at room 30 minutes, then the acetaldehyde (aldehyde) that adds 1 equivalent, continues stirring at room 120 minutes, generates with protectant sulfuration aspartic acid (compound 1b); (2) add 0-4 ° of C of trifluoroacetic acid (TAF) of 1 equivalent to react 60 minutes to remove carboxy protective agent (t-Bu), obtain compound 1c; (3) add the piperidines of 1 equivalent and the methylene dichloride (CH of 1 equivalent
2cl
2), room temperature reaction 60 minutes, removes amino protective material (Fmoc), obtains compound 1d; (4) by vacuum, drain removal solvent and obtain yellow solid, be target product/sulfuration aspartic acid, this product is dissolved in to methylene dichloride (CH
2cl
2) in, with HPLC, purify organic phase, obtain the final product of purity 98%, calculating yield is 82%.By the molecular formula of double focusing nucleus n-ness spectrum instrument (Se Mofei does company (Thermo Finnegan), the U.S.) the bright target product of analytical table, be C
6h
11nSO
4, the molecular weight of target product is 193.036, matches with the molecular weight (193.018) of sulfuration aspartic acid expection.To Fourier transformation infrared spectrometer for reacting final product (production of U.S. Po Jin-Ai Ermo (PerkinElmer) company) carry out spectroscopic analysis, sulfuration aspartic acid at 3500-3300cm
-1region presents stretching vibration absorption peak (representative-NH
2group), this shows successfully to remove amino protecting agent (Pmoc), has recovered-NH
2group; Sulfuration aspartic acid is at 3650-3600cm
-1there is sharp-pointed stretching vibration absorption peak (representative-OH group) in region, illustrates and successfully remove carboxy protective agent (t-Bu); Compare with aspartic acid, sulfuration aspartic acid is at 1400-1300cm
-1there is distinctive strong and sharp-pointed stretching vibration absorption peak (representative-C-SO in region
2group), illustrate that sulphur atom successfully adds in the molecule of aspartic acid.
The preparation of step 2. sulfuration aspartic acid melatonin: the melatonin (compound 2a) (being dissolved in ethanol) (pH=3-5) in the acetic acid aqueous solution of 5ml1Mol/L by the sulfuration aspartic acid stoste (compound 1d) (being dissolved in methylene dichloride) of 2.5ml 500mM with 2.5ml equivalent, at room temperature carry out the reaction of 3 hours, in this condensation reaction, make the ketone group of melatonin form C=N key with the amido dehydrating condensation of sulfuration aspartic acid, then add 200ml frozen water, the condenses generating is water-fast brown color crystal formation solid (compound 2b), by filtering solid precipitation, it is separated from reaction system, in the acetic acid aqueous solution (250mMol/L) that is 3-5 in pH value, carry out recrystallization purification, then with HPLC, purify, obtain purity and be 99% solid product, calculating yield is 75%.To Nicolet6700-Fourier transform thermal infrared spectrum instrument for reacting final product (production of U.S. Se Mo-Fei Sheer science (Thermo Fisher Scientific) company) carry out spectroscopic analysis, melatonin is at 1680-1850cm
-1region high-intensity stretching vibration absorption peak (representing C=O group) is subjected to displacement, and sulfuration aspartic acid is at 3500-3100cm
-1in region, the stretching vibration absorption peak of intensity (represents NH
2group) disappear, at 1620-1580cm
-1there is the stretching vibration absorption peak of a special middle weak intensity in region, shows to have C=N key in molecule, prove sulfuration aspartic acid-NH
2with melatonin-there is dehydrating condensation and form C=N key in C=O.Adopting the molecular formula of double focusing nucleus n-ness spectrum instrument (Se Mofei does company, the U.S.) the bright target product of analytical table is C
19h
25n
3sO
5, the molecular weight of target product is 407.36, coincide with the molecular weight (407.28) of expection conjugate.
1h-NMR (Varian Mercury Plus 400Mhz nuclear magnetic resonance analyser, U.S. Wa Lian (Varian) company produces) measurement result is as follows:
1h-NMR (400MHz, CDCl
3) δ: 7.17 (s, 1H), 7.43 (s, 3H) 7.81 (s, 2H), 7.73 (s, 1H), 1.8 (s, 3H, C-CH3), 3.6 (s, 3H, O-CH3), 7.66 (s, 2H), 6.09 (d, 2H, J1/416.0Hz, CH=CHSO
2cH
3), 11.37 (d, 1H, COOH).Result proves, the product making, for the compound shown in above formula 2, is denoted as 2b in synthetic course.
The preparation of step 3. sulfuration aspartic acid melatonin zinc/magnesium salts: the product of step 2 is dissolved in to the sulfuration aspartic acid melatonin ethanolic soln that 50ml dehydrated alcohol makes 400mM, in addition zinc carbonate/magnesium is dissolved in to zinc carbonate/magnesium solution (also can use magnesium hydroxide and zinc hydroxide as raw material) of preparing 50ml 200mM in 50ml water.First 100ml is vulcanized to aspartic acid melatonin solution and add in the Erlenmeyer flask of 500ml, under induction stirring, 100ml zinc carbonate/magnesium is slowly added.50 ℃ of reactions 2 hours.Continuous heating (50 ℃) makes ethanol volatilization, then add 300ml frozen water, standing 1 hour at 4 ℃, obtain brown color solids sulfuration aspartic acid melatonin zinc/magnesium salts (being denoted as compound 3b in reaction mechanism), with frozen water drip washing three times to remove the impurity such as inorganic salt, with HPLC, recording product purity is 99%, and calculating yield is 85%.With infrared spectrometer (Nicolet6700-Fourier transform thermal infrared spectrum instrument, U.S. Se Mo-Fei Sheer science (Thermo Fisher Scientific) company produces) relatively vulcanize aspartic acid melatonin and the infrared spectra that vulcanizes aspartic acid melatonin magnesium/zinc, sulfuration aspartic acid melatonin is at 3650cm
-1there is a special sharp-pointed carboxyl anion absorption peak at place, and this locates sulfuration aspartic acid melatonin zinc/magnesium special carboxyl anion absorption peak and be displaced to 3750cm
-1, and absorption peak becomes wide and flat, and the carboxyl anion that shows to vulcanize in aspartic acid melatonin is combined with metallic cation.Atomic absorption spectrophotometer (production of S4AA System U.S. Se Mo-Fei Sheer science (Thermo Fisher Scientific) company) is analyzed zinc/magnesium ion, shows that a zinc/magnesium ion is in conjunction with the sulfuration aspartic acid melatonin of two molecules.
