CN102617581B - 58Fe hemin, preparation method and application of 58Fe hemin to study of pharmacokinetics - Google Patents
58Fe hemin, preparation method and application of 58Fe hemin to study of pharmacokinetics Download PDFInfo
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Abstract
The invention relates to the fields of the synthesis of medicines and pharmacokinetics, in particular to hemin containing stable isotope 58Fe and a method for synthesizing the hemin. The method comprises the following steps of: (a), oxidizing isotope 58Fe powder by using excess diluted hydrochloric acid to generate an isotope ferrous chloride solution, evaporating to remove moisture, and drying under vacuum to prepare an isotope ferrous chloride crystal; (b), reacting the prepared isotope ferrous chloride crystal with acidified protoporphyrin disodium, and controlling the pH value of a system before reaction to be 5 to 7; and (c), evaporating to remove most of reaction solvents, washing, adding an inorganic acid, regulating the pH value of the system to be 1 to 2, performing ultrasound oscillation, standing and performing suction filtration to obtain the 58Fe hemin. The invention provides a high-accuracy and high-sensitivity study method for the study of the intracorporal process of an endogenous substance, namely a core skeleton of the endogenous substance is marked by an isotope marking method, and the intracorporal process of the endogenous substance is studied quantitatively by measuring the content of the marked endogenous substance.
Description
Technical field
The present invention relates to medicine and synthesize and the pharmacokinetic studies field, be specifically related to a kind of stable isotope that contains
58The teichmann's crystals of Fe and synthetic method thereof.
Background technology
Teichmann's crystals is the stable form of protoheme (iron porphyrin).It is generally acknowledge in the world prevent and treat the most effective medicine of hypoferric anemia.Its principal feature is that iron-holder is high, without GI irritation, is easy to as human body is absorbed, bioavailability is good, directly is absorbed in gi tract with molecular form after entering human body, and uptake rate is very fast, mends the iron successful; So regarding it as, a lot of scientific research personnel substitute the optimal selection of prevailing inorganic benefit chalybeate in the market.In addition, teichmann's crystals also is widely used in food service industry, as the additive of numerous food, plays the function affect for the treatment of hypoferric anemia.
The method for preparing at present the teichmann's crystals sterling is mainly to extract purifying to obtain teichmann's crystals from natural animal blood; Existing scholar is for the synthetic research report of having made of metalloporphyrin and derivative thereof before, but these reports narration simple fuzzy control mostly, lacks rigorously, is difficult to reproduction; Simultaneously, about utilizing the stable isotope of iron
58Fe carries out the synthetic experiment of teichmann's crystals and there is not yet report.
In the pharmacokinetic studies field, be the endogenous material of human body due to iron, along with the difference of time, in blood, fluctuating largely also can appear in the concentration of iron.Therefore to the iron content medicine, when studying as the benefit iron effect of teichmann's crystals and physiological disposition, how to get rid of the interference of body endogenous iron as far as possible, obtain accurately to reflect the physiological disposition experimental data of exogenous iron, just become the problem that the researchist is concerned about the most.Many scholars also once did this and appeared all trials, but did not find yet so far a kind of effective research method.
Summary of the invention
The invention discloses a kind of utilization
58Teichmann's crystals (I) of Fe synthetic isotope mark and preparation method thereof can be used for this endogenous substance of quantitative examination teichmann's crystals, also provides material base for the physiological disposition of setting up a kind of new other iron content medicines of quantitative examination simultaneously.
Of the present invention with
58The teichmann's crystals of Fe mark, (I) is as follows for structural formula:
Of the present invention
58The preparation method of the teichmann's crystals of Fe mark comprises:
A, with isotropic substance
58The Fe powder generates the isotropic substance solution of ferrous chloride with excessive dilute hydrochloric acid oxidation, and the solution of ferrous chloride rotary evaporation that obtains is flung to moisture, and vacuum-drying makes isotropic substance iron protochloride crystal;
B, with the protoporphyrin disodium reaction of the isotropic substance iron protochloride crystal that makes and acidifying, controlling reacting precursor is that pH is 5～7;
C, boil off most of reaction solvent after, washing, adding mineral acid regulation system pH is 1～2, sonic oscillation, standing rear suction filtration, and get final product.
