CN104814952A - Method for promoting carbon monoxide release of carbon monoxide-releasing molecules and preventing sedimentation - Google Patents
Method for promoting carbon monoxide release of carbon monoxide-releasing molecules and preventing sedimentation Download PDFInfo
- Publication number
- CN104814952A CN104814952A CN201510180597.7A CN201510180597A CN104814952A CN 104814952 A CN104814952 A CN 104814952A CN 201510180597 A CN201510180597 A CN 201510180597A CN 104814952 A CN104814952 A CN 104814952A
- Authority
- CN
- China
- Prior art keywords
- carbon monoxide
- precipitation
- compound
- edta
- release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for promoting carbon monoxide release of carbon monoxide-releasing molecules (CORM) and preventing sedimentation and belongs to the technical field of medical chemistry. The method particularly comprises the following steps: dissolving CO releasing molecules in dimethyl sulfoxide, and adding amino acid, or derivatives thereof, or medicine molecules and an EDTA water solution. After adding of EDTA, generation of CO is effectively promoted, and sedimentation in reaction can be quickly removed. The method has good university; compounds related to the reaction have excellent biocompatibility; and after release of CO, sedimentation can be quickly and effectively prevented, and the CO release time and rate can be easily controlled.
Description
Technical field
The present invention relates to technical field of medical chemistry, particularly relate to a kind of promote carbon monoxide emitter discharge carbon monoxide and prevent formed precipitation method.
Technical background
Carbon monoxide (CO) has bioactive a kind of biological micromolecule in human body.Analog NO with it is the same, and CO plays very important physiology and pathological role in organism, as vasodilator, suppresses reperfusion injury, anti-apoptotic, antiproliferative, antioxidation, antibacterial etc.In order to explore the pharmaceutical potential of this diatomic molecule, its accurate on-the-spot release will be very crucial problem.Transition metal carbonyl compound is a large metalloid-organic compound, can cause leaving away of carbonyl (CO) under suitable condition, as illumination, substitution reaction, oxidoreduction induction etc.Utilize these character of metal carbonyl to design, synthesize some specific transition metal carbonyl compounds, make it to discharge CO under suitable conditions, i.e. so-called carbon monoxide emitter (carbon monoxide-releasing molecules, CORM).The advantage of CORM is both without the need to by organism metabolism process, also without the need to through respiratory system suction, directly at agents area drug administration by injection release CO, in addition, consumption size and medication time easily control.Metal carbonyl can realize the controlled CO release of safety, is a kind of drug molecule with application prospect, the great attention being subject to people for 10 years in the past.
Mann etc. are one of the research worker of carrying out metal carbonyl CORM research that takes the lead in.Animal model test result shows to have fabulous application prospect based on the CORM of metal carbonyl.Research shows CORM-2 ([RuCl
2(CO)
3]
2) and CORM-3 (fac-[Ru (CO)
3cl (glycinate)]) can CO be discharged under certain condition, vasodilator can be played, reduce inflammation reaction; Regulate vasoactive, alleviate myocardial ischemia reperfusion injury; Suppress the effects such as cardiac transplant rejection episode.The compound of the relevant CORM reported nearly ten years has reached tens kinds, mainly concentrate on the metallic elements such as Ru, Mn, Mo, Re, Fe, but some metals such as Ru, Mo etc. are not that organism must element in these compounds, majority of compounds also ubiquity stability or poorly water-soluble and the problem such as rate of release is improper in addition.Ferrum is the essential element of many organisms, and organism has perfect metabolic mechanism to it, but also fewer based on the report of iron molybdenum cofactor CORM at present.
We have synthesized two kinds of iron molybdenum cofactor [Fe recently
2{ μ-SCH
2cH (OH) CH
2-(OH) }
2(CO)
6] (1) and [Fe
2(μ-SCH
2cH
2-cH
2)
2(CO)
6(2)), they can decompose release carbon monoxide under mercaptoethylmaine effect.But this process can produce a certain amount of precipitation, may for the water-fast corresponding iron compound generated.In addition in order to strengthen the bio-compatibility of this carbon monoxide delivery systme, we select the material forming Life Base matter protein elementary cell, i.e. aminoacid and derivant thereof or some drug molecules alternatively induction agent, and have studied the carbon monoxide releasability of the iron molybdenum cofactor of its induction.But the carbon monoxide rate of release of aminoacid and derivant or drug molecule induction is comparatively slow comparatively speaking, and also can produce a certain amount of precipitation in course of reaction.As everyone knows, if really produce precipitation as the compound of medicine in body metabolism process can cause a series of side reaction, be difficult to discharge as assembled in vivo, even artery-clogging causes some other diseases.Therefore find one and can promote that carbon monoxide discharges, and the method simultaneously removing precipitation in drug metabolism reaction is of great significance with regard to tool.