B. the compound shown in formula 3 and magnesium/zinc salt thereof is synthetic.
Repeat the step described in above a, but use 2a ' to replace raw material 2a wherein, the synthetic final product that obtains.To Nicolet6700-Fourier transform thermal infrared spectrum instrument for reacting final product (production of U.S. Se Mo-Fei Sheer science (Thermo Fisher Scientific) company) carry out spectroscopic analysis, 2a ' is at 1680-1850cm
-1region high-intensity stretching vibration absorption peak (representing C=O group) is subjected to displacement, and sulfuration aspartic acid is at 3500-3100cm
-1in region, the stretching vibration absorption peak of intensity (represents NH
2group) disappear, at 1620-1580cm
-1there is the stretching vibration absorption peak of a special middle weak intensity in region, shows to have C=N key in molecule, prove sulfuration aspartic acid-NH
2with melatonin-there is dehydrating condensation and form C=N key in C=O.Adopting the molecular formula of double focusing nucleus n-ness spectrum instrument (Se Mofei does company (Thermo Finnegan), the U.S.) the bright target product of analytical table is C
18h
23n
3sO
5, the molecular weight of target product is 393.262, coincide with the molecular weight (393.286) of expection conjugate.Proof has prepared the compound shown in formula 3 thus.With infrared spectrometer, the magnesium/zinc salt obtaining is analyzed, the infrared spectra of comparison expression 3 compounds and salt thereof, the compound of formula 3 is at 3650cm
-1there is a special sharp-pointed carboxyl anion absorption peak at place, and this locates its salt special carboxyl anion absorption peak and be displaced to 3750cm
-1, and absorption peak becomes wide and flat, and the carboxyl anion in the compound of formula 3 is combined with metallic cation.Atomic absorption spectrophotometer is analyzed zinc/magnesium ion, shows that a zinc/magnesium ion is in conjunction with the compound of the formula 3 of two molecules.
C. the compound shown in formula 4 and magnesium/zinc salt thereof is synthetic.
Repeat the step described in above a, but use 2a " replace raw material 2a wherein, the synthetic final product that obtains.To Nicolet6700-Fourier transform thermal infrared spectrum instrument for reacting final product (production of U.S. Se Mo-Fei Sheer science (Thermo Fisher Scientific) company) carry out spectroscopic analysis, 2a " at 1680-1850cm
-1region high-intensity stretching vibration absorption peak (representing C=O group) is subjected to displacement, and sulfuration aspartic acid is at 3500-3100cm
-1in region, the stretching vibration absorption peak of intensity (represents NH
2group) disappear, at 1620-1580cm
-1there is the stretching vibration absorption peak of a special middle weak intensity (sparse) in region, shows to have C=N key in molecule, prove sulfuration aspartic acid-NH
2with 2a "-C=O generation dehydrating condensation formation C=N key.Adopting the molecular formula of double focusing nucleus n-ness spectrum instrument (Se Mofei does company (Thermo Finnegan), the U.S.) the bright target product of analytical table is C
19h
24clN
3sO
5, the molecular weight of target product is 441.756 and expects that the molecular weight (441.531) of conjugate coincide. with infrared spectrometer, the salt of the compound of formula 4 is analyzed, the compound of comparison expression 4 and the infrared spectra of its magnesium/zinc salt, the compound of formula 4 is at 3650cm
-1there is a special sharp-pointed carboxyl anion absorption peak at place, and its zinc/magnesium salts this locate special carboxyl anion absorption peak and be displaced to 3750cm
-1, and absorption peak becomes wide and flat, shows that the carboxyl anion in the compound of formula 4 is combined with metallic cation.Atomic absorption spectrophotometer is analyzed zinc/magnesium ion, shows that a zinc/magnesium ion is in conjunction with the compound of the formula 4 of two molecules.)
D. the compound shown in formula 5 and magnesium/zinc salt thereof is synthetic.
Repeat the step described in above a, but use 2a " ' replace raw material 2a wherein, the synthetic final product that obtains.To Nicolet6700-Fourier transform thermal infrared spectrum instrument for reacting final product (production of U.S. Se Mo-Fei Sheer science (Thermo Fisher Scientific) company) carry out spectroscopic analysis, 2a " ' at 1680-1850cm
-1region high-intensity stretching vibration absorption peak (representing C=O group) is subjected to displacement, and sulfuration aspartic acid is at 3500-3100cm
-1in region, the stretching vibration absorption peak of intensity (represents NH
2group) disappear, at 1620-1580cm
-1there is the stretching vibration absorption peak of a special middle weak intensity (sparse) in region, shows to have C=N key in molecule, prove sulfuration aspartic acid-NH
2with 2a " '-C=O generation dehydrating condensation formation C=N key.Adopting the molecular formula of double focusing nucleus n-ness spectrum instrument (Se Mofei does company (Thermo Finnegan), the U.S.) the bright target product of analytical table is C
22h
28n
4sO
6, the molecular weight of target product is 476.522 and expects that the molecular weight (476.493) of conjugate coincide. with infrared spectrometer, the salt of the compound of formula 5 is analyzed, the compound of comparison expression 5 and the infrared spectra of its magnesium/zinc salt, the compound of formula 5 is at 3650cm
-1there is a special sharp-pointed carboxyl anion absorption peak at place, and its zinc/magnesium salts this locate special carboxyl anion absorption peak and be displaced to 3750cm
-1, and absorption peak becomes wide and flat, shows that the carboxyl anion in the compound of formula 5 is combined with metallic cation.Atomic absorption spectrophotometer is analyzed zinc/magnesium ion, shows that a zinc/magnesium ion is in conjunction with the compound of the formula 5 of two molecules.)