Aforesaid method also further comprises recrystallization.
Wherein b step reaction temperature is preferred 110 ℃～150 ℃, preferred 0.75～11 hour of reaction times.
Wherein the protoporphyrin disodium mol ratio of isotropic substance iron protochloride crystal and acidifying is preferred 1.2: 1～20: 1.
The preferred DMF of the reaction solvent of b step wherein.
The consumption preferred 1: 100～1 of protoporphyrin disodium and DMF solution: 200g/ml wherein.
Preferred preparation method comprises:
A is to isotropic substance is housed
58Pass into the harsh HCl gas that becomes in the flask of Fe powder and oxygen-free water until the iron powder completely dissolve obtains
58FeCl
2Solution; With what obtain
58FeCl
2Solution is at N
2In protection of the environment, rotary evaporation is flung to solvent, and vacuum-drying 12h makes isotropic substance iron protochloride crystal;
B is take DMF (DMF) as solvent, and the isotropic substance iron protochloride crystal that makes and the protoporphyrin disodium of acidifying are carried out complex reaction, it is 5～7 that the front hierarchy of control of reaction is slightly acidic pH, with the thin-layer chromatography monitoring, when the raw material protoporphyrin disappears or no longer reduces, stopped reaction.
After finishing, the c reaction removes most of solvent on Rotary Evaporators, washing, and adding mineral acid regulation system pH to be strongly-acid pH is 1～2, sonic oscillation 30min, standing rear suction filtration, by recrystallization and column chromatography, purifying obtains isotropic substance teichmann's crystals sterling.
The preparation process of isotropic substance iron protochloride crystal in above-mentioned steps a, wherein hydrochloric acid preferably generates hydrogen chloride gas by sodium-chlor/ammonium chloride and strong sulfuric acid response and is dissolved in oxygen-free water and gets; Fling in dissolving agent process in evaporation, must be with N
2Protect whole process to avoid ferrous iron to be oxidized to high ferro.
In above-mentioned steps b, the ratio of protoporphyrin disodium and reaction solvent DMF is preferably 1: 100～1: 200 (g/ml).The pH of described reacting precursor system should be strict be controlled at 5～7, reflux temperature is 110～150 ℃, the reaction times is 0.75～11h.Acidizing reagent is chosen as concentrated hydrochloric acid or dilute hydrochloric acid.
Answering hierarchy of control pH value after washing in above-mentioned steps c is 1～2, and sonic oscillation is fully to guarantee the dissolving of unnecessary inorganic iron ion.The reagent of adjustment of acidity is chosen as concentrated hydrochloric acid.
In order to improve product purity and productive rate, also preferred product with above-mentioned preparation further comprises the product after suction filtration by recrystallization and/or column chromatography purification.
Described recrystallization method is as solvent recrystallization with DMF (DMF).Preferred method is that isotropic substance teichmann's crystals crude product is dissolved in DMF, filters, and filter cake washs with a small amount of DMF, merging filtrate.According to crude product: water: (w: v: ratio w) is dissolved with filtrate being added in the aqueous solution of tensio-active agent zephiran chloride domiphen tensio-active agent=1: 100: 13, is warming up to 90 ℃, stirs 10min.Slowly dripping 20% hydrochloric acid soln to pH value of solution in the solution is 1～2.Standing solution is after a few hours, and suction filtration, washing leaching cake be to neutral, drying, both highly purified isotropic substance teichmann's crystals.
Described column chromatography method, purpose are in order to guarantee the abundant recovery of product in the filter cake in recrystallization process.Get in recrystallization and to filter last filter cake after crude product, fully dissolve sonic oscillation with DMF.Add proper silica gel, the underpressure distillation desolventizing.The sample that this is to be separated is transferred in chromatography column, and first with methyl alcohol: the eluent of methylene dichloride=1: 50 separates; Constantly change the eluent ratio, adjust polarity, collect methyl alcohol: the elutriant of methylene dichloride=1: 10, mix concentratedly, dry up with nitrogen in 60 ℃ of water-baths.Can obtain the isotropic substance teichmann's crystals sterling of purity＞96%.