Summary of the invention
The invention provides a kind of method that carbon monoxide release also can remove precipitation in drug metabolism reaction simultaneously that can promote.This method adopts the method adding EDTA in carbon monoxide delivery systme, can promote the carrying out reacted, can effectively remove the precipitation produced in reaction again.
The present invention adopts following technical scheme:
Promotion carbon monoxide emitter of the present invention release carbon monoxide also prevents the method detailed process forming precipitation as follows: be dissolved in dimethyl sulfoxine by CO releasing agent, adds aminoacid or derivatives thereof or drug molecule and EDTA aqueous solution.
Described CO releasing agent is transition metal carbonyl compound.
As one of preferred technical scheme: described CO releasing agent is [Fe
2{ μ-SCH
2cH
(OH) CH
2(OH) }
2(CO)
6] (compound 1).
As one of preferred technical scheme: described CO releasing agent is [Fe
2(μ-SCH
2cH
2-cH
2)
2(CO)
6] (compound 2).
Described aminoacid or derivatives thereof is proline.
Described drug molecule is tiopronin.
The concentration that CO releasing agent is dissolved in dimethyl sulfoxine is 0.001mol/L ~ 0.02mol/L, adds aminoacid or derivatives thereof or the drug molecule of three times of moles, and the EDTA of one times of mole.
Iron molybdenum cofactor 1 and 2 can decompose generation carbon monoxide under bio-compatible aminoacid and derivant or drug molecule effect thereof, reaches the object of slow releasing CO, but this reaction rate is slow, and in course of reaction, have precipitation generation.This system has obvious facilitation to reaction after adding EDTA, but also can effectively remove the precipitation generated in reaction.
Compared with prior art, the beneficial effect of the inventive method is:
(1) the method can promote the generation of carbon monoxide effectively;
(2) the method promotes that the opportunity of release carbon monoxide and speed are easily controlled;
(3) compound involved by the method has good bio-compatibility;
(4) the method can remove the precipitation produced in reaction fast.
Accompanying drawing explanation
Fig. 1 is compound 1-[Fe
2{ μ-SCH
2cH (OH) CH
2(OH) } (CO)
6] linear relationship chart (interior illustration) of infrared spectrum variation diagram after adding proline and kinetics lnA-t thereof.
Fig. 2 is compound 1-[Fe
2{ μ-SCH
2cH (OH) CH
2(OH) } (CO)
6] linear relationship chart (interior illustration) of infrared spectrum variation diagram after adding proline and EDTA and kinetics lnA-t thereof.
Fig. 3 is compound 1-[Fe
2{ μ-SCH
2cH (OH) CH
2(OH) } (CO)
6] linear relationship chart (interior illustration) of infrared spectrum variation diagram after adding bio-compatible drug molecule (tiopronin) and kinetics lnA-t thereof.
Fig. 4 is compound 1-[Fe
2{ μ-SCH
2cH (OH) CH
2(OH) } (CO)
6] linear relationship chart (interior illustration) of infrared spectrum variation diagram after adding bio-compatible drug molecule (tiopronin) and EDTA and kinetics lnA-t thereof.
Fig. 5 is compound 2-[Fe
2{ μ-SCH
2cH
2)
2(CO)
6] at the linear relationship chart (interior illustration) of the infrared spectrum variation diagram and kinetics lnA-t thereof that add bio-compatible drug molecule (tiopronin).
Fig. 6 is compound 2-[Fe
2{ μ-SCH
2cH
2)
2(CO)
6] linear relationship chart (interior illustration) of infrared spectrum variation diagram after adding bio-compatible drug molecule (tiopronin) and EDTA and kinetics lnA-t thereof.
