CN102727473A - Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof - Google Patents
Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof Download PDFInfo
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- CN102727473A CN102727473A CN2011103469563A CN201110346956A CN102727473A CN 102727473 A CN102727473 A CN 102727473A CN 2011103469563 A CN2011103469563 A CN 2011103469563A CN 201110346956 A CN201110346956 A CN 201110346956A CN 102727473 A CN102727473 A CN 102727473A
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Abstract
The invention belongs to the field of chemistry and relates to pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine (BPCBG) and derivatives thereof in preparation of medicines used for treating uranium poisoning. The compound of BPCBG is an aminocarboxylic acid chelating agent containing two pyrocatechol functional groups. According to results of in vivo and in vitro tests, the compound has the effect of accelerating elimination of the radionuclide uranium from one's body except a good elimination promotion effect on radioactive thorium, reduces accumulation amount of uranium in the kidney and bones of a rat which has suffered from uranium poisoning, promotes elimination of uranium from human proximal tubular epithelial cells, protects chromosome damage caused by uranium and improves the survival rate of cells. The compound and derivatives thereof are applicable to preparation of medicines used for promoting elimination of uranium and thorium and have high potential social benefits and application prospects.
Description
Technical field
The invention belongs to chemical field, relate to chemical compound, be specifically related to compound N, two [N-(2,3-dihydroxy benzenes methyl)] glycine (BPCBG) of N '-ethylene and derivant thereof and the purposes in preparation treatment uranium poisoning medicine thereof with the effect of treatment uranium poisoning.
Background technology
Known uranium is important nuclear fuel, also is the charging of atomic bomb, and depleted uranium can be used for preparing military weapon.Prior art discloses uranium and has in a single day polluted human body and will produce serious harm to health, and wherein, kidney and skeleton are its main target organs, serious caused renal failure.In the treatment practice, using the discharge of uranium in the decorporation medicine acceleration bodies is its main treatment approach.But still there is not the efficacious therapy medicine at present clinically.DTPA-CaNa
3Be the choice drug of present actinium series nucleic internal contamination treatment, but still undesirable to the therapeutic effect of uranium poisoning.
The relevant research in this area utilizes the biomimetic chemistry principle for many years; Chemical constitution according to main chelation group in the strong effect of microorganisms, the iron chelating agent of the high selectivity-microorganism iron transfer body; The decorporation effect screening that hydroxyl palate acids, catechol (CAM) and hydroxylpyridinones (HOPO) chelating agen are used for the actinium series nucleic has been synthesized in research worker design, in the hope of obtain efficiently, the chemical compound of low toxicity.The U.S. discovers hydroxylpyridinones chelating agen 3,4 in recent years, 3-LI (1,2-HOPO) and 5-LIO (Me-3 2-HOPO) has the effect of arranging uranium preferably, can significantly reduce kidney uranium accumulation, and it is all effective to postpone administration and oral administration after the uranium poisoning.Seek the concern that the medicine of treating uranium poisoning has preferably caused this area research worker.
Summary of the invention
The purpose of this invention is to provide a kind of chemical compound with the effect of treatment uranium poisoning; Be specifically related to compound N; Two [N-(2,3-dihydroxy benzenes methyl)] glycine (BPCBG) of N '-ethylene and derivant thereof and the purposes in preparation treatment uranium poisoning medicine thereof.
Chemical compound provided by the invention can quicken uranium and in body, discharge, and significantly reduces kidney uranium and bone uranium accumulation;
Chemical compound provided by the invention improves cell survival rate through suppressing the generation of oxygen-derived free radicals in the inductive cell of uranium, reduces chromosome damage, has protection uranium and causes the effect in the nephrocyte damage.
Compound N of the present invention, N '-ethylene is two, and [N-(2; 3-dihydroxy benzenes methyl)] glycine (BPCBG) and derivant thereof; Have 2 catechol chelation groups in its molecular structure, through one contain the ammonia carboxylic acid aliphatic chain connect into the line style configuration, can increase molecular flexibility and form effective chelating " hole "; Improve curative effect, it has the structure of general formula (I).