In research process, the contriver finds: utilizing the difficult point of the synthetic teichmann's crystals of iron isotope mainly to be to control in reaction process and the pH value of system during aftertreatment, is secondly the temperature of reacting and the mol ratio of two kinds of reaction raw materials.All about the synthetic report of metalloporphyrin analogue, the pH value of reaction system is not all made detailed research before.When the present invention is disclosed in protoporphyrin disodium and inorganic metal reactant salt, if system pH peracid can suppress the carrying out of complex reaction; If the pH meta-alkali of system, protoporphyrin can again form sodium-salt form two and separate out from solvent DMF, and inorganic metal salt can become alkali, the solvability reduction; Therefore need the pH of guarantee system to be faint acidity, be controlled at 5～7 optimums.Chinese patent CN 1418885A discloses a kind of preparation method of ferriporphyrin sodium salt, crystallization when only being neutralized to pH=4 with protonic acid in its last handling process.But the present invention discloses, and in last handling process, needs the pH of regulation system to be strongly-acid, with 1～2 the best; If acidity is strong not, react remaining inorganic metal ion and can be mixed in product, affect the purity of product.
Aspect the temperature of reaction selection, the temperature of before selecting about the synthetic report of metalloporphyrin analogue is≤70 ℃, or narrate ambiguous.Introduce in the synthetic method of the disclosed metalloporphyrin of Chinese patent CN 1944434A and react under cold condition with mixed solvent; The temperature of reaction that provides in the preparation method of the disclosed ferriporphyrin sodium salt of Chinese patent CN 1418885A is 10～70 ℃.But the present invention reacts in single solvent and higher temperature range, has also obtained the very high product of purity; The temperature range that the present invention selects is 110～150 ℃, and the temperature of finding to react is with the common purity that affects product of the feed ratio of raw material.
At present current metalloporphyrin synthetic method is and drops into excessive inorganic metal salt (be generally protoporphyrin molar weight 3～8 times) to guarantee the abundant reaction of protoporphyrin; In this case, the level of response of this building-up reactions is very complete, and no coupling product generates, and the teichmann's crystals purity that obtains is generally more than 98%.But in this invention, consider the Financial cost of stable isotope iron powder, must guarantee as much as possible the abundant reaction of inorganic molysite, take into account simultaneously the yield of reaction principal product.
Aspect the purification process selection of reactant, the method that the present invention has selected recrystallization to combine with column chromatography, this method can guarantee farthest to realize the recycling of product when obtaining high purity product.About the method for protoheme recrystallization, forefathers had done a lot of researchs.Classical method comprises: ice acetic acid method, acid acetone method, α-amylase hydrolysis and surfactant method.The organic reagent that front several method is a large amount of because needs expend causes larger pollution to environment, and production unit is had relatively high expectations and to obtain product crystal formation after purifying uncertain and do not adopted by the present invention.Aspect the selection of tensio-active agent, forefathers use Nonoxynol-9 more, tetradecyl betaine, citric acid or above several mixing and the tensio-active agent that forms.The kinds of surfactants that the present invention adopts is the zephiran chloride domiphen, uses the resulting isotropic substance teichmann's crystals of this tensio-active agent crystal purity higher, and regular shape, consistent is the narrow parallelogram of red-brown.Collect the surplus products that are dissolved in recrystallization process in solution, with the method gradient elution of silica gel column chromatography, collect corresponding elution fraction, can reclaim and obtain highly purified product, realize the maximum purification process of crude product that synthesizes.
This invention provides a kind of novelty for the physiological disposition research of endogenous material, split hair caccuracy, highly sensitive research method, namely utilize isotope-labeled method partly to carry out mark to the core skeleton of endogenous material, come its physiological disposition of quantitative examination by the endogenous material content of measuring mark.
Description of drawings
Fig. 1 is
58The mass spectrum of the teichmann's crystals of Fe mark
Fig. 2 is that rat single dose gavage gives 40mg/kg
58Plasma Concentration-time curve after the Fe teichmann's crystals
Embodiment
Embodiment 1
1. take the 0.240g isotropic substance
58Fe powder (ISOFLEX USA, San Franciso, No.26-01-58-4030), be transferred in single neck flask, add the 25ml oxygen-free water, to the HCl gas that passes into harsh one-tenth below single neck bottle liquid level (being generated by sodium-chlor/ammonium chloride and strong sulfuric acid response), the oil bath heating until
58The Fe powder thoroughly disappears.Under nitrogen protection, the moisture in Rotary Evaporators Back stroke dereaction liquid obtains isotropic substance iron protochloride solid; Dry 12h in vacuum drying oven obtains isotropic substance iron protochloride crystal.