Detailed description of the invention
Below by specific embodiment, the present invention is further elaborated; but not limiting the scope of the invention; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Embodiment 1:
Compound 1 (17mg, 34mmol) adds 2.4mL DMSO, adds in reaction tube after dissolving, adds appropriate aminoacid or drug molecule aqueous solution (0.1mL, 1.035mol L at 37 DEG C respectively
-1, [compound 1]: [aminoacid or drug molecule]=1:3) and 0.5mL aqueous solution, survey at set intervals once infrared (Varian Scimitar 600).The experimentation and the said process that add EDTA in this system are similar, just need to add 0.1mL EDTA-2Na aqueous solution (3.45mol L again
-1), the aqueous solution added is then 0.4mL, ensures that final solution is 3.0mL.
Add proline or tiopronin in compound 1 after, infrared spectrum generation significant change, as shown in figs. 1 and 3, compound 1 is at 2068,2031,1989cm
-1have three obvious carbonyl absorption peaks, these infrared signature peaks obviously weaken after adding proline or tiopronin.It can thus be appreciated that compound 1 carbonyl after adding proline or tiopronin reduces gradually and discharges as carbon monoxide, illustrate that this process can discharge carbon monoxide.The infrared spectrum that other aminoacid and drug molecule and compound 1 act on is similar.These results illustrate that aminoacid or drug molecule can promote that compound 1 decomposes release carbonyl.Kinetics shows, these reactions all meet first order kinetics process (in Fig. 1 and 3 illustration), and the difference of its reaction rate depends on the difference of aminoacid or drug molecular structure.
But always having precipitation to produce in above-mentioned carbon monoxide delivery systme, may be some insoluble iron compounds.In order to avoid this situation, we select the EDTA with stronger coordination ability to join in above-mentioned system as part, wish that can reduce precipitation generates.In addition, wish that EDTA can precipitate to iron compound and form corresponding coordination compound, thus the carrying out of energy accelerated reaction.Expectedly, in above-mentioned system, add the decomposition (Fig. 2 and 4) that EDTA can accelerate compound 1, and significantly can reduce precipitation generation, finally substantially can form settled solution.And carbon monoxide dispose procedure also all belongs to first-order kinetics process (in Fig. 2 and 4 illustration) after adding EDTA.In addition, as can be seen from table 1 also, in carbon monoxide delivery systme, add EDTA really can the carrying out of accelerated reaction, and its reaction half-time obviously shortens.
Embodiment 2:
Compound 2 (14mg, 34mmol) adds 2.4mL DMSO, adds in reaction tube after dissolving, adds appropriate amount of drug molecular water solution (0.1mL, 1.035mol L at 37 DEG C respectively
-1, [compound 1]: [aminoacid or drug molecule]=1:3) and 0.5mL aqueous solution, survey at set intervals once infrared (Varian Scimitar 600).The experimentation and the said process that add EDTA in this system are similar, just need to add 0.1mL EDTA-2Na aqueous solution (3.45mol L again
-1), and the aqueous solution added is 0.4mL, ensures that final solution is 3.0mL.
After compound 2 adds tiopronin, infrared spectrum generation significant change, as shown in Figure 5, compound 2 is at 2068,2031,1989cm
-1have three obvious carbonyl absorption peaks, these infrared signature peaks obviously weaken after adding tiopronin.After this explanation adds tiopronin, compound 2 carbonyl characteristic peak weakens gradually and discharges as carbon monoxide, and namely this process can discharge carbon monoxide.The infrared spectrum that other drug molecule and compound 2 act on is similar.Kinetics result shows, these reactions all meet first order kinetics process (in Fig. 5 illustration).
Similar with compound 1, in above-mentioned system, add the decomposition (Fig. 6) that EDTA can accelerate compound 2, and significantly can reduce precipitation generation.The carbon monoxide dispose procedure adding EDTA in above-mentioned system also belongs to first-order kinetics process (in Fig. 6 illustration).In addition as can be seen from table 2 also, in above-mentioned carbon monoxide delivery systme, add the carrying out of EDTA energy accelerated reaction, its reaction half-time obviously shortens.
Above two examples all illustrate that adding EDTA in the catabolic process of the compound 1 or 2 promoted at aminoacid or drug molecule can carry out in accelerated reaction, namely accelerates the release of carbon monoxide, and significantly can reduce precipitation generation.
Table 1 compound 1 discharges the half-life of carbon monoxide under aminoacid or derivatives thereof or drug molecule effect
Table 2 compound 2 discharges the half-life of carbon monoxide under amino acid derivativges or drug molecule effect
Although illustrate and describe embodiments of the invention, for the ordinary skill in the art, be appreciated that and can carry out multiple change, amendment, replacement and modification to these embodiments without departing from the principles and spirit of the present invention, scope of the present invention is by claims and equivalents thereof.