Wherein R represents hydrogen base, carboxyl, sulfonic group.
N according to the invention, N '-ethylene is two, and [N-(2; 3-dihydroxy benzenes methyl)] chemical name of its molecule of glycine is: N, and N '-ethylene is two, and [N-(2; 3-dihydroxy benzenes methyl)] ([N-[(2 for 2-ethanediylbis for N, N '-1 for glycine; 3-dihydroxyphenyl) methyl]]-glycine, BPCBG)
In one embodiment of the present of invention,, behind synthetic and purification, make the N of formula I-1 structure through the molecular simulation structural design, two [N-(2,3-dihydroxy benzenes the methyl)] glycine of N '-ethylene,
It calculates molecular weight is 420.
Compound N of the present invention, two [N-(2,3-dihydroxy benzenes methyl)] glycine and the derivants thereof of N '-ethylene are for containing the ammonia carboxylic acid chelating agen of two catechol functional groups.In body, experiment in vitro shows, this chemical compound also has the effect that the plain uranium of accelerating radioactive nuclear is discharged in body except radiothorium being had preferably the decorporation effect, reduce the uranium accumulation of uranium poisoning rat kidney, skeleton, obviously is superior to DTPA-CaNa
3Promote the discharge of uranium in people's kidney proximal tubule epithelial cell (HK-2), and the increase of metallothionein (MT) can not weaken the decorporation effect of BPCBG to uranium in the inductive cell of uranium; This BPCBG also has the effect that protection uranium causes chromosome damage simultaneously, improves cell survival rate, and its mechanism of action produces relevant with the inductive intracellular reactive oxygen of inhibition uranium.
Based on above-mentioned experimental result, the invention provides said compound N, two [N-(2,3-dihydroxy benzenes methyl)] glycine (BPCBG) and the derivant application aspect the uranium poisoning treatment thereof of N '-ethylene.
Among the present invention, preferably at compound N, two [N-(2,3-dihydroxy benzenes methyl)] glycine (BPCBG) of N '-ethylene and derivant preparation thereof are quickened uranium and in body, are discharged, and significantly reduce the purposes in kidney uranium and the bone uranium accumulation medicine.
Among the present invention, uranium poisoning and disease thereof or situation show as:
(1) acute uranium poisoning;
(2) chronic uranium poisoning;
(3) uranium poisoning causes injury of kidney;
(4) uranium poisoning causes bone injury;
Chemical compound according to the invention causes the effect in the nephrocyte damage at protection uranium, through suppressing the generation of oxygen-derived free radicals in the inductive cell of uranium, improves cell survival rate, reduces chromosome damage;
Among the present invention, the characteristic of described chemical compound and derivant thereof is to use with the form of calcium salt and/or sodium salt.
Further purpose of the present invention provides said chemical compound can further process pharmaceutical preparation, uses through route of administration such as intramuscular injection, intravenous injection, nose spraying or oral administrations.
Said pharmaceutical preparation can be used in different time before and after the uranium poisoning (administration immediately, administration in advance and delay administration).
The advantage of chemical compound of the present invention has:
1, zoopery confirms, can quicken uranium and in body, discharge, and significantly reduces the accumulation of kidney uranium and bone uranium, obviously is superior to DTPA-CaNa
3
2, in vitro tests confirms: it can significantly reduce the accumulation of uranium in the kidney proximal tubule epithelial cell, improves cell survival rate, the inductive chromosome damage of protection uranium;
3, can be used for preparing the detoxifcation decorporation medicine of novel uranium poisoning, have higher, potential social benefit and application prospect.
For the ease of understanding, below will describe in detail the present invention through concrete accompanying drawing and embodiment.What need particularly point out is; Instantiation and accompanying drawing only are in order to explain; Obviously those of ordinary skill in the art can explain according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Description of drawings
Fig. 1 has shown the row uranium effect of BPCBG to uranium contamination HK-2 cell,
Wherein: compare BPCBG group and DTPA-CaNa with uranium contamination matched group
3Group is compared, * P＜0.05,
*P＜0.01,
* *P＜0.001.
Fig. 2 shown uranium (VI) induce HK-2 cell MT protein expression to increase and BPCBG to its influence.
Fig. 3 has shown the influence that BPCBG induces the HK-2 cell micronucleus to form to uranium,
Wherein: compare * * * P＜0.001 with the blank group; Compare with uranium contamination matched group,
###P＜0.001.
Fig. 4 has shown the influence of BPCBG to uranium contamination HK-2 cell survival rate.
Fig. 5 has shown that BPCBG induces the influence that ROS produces in the HK-2 cell to uranium,
Wherein: compare * P＜0.05, * * * P＜0.001 with uranium contamination matched group; Under the same treatment condition, compare between the BPCBG of variable concentrations group,
###P＜0.001.
The specific embodiment
Embodiment 1
BPCBG administration immediately is to decorporation effect and the dose-effect relationship experiment of uranium poisoning rat
Adopt cleaning level SD male rat; Behind the ip 100 μ g/ Mus uranium acetates respectively immediately im 60,120 and 600 μ mol/kg BPCBG (BPCBG/ uranium mol ratio is respectively (45-52.5): 1, (90-105): 1 with (450-525): 1), with im 600 μ mol/kg DTPA-CaNa
3Positive contrast, 24h urine after the collection uranium poisoning is put to death rat simultaneously and is got two side kidney and femurs, and treatments of the sample processing back adopts ICP-MS mensuration to urinate uranium accumulation in uranium output and the tissue.The result shows; The BPCBG that gives various dose immediately significantly increases rat 24h urine uranium output; Kidney, bone uranium accumulation obviously reduce, and increase the decorporation effect with dosage and obviously improve, and 24h urine uranium output significantly increases about 37%, 52% and 61% than uranium poisoning matched group respectively; Kidney uranium accumulation significantly reduces about 59%, 67% and 69% respectively than uranium poisoning matched group, bone uranium accumulation significantly reduces about 14%, 43% and 58% than uranium poisoning matched group respectively.The DTPA-CaNa of im 600 μ mol/kg immediately
3Can make kidney uranium accumulation than the obvious reduction about 51% of uranium poisoning matched group; But significantly be lower than the effect of 120 μ mol/kg and 600 μ mol/kg BPCBG; And 24h urine uranium output, do not seen obvious increase; Only increase approximately 23% than the uranium poisoning matched group, bone uranium accumulation is not also seen obvious decline (as shown in table 1).
Experimental result shows that giving compd B PCBG after the uranium poisoning immediately can obviously promote uranium in body, to discharge, and significantly reduces kidney, bone uranium accumulation, obviously is superior to DTPA-CaNa
3
Table 1 is BPCBG administration immediately to decorporation effect and the dose-effect
of uranium poisoning rat is (x ± s).
Table 1
Annotate: compare with the uranium poisoning matched group,
*P＜0.05,
* *P＜0.001; With DTPA-CaNa
3Group compares,
#P＜0.05,
##P＜0.01,
###P＜0.001
Embodiment 2BPCBG shifts to an earlier date and the delay administration is tested the decorporation effect of uranium poisoning rat
Adopt cleaning level SD male rat; Shift to an earlier date 30min, 2h and delay 30min, 1h and 2h im 120 μ mol/kg BPCBG behind the ip 100 μ g/ Mus uranium acetates respectively; With give BPCBG group immediately and compare; 24h urine after the collection uranium poisoning is put to death rat simultaneously and is got two side kidney and femurs, and treatments of the sample processing back adopts ICP-MS mensuration to urinate uranium accumulation in uranium output and the tissue.The result shows, in advance and postpone the 30min administration and still having decorporation effect preferably, 24h urine uranium output improves about 31%-35% than the uranium poisoning matched group; Kidney uranium accumulation reduces all about 48% than the uranium poisoning matched group; Bone uranium accumulation reduces about 23%-25% than the uranium poisoning matched group, but with the prolongation that shifts to an earlier date or postpone delivery time, the decorporation effect reduces gradually; It is still effective wherein to postpone the 1h administration; Kidney, bone uranium accumulation be than the remarkable reduction about 44% and 11% of uranium poisoning matched group, and urine uranium output increases about 15%, but in advance or postpone the 2h administration except that kidney uranium accumulation than the obvious reduction of uranium poisoning matched group (25%-29%); Bone uranium accumulation is not seen obvious decline, and urine uranium output only increases about 8% than the uranium poisoning matched group.
Experimental result shows that BPCB6 shifts to an earlier date or postpones administration also has decorporation effect preferably to the uranium poisoning rat, but with prolonging blanking time, the decorporation effect descends gradually.
Table 2 be BPCB6 in advance and postpone administration to the decorporation effect of uranium poisoning rat (x ± s).
Table 2
Annotate: compare with the uranium poisoning matched group,
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with BPCBG administration group immediately,
#P＜0.05,
##P＜0.01,
###P＜0.001
Embodiment 3
BPCBG is to the decorporation effect test of uranium (VI) contamination people's kidney proximal tubule epithelial cell (HK-2 cell)
(1) to the influence of HK-2 cellular uptake uranium
Behind the 1 μ mol/L uranium acetate contamination HK-2 cell, add BPCBG (chelating agen/uranium mol ratio is respectively 50 and 250) the combined effect 24h of 50 and 250 μ mol/L immediately respectively, 250 μ mol/L DTPA-CaNa
3As positive control, blank group and uranium contamination matched group is set simultaneously.Collecting cell behind the effect 24h adopts ICP-MS to detect uranium content in the cell.Visible by Figure 1A; 50 and 250 μ mol/L BPCBG all can obviously block the picked-up of HK-2 cell to uranium; Make the interior uranium accumulation of cell obviously reduce about 27%-32% than uranium contamination matched group, its effect is increase trend with the dosage increase, but 250 μ mol/L DTPA-CaNa
3Can not block of the picked-up of HK-2 cell, uranium accumulation and uranium contamination matched group no significant difference in the cell to uranium.
(2) the HK-2 cell is discharged the influence of uranium
Behind the 10 μ mol/L uranium acetates contamination HK-2 cell 24h, add BPCBG (chelating agen/uranium mol ratio is about 8.8,44 and 220 respectively) the effect 24h of 10,50 and 250 μ mol/L respectively, 250 μ mol/L DTPA-CaNa
3As positive control, blank group and uranium contamination matched group is set simultaneously.The result shows that 10,50 and 250 μ mol/L BPCBG can make the interior uranium content of cell significantly reduce about 38%-59% than uranium contamination matched group, and its effect is increase trend with the dosage increase.250 μ mol/L DTPA-CaNa
3Also present tangible row's uranium effect, it is about 38% that uranium content is reduced than uranium contamination matched group, but be starkly lower than the effect (seeing Figure 1B) of BPCBG.Behind the 5 μ mol/L uranium acetates contamination HK-2 cell 48h; The BPCBG effect 24h (chelating agen/uranium mol ratio is about 7.6,38 and 191 respectively) that adds 10,50 and 250 μ mol/L respectively; Extend to 48h although postpone time of administration; But the BPCBG of 50 and 250 μ mol/L still shows tangible row's uranium effect, makes the interior uranium content of cell reduce about 21%-34% than uranium contamination matched group, and the BPCBG of 10 μ mol/L is then invalid; 250 μ mol/L DTPA-CaNa
3The also row's of not showing uranium effect.
Experimental result shows that compd B PCBG can block the picked-up of HK-2 cell to uranium, postpones the discharge that 24h and 48h administration also can promote uranium in the HK-2 cell, significantly reduces accumulating of the interior uranium of cell, and its effect obviously is superior to DTPA-CaNa
3
Embodiment 4
Uranium (VI) induce HK-2 cell MT protein expression to change and BPCBG to its influence
After adopting contamination of 600 μ mol/L uranium or 250 μ mol/L BPCBG to act on HK-2 cell 48h individually or simultaneously, measure the proteic expression of MT in the cell with Western Blot method.Visible by Fig. 1, uranium contamination 48h can significantly improve the proteic expression of HK-2 cell MT; BPCBG itself does not have influence to the MT protein expression, but fails to reduce the proteic expression of MT of the inductive increase of uranium yet.
Experimental result combines the result of embodiment 2 to show that uranium induces the increase of HK-2 cell MT protein expression to fail to reduce the decorporation effect of compd B PCBG to uranium in the HK-2 cell.
Embodiment 5
BPCBG causes the protective effect experiment of HK-2 cell injury to uranium (VI)
1) BPCBG induces the influence of HK-2 cell micronucleus formation to uranium
After adopting 600 μ mol/L uranium acetates contaminations HK-2 cell, immediately or postpone 24h and add 50 and 250 μ mol/L BPCBG combined effect 48h, 250 μ mol/L DTPA-CaNa respectively
3Compare, blank group and uranium contamination matched group is set simultaneously, adopt cytokinesis-block method to detect micronucleus and form.Visible by Fig. 2,600 μ mol/L uranium acetates contamination HK-2 cell 48h and 72h can induce the micronucleus formation rate to reach 13.2% and 16.9% respectively, are significantly higher than the blank group, and increase with the contamination time prolongation; Add 50 and 250 μ mol/L BPCBG effect 48h immediately respectively after the uranium contamination, all can make the micronucleus formation rate significantly reduce about 44%-45%, 250 μ mol/L DTPA-CaNa than uranium contamination matched group
3It is about 25% that micronuclear rates is descended, but with uranium contamination group no significant difference; Behind uranium contamination HK-2 cell 24h, give 50 and 250 μ mol/L BPCBG and 250 μ mol/L DTPA-CaNa more respectively
3Effect 48h also can make micronuclear rates respectively than remarkable about 42% and 52%, the 250 μ mol/L DTPA-CaNa of decline of uranium contamination matched group
3It is about 15% that micronuclear rates is descended, with uranium contamination matched group no significant difference.
Experimental result shows, compd B PCBG immediately or postpone the 24h administration and all can protect uranium to cause the chromosome damage of HK-2 cell obviously is superior to DTPA-CaNa
3Effect.
2) BPCBG suppresses the influence of HK-2 cell proliferation to uranium
The uranium acetate that adopts 100,300,600 and 900 μ mol/L variable concentrations respectively with 250 μ mol/LBPCBG and DTPA-CaNa
3Combined effect HK-2 cell 48h is provided with blank group and uranium contamination group simultaneously.Behind the chelating agen effect 48h, each experimental group cell is inoculated in 96 orifice plates and cultivates 24h through trypsinization, counting, adopts the method for CCK-8 kit detection cell survival, measures the absorbance (0D) in every hole in the 490nm place.Set up the standard curve of cell number and 0D value simultaneously, each experimental group gained 0D value is converted into the survivaling cell number, and calculate cell survival rate.Can see from Fig. 4, dye uranium dosage when 100 μ mol/L increase to 900 μ mol/L, cell survival rate increases with the uranium poisoning dosage and significantly descends.After adding 250 μ mol/L BPCBG effect 48h immediately after the uranium contamination, can significantly improve survival rate (p＜0.01 of 600 and 900 μ mol/L uranium contamination cell; P＜0.05).The DTPA-CaNa of same concentrations
3Do not see obvious effect is arranged.
Experimental result shows that compd B PCBG can significantly improve the survival rate of uranium contamination cell, DTPA-CaNa
3Then invalid.