2. with stirrer, add 2.0918g protoporphyrin disodium (Tokyo HuaCheng Industry Co., Ltd in three mouthfuls of round-bottomed flasks of the 500ml of thermometer and air return condenser, the rich island 6-15-9 in North Area, Tokyo, Lot.GG01), take about 220ml DMF as dissolution with solvents, add the acidifying of 770ul concentrated hydrochloric acid, sonic oscillation fully dissolves, and this moment, system pH was 6～7.The isotropic substance iron protochloride crystal of gained in step 1 is added in reaction system, and under agitation controlling temperature is 120 ℃, and reaction 11h is with the shade of thin-layer chromatography point plate monitoring raw material point, the rear stopped reaction until the color of raw material point no longer shoals.The pH of assaying reaction stop buffer is to guarantee its slightly acidic, and underpressure distillation goes out most of DMF, and is cooling, adds the cold distilled water flushing of 1200ml.Add the acidifying of 12ml concentrated hydrochloric acid, measuring its pH is 1～2, sonic oscillation 30min, standing suspension liquid; Suction filtration discards filtrate, and dry rear recrystallization obtains the sterling of isotropic substance teichmann's crystals.
3. get isotropic substance teichmann's crystals crude product 2g, fully dissolve stirring with 150ml DMF.Filter, filter cake is with 5ml DMF washing, merging filtrate.Add 500ml water and 26g zephiran chloride domiphen in filtrate, be warming up to 90 ℃, stir 10min.Dripping 20% hydrochloric acid soln to pH value of solution in the solution is 1～2.Standing solution is after a few hours, and suction filtration, washing leaching cake be to neutral, drying, both highly purified isotropic substance teichmann's crystals.
4. get in previous step and to filter last filter cake after crude product, fully dissolve sonic oscillation with DMF.Add proper silica gel, the underpressure distillation desolventizing.The sample that this is to be separated is transferred in chromatography column, and first with methyl alcohol: the eluent of methylene dichloride=1: 50 separates; Constantly change the eluent ratio, adjust polarity, collect methyl alcohol: the elutriant of methylene dichloride=1: 10, mix concentratedly, dry up with nitrogen in 60 ℃ of water-baths.RP-HPLC analyzes, and purity is 96.7%, satisfies the purity requirement of isotropic substance teichmann's crystals.
RP-HPLC：
Hypersil C18 post 4.6mm * 200mm, 20 ℃
Moving phase: methyl alcohol: acetonitrile: water: acetic acid: pyridine=40: 40: 19: 1: 0.6
Flow velocity: 1ml/min
Wavelength: 399nm (UV-detector)
Productive rate: 9.74min (96.7%)
Its mass spectrum is seen Fig. 1, leading ion peak ownership explanation:
1. m/z 617.132 peaks: [M-Cl]
+
2. m/z 559.194 peaks: [M-Cl-C
2H
3O
2]
+
(3. m/z 499.983 peaks: [M-Cl-C
2H
3O
2-C
2H
3O
2]
+
Embodiment 2
1. take the 0.8589g isotropic substance
58Fe powder (ISOFLEX USA, San Franciso, No.26-01-58-4030), be transferred in single neck flask, add the 20ml oxygen-free water, to the HCl gas that passes into harsh one-tenth below single neck bottle liquid level (being generated by sodium-chlor/ammonium chloride and strong sulfuric acid response), the oil bath heating until
58The Fe powder thoroughly disappears.Under nitrogen protection, the moisture in Rotary Evaporators Back stroke dereaction liquid obtains isotropic substance iron protochloride solid; Dry 12h in vacuum drying oven obtains isotropic substance iron protochloride crystal.
2. with stirrer, add 0.4652g protoporphyrin disodium (Tokyo HuaCheng Industry Co., Ltd in three mouthfuls of round-bottomed flasks of the 100ml of thermometer and air return condenser, the rich island 6-15-9 in North Area, Tokyo, Lot.GG01), take about 50ml DMF as dissolution with solvents, add the acidifying of 130ul concentrated hydrochloric acid, sonic oscillation fully dissolves, and this moment, system pH was 5～6.The isotropic substance iron protochloride crystal of gained in step 1 is added in reaction system, and under agitation controlling temperature is 110 ℃, and reaction 0.75h is with the shade of thin-layer chromatography point plate monitoring raw material point, the rear stopped reaction until the color of raw material point no longer shoals.The pH of assaying reaction stop buffer is to guarantee its slightly acidic, and underpressure distillation goes out most of DMF, and is cooling, adds the cold distilled water of 600ml to rinse.Add the acidifying of 10ml concentrated hydrochloric acid, measuring its pH is 1～2, sonic oscillation 30min, standing suspension liquid; Suction filtration discards filtrate, and dry rear recrystallization obtains highly purified isotropic substance teichmann's crystals, analyzes with RP-HPLC, and purity is 98.68%.
RP-HPLC：
Hypersil C18 post 4.6mm * 200mm, 20 ℃
Moving phase: methyl alcohol: acetonitrile: water: acetic acid: pyridine=40: 40: 19: 1: 0.6
Flow velocity: 1ml/min
Wavelength: 399nm (UV-detector)
Productive rate: 9.74min (98.68%)
Embodiment 3
Repeat the process of embodiment 2, change is that the reaction mol ratio of controlling isotropic substance iron powder and protoporphyrin disodium was respectively 1: 10 and 1: 15.Can obtain purity and be respectively 91.89% and 94.85% isotropic substance teichmann's crystals sterling.
Embodiment 4
Repeat the process of embodiment 2, change is that the temperature of controlling complex reaction is respectively 100 ℃, 110 ℃ and 150 ℃.Can obtain purity and be respectively 90.83%, 93.26% and 95.11% isotropic substance teichmann's crystals sterling.
Get 6 of cleaning level SD rats, male and female half and half.Get and prepare
58Fe teichmann's crystals solution, press 40mg/kg dosage gastric infusion, get blank blood before administration, get blood 300 μ L in 0.5h, 1h, 1.5h, 2h, 4h, 8h, 15h, 24h and 36h through eyeground vein after administration and be placed in the eppendorf pipe mixing that has added in advance heparin, rapidly in the centrifugal 5min of 14000rpm, get blood plasma 150 μ L ,-70 ℃ of preservations are for test.Measure in plasma sample with icp ms (ICP-MS)
58The concentration of Fe just can obtain giving
58The plasma concentration curve of Fe teichmann's crystals and corresponding pharmacokinetic parameter.The results are shown in Table 1, table 2 and Fig. 2:
ICP-MS (X SERIES 2, Thermo SCIENTIFIC) condition determination: ion source is the ICP source, adopting quartz glass concentric atomizer (0.8mL/m), and the quartzy torch pipe of monolithic devices, the 1.5mm bore sprays.The spraying gun argon flow amount is 0.95L/min.Detecting pattern is the CCT pattern.Detector inert stage voltage is 1830v, the detector pulses step voltage is 3500v, and radio frequency power is 1200w, and cooling gas flow is 14.3L/min, the sample lifting capacity is 1mL/min, the sample lifting time is 40s, and multiplicity is 3 times, selects respectively iron Fe (58), nickel (58), chromium Cr (53), germanium Ge (72) is scan element, scan mode is for jumping peak scanning.
Table 1. rat oral gavage gives 40mg/kg
58Plasma Concentration after the Fe teichmann's crystals (ng/mL)
Table 2. rat oral gavage gives 40mg/kg
58Pharmacokinetic parameters after the Fe teichmann's crystals
Claims (6)
- One kind with 58The preparation method of the teichmann's crystals I of Fe mark comprises:
A, with isotropic substance 58The Fe powder generates the isotropic substance solution of ferrous chloride with excessive dilute hydrochloric acid oxidation, and the solution of ferrous chloride rotary evaporation that obtains is flung to moisture, and vacuum-drying makes isotropic substance iron protochloride crystal;B, with the protoporphyrin disodium reaction of the isotropic substance iron protochloride crystal that makes and acidifying, controlling reacting precursor is that pH is 5～7, reaction solvent is DMF;C, boil off most of reaction solvent after, washing, adding mineral acid regulation system pH is 1～2, sonic oscillation, standing rear suction filtration, and get final product. - 2. the preparation method of claim 1, also comprise the product after suction filtration by recrystallization and column chromatography purification.
- 3. the preparation method of claim 1, wherein b step reaction temperature is 110 ℃～150 ℃, the reaction times is 0.75～11 hour.
- 4. the preparation method of claim 1, wherein the protoporphyrin disodium mol ratio 1.2:1～20:1 of isotropic substance iron protochloride crystal and acidifying.
- 5. the preparation method of claim 1, wherein the consumption of protoporphyrin disodium and DMF solution is 1:100～1:200g/ml.
- 6. claim 1 58The teichmann's crystals of Fe mark is used for the purposes of the marker of quantitative assay medicine internal metabolism process.
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| CN102967649B (en) * | 2012-05-24 | 2015-03-04 | 新疆科丽生物技术有限公司 | Application of inductively coupled plasma mass spectrometry in drug testing of hemin |
| CN104478905A (en) * | 2014-12-15 | 2015-04-01 | 江西师范大学 | Novel copper-hemin organic frame structure with three-dimensional porous ball-flower structure and preparation method of novel copper-hemin organic frame structure |
| CN105267223B (en) * | 2015-10-08 | 2018-04-13 | 中国科学院合肥物质科学研究院 | A kind of plasma promotees blood coagulation adjuvant |
| CN110568058A (en) * | 2019-09-27 | 2019-12-13 | 浙江艾摩柯斯环境科技有限公司 | ICP-MS-based method for rapidly determining activity of anammox sludge |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87101834A (en) * | 1986-03-12 | 1988-01-06 | 巴斯福股份公司 | The separation of protohemine and purifying |
| WO2002060383A2 (en) * | 2001-01-19 | 2002-08-08 | National Jewish Medical And Research Center | Cancer therapy |
| CN1388129A (en) * | 2002-06-06 | 2003-01-01 | 任家云 | Extraction process of chlorhematin as iron-replenishing agent |
| CN1418885A (en) * | 2001-11-14 | 2003-05-21 | 上海金赤生物制品有限公司 | Process for preparing ferriporphyrin sodium salt |
| CN1844123A (en) * | 2006-04-28 | 2006-10-11 | 新疆科丽生物技术有限公司 | Process for extracting protohemin by using surfactant |
| CN1944434A (en) * | 2006-10-27 | 2007-04-11 | 北京工业大学 | Method for synthesizing porphyrin and metal porphyrin |
| WO2008045358A1 (en) * | 2006-10-06 | 2008-04-17 | Trustees Of Princeton | Porphyrin catalysts and methods of use thereof |
| CN102285992A (en) * | 2011-06-28 | 2011-12-21 | 南京师范大学 | Dihydroporphin (III) chelates having plant growth regulating activity and use thereof as plant growth regulator |
-
2012
- 2012-03-15 CN CN 201210068181 patent/CN102617581B/en not_active Expired - Fee Related
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87101834A (en) * | 1986-03-12 | 1988-01-06 | 巴斯福股份公司 | The separation of protohemine and purifying |
| WO2002060383A2 (en) * | 2001-01-19 | 2002-08-08 | National Jewish Medical And Research Center | Cancer therapy |
| CN1418885A (en) * | 2001-11-14 | 2003-05-21 | 上海金赤生物制品有限公司 | Process for preparing ferriporphyrin sodium salt |
| CN1388129A (en) * | 2002-06-06 | 2003-01-01 | 任家云 | Extraction process of chlorhematin as iron-replenishing agent |
| CN1844123A (en) * | 2006-04-28 | 2006-10-11 | 新疆科丽生物技术有限公司 | Process for extracting protohemin by using surfactant |
| WO2008045358A1 (en) * | 2006-10-06 | 2008-04-17 | Trustees Of Princeton | Porphyrin catalysts and methods of use thereof |
| CN1944434A (en) * | 2006-10-27 | 2007-04-11 | 北京工业大学 | Method for synthesizing porphyrin and metal porphyrin |
| CN102285992A (en) * | 2011-06-28 | 2011-12-21 | 南京师范大学 | Dihydroporphin (III) chelates having plant growth regulating activity and use thereof as plant growth regulator |
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