In following examples, use compound prepared by Preparation Example 1a-1d to carry out Bioexperiment as protective material.Also use in addition protective material known in the art (Amifostine) to carry out contrast experiment.The Amifostine that following examples are used, taxol, cis-platinum, carboplatin, Zorubicin, indomethacin, endoxan, 5 FU 5 fluorouracil, tumour necrosis factor (TNF), FasL (Fas Ligand), recombinant human interleukin--2, and all related reagents are all purchased from the strange HeEMD Chemical Co., Ltd. of (Sigma-Aldrich) company (EMD Chemicals Inc) in SIGMA-Ai Er Delhi, Co 60 theratron is Theratron, purchased from Canadian nuclear power (Atomic Energy Agency) company, the biological γ irradiator of G50 type is purchased from Hope's Weir (HOPEWELL) company of the U.S..
In following embodiment and accompanying drawing 1-13, with " melatonin of modification " or " melatonin that sulfuration aspartic acid is modified ", represent the compound of formula 2-5 of the present invention; With " the melatonin zinc/magnesium of modification " or " melatonin zinc/magnesium that sulfuration aspartic acid is modified ", represent its corresponding metal-salt.For example, embodiment 2 is experiments that the compound that uses embodiment 1a to prepare carries out, and in figure, " melatonin of modification " and " the melatonin zinc of modification " represents respectively compound and the zinc salt thereof shown in this formula 2.
Embodiment 2: the compound that embodiment 1a is synthetic and zinc salt thereof cause the provide protection experiment of people's peripheral leukocytes damage to 60Co γ-rays as protective material.
In this embodiment, separating health people's peripheral leukocytes (lymphocyte) (contains 10% newborn calf serum at RPMI1640 substratum in 96 porocyte culture plates, 1000IU/ml recombinant human interleukin--2,1% penicillin, 1% Streptomycin sulphate) middle cellar culture.Use the melatonin raw material 2a of compound of preparation formula 2 (be used in embodiment 1a); and the sulfuration aspartic acid melatonin (compound 2b) of preparing in embodiment 1a and sulfuration aspartic acid melatonin zinc (compound 3b); Amifostine (the clinical protective material having used is as positive control) adds respectively people's peripheral leukocytes of vitro culture to as protective material; end level is respectively: melatonin (3 μ M and 15 μ M) and sulfuration aspartic acid melatonin (3 μ M and 15 μ M); sulfuration aspartic acid melatonin zinc (3 μ M and 15 μ M), Amifostine (200 μ M and 1000 μ M).After administration 12 hours (administration in 30 minutes of Amifostine pre-irradiation), use the biological γ irradiator of G50 type with the dose rate of 1GY/ minute, described people's peripheral leukocytes to be irradiated 8 minutes, total dose is 8GY.Irradiate latter 72 hours, by tetramethyl-azo azoles salt method (MTT), detect cell survival rate, by microplate reader, at 570nm wavelength place, measure OD absorbance, absorbancy is higher, and cell count is more, otherwise, absorbancy is lower, and cell count is fewer, reflects thus the quantity of viable cell.Independent repeat 3 times (the 3 multiple hole/drug treating group) of experiment. each measurement in triplicate, get its mean value as single experiment value. data are carried out to variance analysis.Cellular control unit is not given any medicine, does not also irradiate, and irradiation group cell is only accepted the 60Co γ-rays irradiation that total dose is 8GY, does not give any drug intervention.Using the cell survivaling number of control group as 100%, and the cell survivaling number that other experiment the records percentage ratio obtaining of comparing with control sample is cell survival rate, and result gathers sees Fig. 1.Control experiment in figure represents not give protective material and does not also carry out the cell sample of radiotreatment.From the experimental result of Fig. 1, can find out; under the radiotherapy condition of simulation; the protective materials such as the melatonin known with prior art, Amifostine are compared, the survival rate that the sulfuration aspartic acid melatonin shown in formula 2 prepared by use embodiment 1a and zinc salt thereof can significantly improve cell.Particularly when using the protective material of lower concentration, at existing melatonin, when the protective materials such as Amifostine are completely invalid, the melatonin of chemically modified is Cell protection effectively still, and cell survival rate is approached increases by 2 times, reaches 40%.The in the situation that of heavy dose of once irradiating, the peace phosphorus fourth dialogue cytoprotective of high dosage will be better than the melatonin zinc of learning chemically modified a little.
The synthetic compound of embodiment 3 embodiment 1a causes the provide protection of people's peripheral leukocytes damage to Zorubicin, FAS part (FasL) and (TNF+ endoxan) as protective material
Repeat the experimental procedure of embodiment 2, but difference is, the present embodiment does not re-use 60Co γ-rays and carries out irradiation, but give respectively melatonin at each cell sample, sulfuration aspartic acid melatonin prepared by embodiment 1a or its zinc salt (end level of cell culture fluid Chinese traditional medicine is 15 micromoles per liter) 12 hours afterwards, and give Amifostine (end level of cell culture fluid Chinese traditional medicine is 1000 micromoles per liter) 30 minutes afterwards, in cell culture fluid, add respectively Zorubicin, FasL and (TNF+ endoxan) make its end level in substratum be respectively 100 nmoles/liter, 50 nmoles/liter and (20 nmoles/liter+5000 nmoles/liter).Giving Zorubicin, FasL and (TNF+ endoxan) detected cell survival rate by mtt assay after 48 hours, and result gathers sees Fig. 2.From the experimental result of Fig. 2, can find out; under the chemotherapy condition of simulation; the Amifostine protective material known with prior art compared, and uses the synthetic sulfuration aspartic acid melatonin of embodiment 1a or sulfuration aspartic acid melatonin zinc salt can obtain the cell survival rate significantly improving.Strikingly; melatonin and Amifostine can not Cell protection make it avoid suffering the apoptosis due to FasL and (TNF+ endoxan); only have the melatonin through chemically modified of the present invention could effectively suppress the apoptosis of FasL and (TNF+ endoxan) induction; explanation except having the function of anti-oxidative damage, can also directly suppress the activity of L-Cysteine HCL Anhydrous (Caspase) through the melatonin of chemically modified.Melatonin of this proof chemically modified has not only strengthened the dynamics of anti-apoptosis, and expanded anti-apoptosis effect for the scope of chemotherapeutics, be the apoptosis inhibitor of a wide spectrum.
The synthetic compound of embodiment 4 embodiment 1a as protective material on the impact of the mouse survival rate of gammairradiation (experiment in body)
It is experimental subjects that the male mice in 10 week age (C57BL/6J) of 20 grams of left and right of body weight is take in this experiment, take 12 mouse as one group.12 mouse in control group had not both given gamma-ray irradiation, did not give protective material yet; " irradiate+modify the melatonin zinc " group of take be example, and expression is vulcanized aspartic acid melatonin zinc before applying the gammairradiation of Co 60.The sulfuration aspartic acid melatonin that the present embodiment is used and sulfuration aspartic acid melatonin zinc are made by embodiment 1a.First to each group mouse, correspondingly give protective material; concrete consumption is as follows: melatonin: 23 mg/kg/day (0.1 mmole); sulfuration aspartic acid melatonin: 52 mg/kg/day (0.1 mmole); sulfuration aspartic acid melatonin zinc: 59 mg/kg/day (0.1 mmole), Amifostine: 400 mg/kg/day (1 mmole).Except Amifostine is abdominal injection (administration in 30 minutes of Amifostine pre-irradiation), the same gastric infusion of all the other protective materials.Administration was carried out full-body exposure with 60Co γ-rays with the dosage of 7Gy after 12 hours, and source of radiation is apart from 80 centimetres of mouse, dose rate 0.2Gy/ minute, and irradiation time is 35 minutes.Irradiate once, after irradiating, successive administration is 5 days, once a day.Record the survival digit rate of mouse, the survival number of mouse and experimental mice sum (12) percentage ratio obtaining of comparing is mouse survival rate, and result gathers sees Fig. 3.The control group mice of physiological saline gavage is subject to 7Gy to be radiated at the 30th day dead 11, survival rate is 8.33%, melatonin group is 3 of survivals in the 30th day, survival rate is 25%, and sulfuration aspartic acid melatonin group is 6 of survivals in the 30th day, and survival rate is 50%, sulfuration aspartic acid melatonin zinc group is 9 of survivals in the 30th day, survival rate is 75%, and Amifostine group is 7 of survivals in the 30th day, and survival rate is 58%.Through the melatonin of chemically modified, obviously reduce the mortality ratio of animal due to high dosage ray.
The inventor also finds that by above-mentioned experiment in vivo and vitro the anti-apoptosis capacity of vulcanizing aspartic acid melatonin magnesium/zinc is than the high 15-20% of sulfuration aspartic acid melatonin left and right, meanwhile, the another one object that the melatonin of sulfuration aspartic acid being modified is made salt is to make compound more stable.
The synthetic compound of embodiment 5 embodiment 1b causes the provide protection experiment of people's peripheral leukocytes damage to 60Co γ-rays as protective material
In this embodiment, separating health people's peripheral leukocytes (lymphocyte), adds recombinant human interleukin--2's (1000 units/ml adds once for every 2 days) to carry out vitro culture.Use the compounds such as melatonin zinc salt (being the zinc salt of the compound shown in formula 3) that sulfuration aspartic acid prepared by embodiment 1b modifies, Amifostine as protective material, to add culture in people's peripheral leukocytes of vitro culture to respectively; end level is respectively sulfuration aspartic acid melatonin zinc (15 μ M), Amifostine (1000 μ M).Give (administration in 30 minutes of Amifostine pre-irradiation) after protective material 12 hours; use the dosage that 60Co γ-rays irradiates 1GY/ minute to irradiate 2 minutes described people's peripheral leukocytes; the total dose of single fraction irradiation is 2GY; irradiate once every day; Continuous irradiation 5 days; each pre-irradiation all gives protective material, in last postradiation the 2nd day, with mtt assay, detects cell survival rate.Cellular control unit is not given any medicine, does not irradiate yet, and irradiation group cell is only accepted the gammairradiation that total dose is 10GY, does not give any drug intervention.Using the cell survivaling number of control group as 100%, and the cell survivaling number that other experiment the records percentage ratio obtaining of comparing with control group is cell survival rate, and result gathers sees Fig. 4.From the experimental result of Fig. 4, can find out; under the radiotherapy condition of simulation; the Amifostine protective material known with prior art compared; the sulfuration aspartic acid melatonin zinc that uses embodiment 1b to prepare can significantly improve the survival rate of cell, and the protection effect of vulcanizing aspartic acid melatonin zinc in the situation that continuous several times is irradiated is better than Amifostine.
The synthetic compound of embodiment 6 embodiment 1d causes the provide protection experiment of people's peripheral leukocytes damage to taxol as protective material
The product (being the zinc salt of the compound of formula 5) that the present embodiment is used embodiment 1d to prepare is tested.Repeat the experimental procedure of embodiment 5, but difference is, the present embodiment does not re-use 60Co γ-rays and carries out irradiation, but at each cell sample, give the zinc salt (end level of cell culture fluid Chinese traditional medicine is 15 micromoles per liter) 12 hours afterwards of product prepared by embodiment 1d, Amifostine (end level of cell culture fluid Chinese traditional medicine is 1000 micromoles per liter) 30 minutes afterwards, in cell culture fluid, add taxol, make its end level be 3.5 nmoles/liter, give continuously taxol 5 days, give all to give protective material before taxol at every turn, give the last time taxol and by mtt assay, detect cell survival rate afterwards in 48 hours, result gathers sees Fig. 5.From the experimental result of Fig. 5, can find out; under the chemotherapy condition of simulation; the Amifostine protective material known with prior art compared, and uses the synthetic sulfuration aspartic acid melatonin zinc of embodiment 1d can obtain the cell survival rate significantly improving, and successful is better than Amifostine.
The synthetic compound of embodiment 7 embodiment 1c causes the provide protection experiment of people's peripheral leukocytes damage to cis-platinum as protective material
The present embodiment is used the synthetic compound of embodiment 1c (being the zinc salt of the melatonin of the sulfuration aspartic acid modification shown in formula 4), repeat the experimental procedure of embodiment 6, but difference is, the present embodiment does not re-use taxol treatment cell, but vulcanize aspartic acid melatonin zinc (end level of cell culture fluid Chinese traditional medicine is 15 micromoles per liter) 12 hours afterwards at each cell sample, Amifostine (end level of cell culture fluid Chinese traditional medicine is 1000 micromoles per liter) 30 minutes afterwards, in cell culture fluid, add cis-platinum, making its end level is 5 micromoles per liter, give continuously cis-platinum 5 days, give all to give protective material before cis-platinum at every turn, give the last time cis-platinum and by mtt assay, detect cell survival rate afterwards in 48 hours, result gathers sees Fig. 6.From the experimental result of Fig. 6, can find out, under the chemotherapy condition of simulation, the Amifostine protective material known with prior art compared, and uses the sulfuration aspartic acid melatonin zinc of embodiment 1c can obtain the cell survival rate significantly improving.
The synthetic compound of embodiment 8 embodiment 1b causes the provide protection (experiment in body) of bone marrow cells in mice damage to gamma-rays as protective material
The present embodiment is used the synthetic compound (being the zinc salt of the compound of formula 3) of embodiment 1b to test.It is experimental subjects that the male mice in 10 week age of 20 grams of left and right of body weight is take in this experiment, take 9 mouse as one group.Irradiation group only gives gamma-ray irradiation, does not give protective material, and 9 mouse in control group had not both given gamma-ray irradiation, did not give protective material yet; " the melatonin zinc that irradiates+modify " group of take is example, represents that applying 60Co γ-rays pre-irradiation vulcanizes aspartic acid melatonin zinc.First to each group mouse, correspondingly give protective material, concrete consumption is as follows: sulfuration aspartic acid melatonin zinc: 56 mg/kg/day, Amifostine: 400 mg/kg/day.Except Amifostine is abdominal injection (pre-irradiation is given Amifostine for 30 minutes), the same gastric infusion of all the other protective materials.Administration was carried out full-body exposure with 60Co γ-rays with the dosage of 2GY after 12 hours, and source of radiation is apart from 80 centimetres of mouse, dose rate 0.25Gy/ minute, and irradiation time is 8 minutes.Irradiate once every day, Continuous irradiation 5 days, and every day, pre-irradiation gave protective material, stopped irradiating still giving protective material successive administration 5 days rear every day, then fed 5 days.Respectively at the 3rd day, the 8th day, within the 13rd day, de-neck was put to death mouse (at every turn putting to death 3 mouse).Under aseptic condition, get the complete femur of right side of mice, cut off proximal femur, with the syringe (rinsing with RPMI1640 nutrient solution in advance) that No. 6 syringe needles are housed, by cuboid lower end, thrust, the whole medullary cells in medullary space are poured in the wide-necked bottle that fills 10ml nutrient solution and (repeatedly rushed 3 times).Then, change syringe needle piping and druming cell No. 4, prepare single cell suspension.Get 100ul single cell suspension+0.9ml white corpuscle diluent, by white blood cell count(WBC) method counting number of nucleated cells, carry out one-way analysis of variance, data represent with x ± s.In every group, the cell counting results averaged of 3 mouse is as final testing result.Using the result of control group as 100% cell survival, by the final testing result of each group and control group are compared, obtain corresponding cell survival rate percentage ratio, result gathers sees Fig. 7.From the experimental result of Fig. 7, can find out; under the radiotherapy condition of simulation; the Amifostine protective material known with prior art compared; use embodiment 1b preparation sulfuration aspartic acid melatonin zinc between the light period, can obtain the marrow defencive function similar to Amifostine; yet; sulfuration aspartic acid melatonin zinc has the effect that marrow recovers after remarkable promotion radiotherapy, and Amifostine is without this function.
Compound prepared by embodiment 9 embodiment 1c causes the provide protection (experiment in body) of bone marrow cells in mice damage to endoxan as protective material
The compound (being the zinc salt of the compound of formula 4) that the present embodiment is used embodiment 1c to prepare is tested.Repeat the step of embodiment 8, but difference is, the present embodiment no longer carries out 60Co γ-rays radiation, but within 12 hours giving protective material after, passes through abdominal injection, with the dosage of 35 mg/kg, gives mouse endoxan.According to above-mentioned dosage, give continuously endoxan 5 days and give continuously protective material 5 days, first, to giving endoxan after protective material, stop to still giving protective material every day after endoxan continuous 5 days, then feed 3 days every day.Respectively at the 3rd day, the 8th day, the 13rd day de-neck was put to death mouse (3 mouse/time).Get the separated marrow of the complete femur of right side of mice and calculate medullary cell survival rate.Result gathers sees Fig. 8.From the experimental result of Fig. 8, can find out; under analogue body chemotherapy condition; the protective materials such as Amifostine known with prior art compared; the sulfuration aspartic acid melatonin zinc that uses embodiment 1c to prepare can obtain the marrow defencive function similar to Amifostine at chemotherapeutic period; yet; sulfuration aspartic acid melatonin zinc has the effect that marrow recovers after remarkable promotion chemotherapy, and Amifostine is without this function.
Compound prepared by embodiment 10 embodiment 1a causes the provide protection (experiment in body) of mouse platelets damage to carboplatin as protective material
The product (being the zinc salt of the compound of formula 2) that the present embodiment is used embodiment 1a to prepare is tested.Repeat the step of embodiment 9, but difference is, the present embodiment is no longer processed mouse with endoxan, but within 12 hours giving protective material after, passes through abdominal injection, with the dosage of 30 mg/kg, gives mouse carboplatin.According to above-mentioned dosage, give continuously carboplatin 5 days and give continuously protective material 5 days, first, to giving carboplatin after protective material, stop to still giving protective material successive administration every day after carboplatin 5 days every day, continues to feed.Respectively at the 7th day, the 14th day, within the 21st day, extract mouse whole blood, with cellanalyzer, measure hematoblastic number.Result gathers sees Fig. 9.From the experimental result of Fig. 9, can find out; under analogue body chemotherapy condition; the protective materials such as Amifostine known with prior art compared; the sulfuration aspartic acid melatonin zinc that uses embodiment 1a to prepare can obtain the marrow defencive function similar to Amifostine at chemotherapeutic period; yet; sulfuration aspartic acid melatonin zinc has the effect of platelet recovery after remarkable promotion chemotherapy, and Amifostine is without this function.
Compound prepared by embodiment 11 embodiment 1a causes the provide protection (experiment in body) of mouse heart toxicity to Zorubicin as protective material
The step that repeats embodiment 10, protective material dosage is constant, but difference is, and the present embodiment is no longer processed mouse with carboplatin, but within 12 hours giving protective material after, passes through abdominal injection, with the Zorubicin of larger dose (5 mg/kg), gives mouse.According to above-mentioned dosage, give continuously Zorubicin 5 days and give continuously protective material 5 days; every day is first to giving Zorubicin after protective material; stop to still giving protective material successive administration every day after Zorubicin 5 days; feed again after 3 days; the survival de-neck of mouse that gets off is put to death to (3 mouse/groups); paraffin section is made to by cardiac muscular tissue, and end-labelling detects apoptosis.Simultaneously; when mouse is put to death; the variation of mice serum myocardial enzymes (glutamic-oxal(o)acetic transaminase/AST, serum lactic dehydrogenase/LDH, Creatine kinase MB/CKMB) after leaving and taking whole blood use automatic clinical chemistry analyzer device (UniCel DxC 600 Synchron, Beckman company (Beckman) U.S.) mensuration Zorubicin and share protective material.Result gathers sees Figure 10 A and 10B.From the experimental result of Figure 10 A, can find out; under analogue body chemotherapy condition; the protective materials such as Amifostine known with prior art compared; the sulfuration aspartic acid melatonin zinc that uses embodiment 1a to prepare can obtain than the more effective myocardial preservation function of Amifostine at chemotherapeutic period, and sulfuration aspartic acid melatonin zinc significantly reduces the apoptosis of cardiac muscle of caused by doxorubicin.From Figure 10 B, the content of the seroenzyme of the mouse of sulfuration aspartic acid melatonin zinc treatment group, significantly lower than control group, is better than Amifostine treatment group, illustrates that sulfuration aspartic acid melatonin zinc can suppress the myocardial necrosis that Zorubicin causes.
By above embodiment, can see; melatonin derivatives or its metal-salt with sulfuration aspartic acid is modified that the present invention synthesizes can be used for effectively alleviating the side effect that various chemicotherapies bring; normal tissue cell applies protection more fully, has effectively solved the high side-effect problem that cannot overcome in current cancer treatment procedure.
In addition, the protective material using in tumor therapeutic procedure often can bring provide protection to tumour cell too, so protective material is when reducing the side effect of malignant cell chemicotherapy, also may make tumour have tolerance to chemicotherapy.The inventor finds by deep research; by melatonin derivatives or its metal-salt and indomethacin coupling that sulfuration aspartic acid is modified; can, effectively protecting the Normocellular while significantly to reduce the protection effect to tumour cell, realize thus optionally provide protection.Once, in embodiment, shown this kind of selectivity.
Under embodiment 12 indomethacins and protective material coupling condition of the present invention, gamma-rays is caused the selectivity effect (experiment in body) of tumor killing effect and healthy tissues in nude mice transplanted tumor body
Use in the present embodiment the synthetic product of embodiment 1a (being the zinc salt of the compound of formula 2) to test.Under aseptic condition, the breast cancer cell in logarithmic phase (MCF-7) suspension (is adjusted to 1 * 10 with physiological saline by cell concn
7w/mL) be inoculated in experiment armpit back, female nude mice right side subcutaneous, every nude inoculation amount is 0.3ml, containing cell count be 3 * 10
6/ only.After 10 days, there is the subcutaneous transplantation knurl that 4-6 millimeter is large.Tumor bearing nude mice is divided into group at random, 3 every group.(1) control group, is left intact; (2) irradiation group, does not give any protective material; (3) radiotherapy+sulfuration aspartic acid melatonin zinc; (4) radiotherapy+indomethacin; (5) radiotherapy+(sulfuration aspartic acid melatonin zinc+indomethacin); (6) radiotherapy+Amifostine.First according to the dosage of the following stated, to each group tumor bearing nude mice, give following compound: indomethacin (10 mg/kg/day, gastric infusion) and protective material (sulfuration aspartic acid melatonin zinc; 56 mg/kg/day, Amifostine: 400 mg/kg/day, except Amifostine (pre-irradiation 30 minutes) subcutaneous injection, the same gastric infusion of all the other protective materials.Within after administration 12 hours, with 60Co-γ rays, tumor bearing nude mice is carried out to irradiation therapy, dosage is 2GY, and source of radiation is apart from 80 centimetres of animals, dose rate 0.25GY/ minute, irradiation time is 8 minutes, fractionated irradiation, irradiate once every day, each 2GY, Continuous irradiation 5 times (totally 5 days).Each pre-irradiation gives protective material.Between the light period, use weekly precise electronic balance measurement nude mice body weight, after inoculation, observe the growing state of tumour and have or not redness, ulceration every day.Become after knurl, check configuration of surface and the mobility of transplanted tumor, every 2～3 days major diameters (a) with vernier caliper measurement tumor nodule and minor axis (b), by formula V=0.5ab
2calculate gross tumor volume, ask its mean value, draw tumor growth curve and calculate tumour inhibiting rate, inhibition rate of tumor growth=(control group average-volume-irradiation group average-volume)/control group average-volume * 100%.And within 5,15,20,25,30 days after irradiation, get respectively mouse tail vein blood respectively and carry out white blood cell count(WBC), the BECKMANLH750 five classification Automatic Blood Cell Analyzers that produce with the U.S. detect white corpuscle number.The Relative volume fraction of the interior nude mice tumor tissues of each group gathers sees Figure 11 A.From Figure 11 A, can see; compare with known protective material Amifostine, when sulfuration aspartic acid melatonin zinc is combined use with indomethacin, the tolerance of inhibition tumor cell to radiotherapy significantly; obtain thus more significant radiotherapeutic effect, cause the volume of tumor tissues significantly to reduce.What is more important, from Figure 11 B, can see, sulfuration aspartic acid melatonin zinc does not strengthen ray to normal leukocytic lethal effect when combining use with indomethacin, can not cause adverse influence by normal tissue cell, this has shown that sulfuration aspartic acid melatonin zinc of the present invention combines the selectivity inhibition for tumour cell that use shows with indomethacin, and alone indomethacin can have slight increase ray to normal leukocytic damage, sulfuration aspartic acid melatonin zinc can alleviate the such side effect of indomethacin.By Figure 11 A, can be found out; alone sulfuration aspartic acid melatonin zinc has protection tumor tissues to a certain degree to avoid the damage of ray; make tumour become insensitive to radiotherapy; there is the worry slightly lessening the curative effect; this is because sulfuration aspartic acid melatonin zinc has powerful anti-apoptosis capacity; sulfuration aspartic acid melatonin zinc lacks certain selectivity entering cell, thus also can protect to a certain extent tumour cell, although its protection intensity is lower than the protection intensity of normal tissue.Not wishing to be subject to vulcanize aspartic acid melatonin zinc has protection tumor tissues to a certain degree to avoid the restriction of the damage of chemicotherapy, contriver thinks, indomethacin is an antiphlogiston, mainly by suppressing COX-2, play a role, COX-2 while or an inhibitor of apoptosis protein, its high expression level makes cell resist chemicotherapy, so suppress COX-2, can strengthen the susceptibility of cell to chemicotherapy, due to tumour cell high expression level COX-2, in addition tumor tissues is generally with inflammation pathological change and weakly acidic condition, these factors make the indomethacin with weak acid character optionally preferentially to enter and to accumulate in tumor tissues, thereby make tumour cell become more responsive to treatment, can effectively resist the protection of sulfuration aspartic acid melatonin zinc to tumour, and to normal cell without obvious cellulotoxic effect.Indomethacin is used simultaneously or they are made to compound preparation with sulfuration aspartic acid melatonin zinc all can be in the clinical effect reaching chemicotherapy attenuation enhanced sensitivity.
Embodiment 13 indomethacins and protective material cause the impact of the interior tumor killing effect of nude mice transplanted tumor body and healthy tissues on combined chemotherapy (Zorubicin+5 FU 5 fluorouracil+endoxan)
The present embodiment is used the synthetic product (being the zinc salt of the compound of formula 3) of embodiment 1b to test.Repeat the step of embodiment 12; protective material dosage is constant; difference is that the present embodiment no longer carries out 60Co-γ rays irradiation; but by combined utilization chemotherapeutics (Zorubicin: 2 mg/kg/time; 5 FU 5 fluorouracil: 25 mg/kg/time, endoxan: 30 mg/kg/time) row intraperitoneal injection carries out chemotherapy to tumor bearing nude mice.According to above-mentioned dosage every day to chemotherapeutic once; continuous use 5 days; before chemotherapy, give protective material continuous 5 days every day; the de-neck in after Shut-down Protection agent the 3rd day puts to death nude mice, get tumor tissues and normal gastric hole tissue is made paraffin section; with end-labelling, detect that apoptotic a situation arises, and measure the relative survival percentage ratio that calculates healthy tissues (stomach hole tissue) and tumor tissues and gather and see Figure 12 A.And the 3rd day after chemotherapy, from mouse tail vein blood sampling, gathered and seen Figure 12 B with Blood cell analyzer detection leukocyte count the last time.Specifically, the relative survival percentage ratio of one group of data representation healthy tissues in X-coordinate left side in Figure 12 A, and the relative survival percentage ratio of one group of data representation tumor tissues on X-coordinate right side.From Figure 12 A, can find out, when the sulfuration aspartic acid melatonin zinc of embodiment 1b is combined with indomethacin, the result of the relative survival percentage ratio of healthy tissues when using separately sulfuration aspartic acid melatonin zinc equate substantially, and the survival rate of tumour cell significantly declines.As can be seen here, compare with the situation of independent use sulfuration aspartic acid melatonin zinc, if sulfuration aspartic acid melatonin zinc is combined use with indomethacin, can significantly strengthen chemotherapeutic killing and wounding tumour cell, reduce the tolerance of tumour cell to chemotherapeutic, can not cause adverse influence by normal tissue cell, this has shown the selectivity effect for tumour cell that sulfuration aspartic acid melatonin zinc of the present invention and indomethacin coupling show simultaneously.From Figure 12 B, can find out that aspartic acid melatonin zinc and indomethacin coupling do not strengthen the inhibition of chemotherapeutic to hemopoietic system yet.
Embodiment 14 protective material of the present invention and the anti-apoptosis character comparison of vulcanizing aspartic acid
For the further protectant excellent properties of proof the present invention, applicant has further tested the melatonin that sulfuration aspartic acid, melatonin, sulfuration aspartic acid+melatonin, sulfuration aspartic acid modify and has reduced the effect of Zorubicin to the damage of people's kidney embryonic cell (HEK293).