Embodiment 6
BPCBG induces the influence that oxygen-derived free radicals (ROS) produces in the HK-2 cell to uranium (VI)
Take the logarithm the trophophase cell by every hole 8 * 10
3Individual cell inoculation in 96 orifice plates, 600 μ mol/L uranium acetates and chelating agen combined effect HK-2 cell 48h, or uranium acetate contaminates in advance and add chelating agen effect 24h again behind the 24h, BPCBG concentration is 50 and 250 μ mol/L, DTPA-CaNa
3Be 250 μ mol/L.After chelating agen is handled, adopt DCFH-DA fluorescent probe method, in multi-functional ELIASA (BioTek) 488nm excitation wavelength, 525nm transmitted wave strong point fluorescence intensity.The fluorescence intensity of the fluorescence intensity/blank group of ROS amount (being the % of blank group)=each experimental group in the cell.Visible by table 5, induce the interior ROS of HK-2 cell significantly to increase behind the 600 μ mol/L uranium contamination HK-2 cell 48h, be about 2.7 times of blank group.Add chelating agen immediately or postpone 24h adding chelating agen after dying uranium, 50 μ mol/L and 250 μ mol/L BPCBG all can significantly suppress the inductive ROS of uranium and generate, and increasing inhibitory action with drug level has increase trend, and 250 μ mol/L DTPA-CaNa
3There is not the effect of removing ROS.
This experimental result shows that compd B PCBG can significantly suppress the generation of ROS in the inductive cell of uranium, DTPA-CaNa
3Then invalid.
Claims (8)
1. compound N, two [N-(2,3-dihydroxy benzenes methyl)] glycine of N '-ethylene and derivant thereof the purposes in preparation treatment uranium poisoning medicine.
2. purposes as claimed in claim 1 is characterized in that, described uranium poisoning comprises: acute uranium poisoning, chronic uranium poisoning, uranium poisoning cause injury of kidney or uranium poisoning causes bone injury.
3. purposes as claimed in claim 2 is characterized in that, described chemical compound and derivant thereof improve cell survival rate through suppressing the generation of oxygen-derived free radicals in the inductive cell of uranium, reduce chromosome damage.
4. purposes as claimed in claim 2 is characterized in that, described chemical compound and derivant thereof are used with the form of calcium salt and/or sodium salt.
5. purposes as claimed in claim 2 is characterized in that described chemical compound and derivant thereof are processed pharmaceutical preparation, uses through intramuscular injection, intravenous injection, nose spraying or oral administration route.
6. purposes as claimed in claim 2 is characterized in that, described chemical compound and derivant thereof are before acute uranium poisoning, use simultaneously or afterwards.
7. the compound N of formula I, two [N-(2,3-dihydroxy benzenes methyl)] glycine and the derivants thereof of N '-ethylene,
Wherein, R represents hydrogen base, carboxyl, sulfonic group.
8. chemical compound as claimed in claim 7 is characterized in that, described chemical compound have a following structural formula:
It calculates molecular weight is 420.
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| CN108403679A (en) * | 2018-06-11 | 2018-08-17 | 中国人民解放军陆军军医大学 | Application of the Levothyroxinnatrium sodium in preparing treatment depleted uranium and causing the drug of injury of kidney |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103848749A (en) * | 2012-11-28 | 2014-06-11 | 复旦大学 | Compound [2,3-dihydroxy-1,4-phenylene] diamine tetraacetic acid salt and medicinal composition and application thereof |
| CN103848749B (en) * | 2012-11-28 | 2016-03-30 | 复旦大学 | Compound [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) and medicinal compositions thereof and application |
| CN102942497A (en) * | 2012-12-06 | 2013-02-27 | 中国人民解放军第四军医大学 | Preparation and application of amino substituted carboxylic acid compounds |
| CN108403679A (en) * | 2018-06-11 | 2018-08-17 | 中国人民解放军陆军军医大学 | Application of the Levothyroxinnatrium sodium in preparing treatment depleted uranium and causing the drug of injury of kidney |
| CN108403679B (en) * | 2018-06-11 | 2021-06-22 | 中国人民解放军陆军军医大学 | Application of L-thyroxine sodium in preparation of medicine for treating renal injury caused by depleted uranium |
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