Claims (7)
1. promote carbon monoxide emitter to discharge carbon monoxide and prevent from being formed the method for precipitation, it is characterized in that: described method specific as follows: CO releasing agent is dissolved in dimethyl sulfoxine, adding aminoacid or derivatives thereof or drug molecule and EDTA aqueous solution.
2. promotion carbon monoxide emitter as claimed in claim 1 discharges carbon monoxide and prevents from being formed the method for precipitation, it is characterized in that: described CO releasing agent is transition metal carbonyl compound.
3. promotion carbon monoxide emitter as claimed in claim 1 discharges carbon monoxide and prevents from being formed the method for precipitation, it is characterized in that: described CO releasing agent is
[Fe
2{μ-SCH
2CH(OH)CH
2(OH)}
2(CO)
6]。
4. promotion carbon monoxide emitter as claimed in claim 1 discharges carbon monoxide and prevents from being formed the method for precipitation, it is characterized in that: described CO releasing agent is
[Fe
2(μ-SCH
2CH
2-CH
2)
2(CO)
6]。
5. promotion carbon monoxide emitter as claimed in claim 1 discharges carbon monoxide and prevents from being formed the method for precipitation, it is characterized in that: described aminoacid or derivatives thereof is proline.
6. promotion carbon monoxide emitter as claimed in claim 1 discharges carbon monoxide and prevents from being formed the method for precipitation, it is characterized in that: described drug molecule is tiopronin.
7. promotion carbon monoxide emitter as claimed in claim 1 discharges carbon monoxide and prevents from being formed the method for precipitation, it is characterized in that: the CO releasing agent concentration be dissolved in dimethyl sulfoxine is 0.001mol/L ~ 0.02mol/L, add aminoacid or derivatives thereof or the drug molecule of three times of moles, and the EDTA of one times of mole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510180597.7A CN104814952B (en) | 2015-04-16 | 2015-04-16 | A kind of method for promoting carbon monoxide emitter release carbon monoxide and preventing from being formed precipitation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510180597.7A CN104814952B (en) | 2015-04-16 | 2015-04-16 | A kind of method for promoting carbon monoxide emitter release carbon monoxide and preventing from being formed precipitation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104814952A true CN104814952A (en) | 2015-08-05 |
| CN104814952B CN104814952B (en) | 2017-12-26 |
Family
ID=53725600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510180597.7A Expired - Fee Related CN104814952B (en) | 2015-04-16 | 2015-04-16 | A kind of method for promoting carbon monoxide emitter release carbon monoxide and preventing from being formed precipitation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104814952B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134551A (en) * | 2018-06-15 | 2019-01-04 | 嘉兴学院 | Water-soluble iron carbonyl complex and its preparation method and application |
| CN111505211A (en) * | 2020-05-07 | 2020-08-07 | 嘉兴学院 | Method for regulating and controlling carbon monoxide releasing rate of carbon monoxide releasing agent |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001022960A1 (en) * | 1999-09-30 | 2001-04-05 | Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center | Treatment of carbon monoxide poisoning |
| CN1561207A (en) * | 2001-05-15 | 2005-01-05 | 北威克公园医学研究所 | Therapeutic delivery of carbon monoxide |
| WO2006134474A2 (en) * | 2005-06-17 | 2006-12-21 | Ge Healthcare Limited | Method for the use of [11c] carbon monoxide in labeling synthesis of 11c-labelled acids by photo-induced free radical carbonylation under mild conditions using sulfoxides |
| CN101642570A (en) * | 2008-08-07 | 2010-02-10 | 江苏大学附属医院 | Application of carbon monoxide-releasing molecules and heparin in preparing medicament for treating sepsis |
| CN102813925A (en) * | 2012-07-30 | 2012-12-12 | 江苏大学附属医院 | Application of carbon monoxide releasing molecules in preparing medicines for inhibiting blood coagulation activation diseases |
| CN102850403A (en) * | 2012-05-29 | 2013-01-02 | 嘉兴学院 | Water-soluble iron carbonyl compound, and preparation method and application thereof |
-
2015
- 2015-04-16 CN CN201510180597.7A patent/CN104814952B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001022960A1 (en) * | 1999-09-30 | 2001-04-05 | Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center | Treatment of carbon monoxide poisoning |