This embodiment is used the synthetic product of embodiment 1a, i.e. compound shown in formula 2.In this embodiment use, separated people's kidney embryonic cell (HEK293) carries out vitro culture as described in Example 2.In cell culture fluid, add Zorubicin, make its end level be 25 nmoles/liter.Give Zorubicin after 2 hours, use the melatonin raw material 2a of compound of preparation formula 2 (be used in embodiment 1a), the sulfuration aspartic acid melatonin (compound 2b) of preparing in sulfuration aspartic acid (the raw material 1d in embodiment 1a) and embodiment 1a, as protective material, add in people's kidney embryonic cell (HEK293) of vitro culture respectively, end level is respectively: sulfuration aspartic acid (3 μ M, 15 μ M and 75 μ M), melatonin (3 μ M, 15 μ M and 75 μ M), sulfuration aspartic acid+melatonin (molar ratio 1:1, concentration is separately 3 μ M, 15 μ M and 75 μ M), melatonin (the 3 μ M that sulfuration aspartic acid is modified, 15 μ M and 75 μ M).Give protective material detects cell for 48 hours afterwards survival condition with mtt assay, summarized results is shown in Figure 13.In figure, control group represents not give the cell sample that protective material does not give Zorubicin yet, and Zorubicin group represents only to give Zorubicin and do not give protectant cell sample.As seen from Figure 13, the in the situation that of same amount, the protection effect of the melatonin that sulfuration aspartic acid is modified is significantly better than vulcanizing the mixture of aspartic acid, melatonin and sulfuration aspartic acid and melatonin.
Embodiment 15 protectant chmice acute toxicity data of the present invention (LD50)
In the present embodiment, by following steps, measure melatonin that the sulfuration aspartic acid of formula 2 modifies and the mouse medium lethal dose (LD50) of zinc salt thereof: it is experimental subjects that the male mice in 10 week age of 20 grams of left and right of body weight is take in this experiment, take 9 mouse as one group.Adopt gastric infusion approach to test, the disposable aspartic acid melatonin of modifying and the melatonin zinc that vulcanizes aspartic acid modification of vulcanizing, makes mouse dead successively.Observe to after administration 15 days, record the mortality of every group of mouse, result shows that the LD50 of the melatonin that the oral sulfuration aspartic acid of mouse is modified is 2050mg/kg, and the LD50 of the melatonin zinc that sulfuration aspartic acid is modified is 1525mg/kg.The melatonin zinc that sulfuration aspartic acid is modified is better than to the acute toxicity of mouse the melatonin that sulfuration aspartic acid is modified, and may be that zine ion has weakened the tolerance of mouse to its compound.
In sum, the inventor is by modifying melatonin and melatonin derivatives, developed the protective material that a class has splendid performance.This protective material can reduce the negative impact that chemicotherapy brings more significantly; and with indomethacin coupling in can show beat all selectivity, when reducing chemicotherapy toxic side effects, can also significantly suppress the tolerance of tumor tissues to chemicotherapy.Thereby two challenge-side effect and resistances greatly of oncotherapy have been solved at one stroke to a great extent.
Claims (14)
1. the compound as shown in following formula 1, and pharmacy acceptable salt:
In above structural formula 1, radicals R
1be selected from H, C
1-C
4alkyl, C
2-C
4thiazolinyl; Radicals R
2be selected from hydrogen or halogen; Radicals R
3be selected from C
1-C
4alkyl, C
2-C
4thiazolinyl or
2. compound as claimed in claim 1, is characterized in that, described radicals R
1be selected from H and methyl; Described halogen is chlorine; Described radicals R
3be selected from methyl or
3. compound as claimed in claim 1, is characterized in that, described compound is selected from the compound shown in any in following formula 2-5:
4. the compound as described in any one in above claim 1-3, is characterized in that, described salt is the salt forming with the positively charged ion that is selected from following metal: sodium, lithium, potassium, calcium, magnesium, strontium, manganese, aluminium, magnesium, iron, nickel, copper.
5. compound as claimed in claim 1, is characterized in that, described salt is the metal-salt shown in the following structural formula forming with magnesium ion or zine ion:
6. a pharmaceutical composition, described pharmaceutical composition comprises the compound described in any one or its pharmacy acceptable salt in above claim 1-5, and pharmaceutically acceptable auxiliary material.
7. pharmaceutical composition as claimed in claim 6, is characterized in that, described pharmaceutical composition also comprises indomethacin.
8. a compound as shown in following structural formula and pharmacy acceptable salt thereof are for the preparation of the application that reduces the medicine of concurrent chemoradiotherapy of malignant tumor toxic side effects:
In above structural formula, radicals R
1be selected from H, C
1-C
4alkyl, C
2-C
4thiazolinyl; Radicals R
2be selected from hydrogen or halogen; Radicals R
3be selected from C
1-C
4alkyl, C
2-C
4thiazolinyl or
9. application as claimed in claim 8, is characterized in that, described radicals R
1be selected from H and methyl, described halogen is chlorine; Described radicals R
3be selected from methyl or
10. application as claimed in claim 8, is characterized in that, described compound is selected from the compound shown in any in following formula 2-5:
11. application as described in any one in above claim 8-10, is characterized in that, described salt is and is selected from the salt that the positively charged ion of following metal forms: sodium, lithium, potassium, calcium, magnesium, strontium, manganese, aluminium, magnesium, iron, nickel, copper.
12. application as claimed in claim 8, is characterized in that, described salt is the metal-salt shown in the following structural formula forming with magnesium ion or zine ion:
13. application as described in any one in claim 8-10 and 12, is characterized in that, the medicine of described reduction concurrent chemoradiotherapy of malignant tumor toxic side effects also comprises indomethacin.
14. application as claimed in claim 11, is characterized in that, the medicine of described reduction concurrent chemoradiotherapy of malignant tumor toxic side effects also comprises indomethacin.
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| Title |
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| Jeong Tae Lee et al.Design, syntheses, and evaluation of Taspase1 inhibitors.《Bioorganic & Medicinal Chemistry Letters》.2009,第19卷第5086–5090页. |
| Jeong Tae Lee et al.Design, syntheses, and evaluation of Taspase1 inhibitors.《Bioorganic & * |
| JP特开2002-234872A 2002.08.23 |
| Medicinal Chemistry Letters》.2009,第19卷第5086–5090页. * |
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