| CN1561207A (en) * | 2001-05-15 | 2005-01-05 | 北威克公园医学研究所 | Therapeutic delivery of carbon monoxide |
| WO2006134474A2 (en) * | 2005-06-17 | 2006-12-21 | Ge Healthcare Limited | Method for the use of [11c] carbon monoxide in labeling synthesis of 11c-labelled acids by photo-induced free radical carbonylation under mild conditions using sulfoxides |
| CN101642570A (en) * | 2008-08-07 | 2010-02-10 | 江苏大学附属医院 | Application of carbon monoxide-releasing molecules and heparin in preparing medicament for treating sepsis |
| CN102850403A (en) * | 2012-05-29 | 2013-01-02 | 嘉兴学院 | Water-soluble iron carbonyl compound, and preparation method and application thereof |
| CN102813925A (en) * | 2012-07-30 | 2012-12-12 | 江苏大学附属医院 | Application of carbon monoxide releasing molecules in preparing medicines for inhibiting blood coagulation activation diseases |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134551A (en) * | 2018-06-15 | 2019-01-04 | 嘉兴学院 | Water-soluble iron carbonyl complex and its preparation method and application |
| CN109134551B (en) * | 2018-06-15 | 2021-01-05 | 嘉兴学院 | Water-soluble iron carbonyl compound and preparation method and application thereof |
| CN111505211A (en) * | 2020-05-07 | 2020-08-07 | 嘉兴学院 | Method for regulating and controlling carbon monoxide releasing rate of carbon monoxide releasing agent |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104814952B (en) | 2017-12-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Rašović | Water-soluble fullerenes for medical applications | |
| Zhu et al. | Two-dimensional metal-organic-framework as a unique theranostic nano-platform for nuclear imaging and chemo-photodynamic cancer therapy | |
| Williams | Metals, ligands, and cancer | |
| CA2816895C (en) | Bismuth-containing compounds for modulating properties of biologically active agents | |
| Jain | Targeted drug delivery for cancer | |
| CN104814952A (en) | Method for promoting carbon monoxide release of carbon monoxide-releasing molecules and preventing sedimentation | |
| Guo et al. | Photoacoustic imaging guided photothermal and chemodynamic combined therapy for cancer using | |
| CN102850403B (en) | Water-soluble iron carbonyl compound, and preparation method and application thereof | |
| CN107141371A (en) | A kind of preparation method of chitosan L cysteine rare earth compoundings | |
| CN1549712A (en) | Antitumor agents and process for producing the same | |
| RU2014132184A (en) | KALMANGAFODIPIR, NEW CHEMICAL COMPOUND AND OTHER MIXED COMPLEX COMPOUNDS WITH METALS, METHODS FOR PRODUCING, COMPOSITIONS AND METHODS OF TREATMENT | |
| KR101415094B1 (en) | Bis-platinum complexes with antitumor activity | |
| CN104667301B (en) | A kind of preparation method and applications of single dispersing core shell structure AuNCs A@CaP nano-particles | |
| Karges | Chemical and Photophysical Triggers for the Reduction of Pt (IV) Prodrugs for Anticancer Therapy | |
| CN110917349A (en) | Bowl-shaped ISP (internet service provider) composite functional nano particle as well as preparation method and application thereof | |
| CN105688221A (en) | Preparation method of HA/RGD double-receptor multi-target-point drug administration system | |
| EP2831151B1 (en) | Benzene polycarboxylic acid compounds and their use as drug | |
| CN1674891A (en) | Porphyrin oxygen infusion preparation for increasing oxygen concentration in tumor tissue | |
| Ghoreishi et al. | The use of carbon quantum dot as alternative of stannous chloride application in radiopharmaceutical kits | |
| WO2013054770A1 (en) | Anemia of cancer improving / prophylactic agent | |
| CN107602623B (en) | Transition metal cobalt complex containing multi-coordination sites and preparation method thereof | |
| Romanova et al. | SYNTHESIS OF BIOLOGICALLY RELEVANT COMPLEXES BASED ON FULLERENE AND VITAMIN B12 DERIVATIVE | |
| CN107638567B (en) | Metal Lawsonia inermis black salt and preparation method and application thereof | |
| Thomson et al. | Hypoxia-driven elimination of thiopurines from their nitrobenzyl prodrugs | |
| CN110302378A (en) | A kind of preparation method of the targeting photo-thermal nanocomposite based on graphene oxide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171226 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |