CN103788139B - The synthesis of the different binuclear complex of laminine schiff bases with anticancer activity and pharmaceutical composition thereof - Google Patents
The synthesis of the different binuclear complex of laminine schiff bases with anticancer activity and pharmaceutical composition thereof Download PDFInfo
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Abstract
The present invention relates to synthesis and the pharmaceutical composition thereof of the different binuclear complex of a kind of laminine schiff bases with anticancer activity, specifically include: the different binuclear complex of (1) azide bridge laminine contracting 2 pyridine carboxaldehyde schiff bases copper platinum；(2) the different binuclear complex of thiocyanate bridging laminine contracting 2 pyridine carboxaldehyde schiff bases copper ruthenium；(3) the different binuclear complex of azide bridge laminine contracting 3,5 Dibromosalicylaldehyde schiff bases copper platinum；(4) the different binuclear complex of Bridging oxalate laminine contracting 3,5 Dibromosalicylaldehyde schiff bases copper platinum；(5) the different binuclear complex of Bridging oxalate laminine contracting 3,5 Dibromosalicylaldehyde schiff bases ruthenium platinum, and carry out Pharmacological Analysis research for above-claimed cpd.The invention provides a kind of pharmaceutical composition synthetic method, this compound has active anticancer effect, is suitable in anti-cancer field using, has bigger medical science and pharmacy value, is that research and development and the popularization of cancer therapy drug provides an important foundation.
Description
Technical field
The present invention relates to synthesis and the pharmaceutical composition thereof of the different binuclear complex of laminine schiff bases with anticancer activity, belong to
In technical field of medicine synthesis.
Background technology
American Cancer Society in 2013 issues statistical report on CA CANCER J CLIN and claims, and within 2013, the U.S. will
Having 1660290 case new cancer cases, 580350 patients can pass because of cancer.And in China, although statistics
Very incomplete, but " the 2012 China's tumour registration annual report " issued the first quarter in 2013 claims: every 6 minutes of the whole nation
Just there is a people to be diagnosed as cancer, have every day 8550 people to become cancer patient, every 7-8 people just has a people die from cancer.
Annual new cancer cases about 3,500,000, because of cancer mortality about 2,500,000.Coming 10 years, China cancer morbidity with
The death rate will continue to rise.From " cancer county " to " cancer village ", the situation occurred frequently of China's tumour be social development with
The result that life style many decades transition bring.Estimate according to World Health Organization, if do not intervened, 2005 to 2015
Period will have 84,000,000 people to die from cancer.Cancer is still one of primary cause of the death in the whole world, and the body of the mankind in serious threat
The heart is healthy, hampers people and moves towards the paces of rich, healthy happy life.
At present, operation, radiotherapy, chemotherapy are still the three big means treating cancer.Wherein, chemotherapy is dependent on chemicals and controls
The drug response of a kind of means treated, curative effect and patient has direct relation with the quality of cancer therapy drug.Since 20th century
The nineties begins, and the combined clinical chemotherapy regimen of cis-platinum and carboplatin cancer therapy drug about 65% is with them as main ingredient or participation is joined
5.This has established the critical role as effective antitumor medicine for the metal complex.But cis-platinum and carboplatin cancer therapy drug because of
The side effects such as the n and V of renal toxicity and initiation are bigger, and this promotes people to break through tradition cis-platinum architectural concept, seeks height
Effect, low toxicity, selectively high cancer therapy drug, develop the research tendency that more preferable metal complex cancer therapy drug is this field.
A kind of nonprotein amino acid with unique bioactive that laminine is derived from sea-plant sea-tangle, uses it
Synthesis PTS has the advantage of Nantural non-toxic, water-soluble, good biocompatibility, is current medicine still leaved for development
Treasure-house.
Content of the invention
It is an object of the invention to provide the different binuclear complex of a kind of laminine schiff bases with anticancer activity synthesis and
Its pharmaceutical composition, and carry out Pharmacological Analysis, to characterize the tool active anticancer effect of this compound.
To achieve these goals, technical scheme is as follows.
The synthesis of the different binuclear complex of laminine schiff bases with anticancer activity and pharmaceutical composition thereof, comprising: (1) fold
The different binuclear complex of nitrogen-bridged laminine contracting 2-pyridine carboxaldehyde schiff bases copper platinum；(2) thiocyanate bridging laminine contracting
The different binuclear complex of 2-pyridine carboxaldehyde schiff bases copper ruthenium；(3) azide bridge laminine contracting 3,5-Dibromosalicylaldehyde Schiff
The different binuclear complex of alkali copper platinum；(4) Bridging oxalate laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper platinum isodigeranyl core
Complex；(5) Bridging oxalate laminine contracting 3, the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases ruthenium platinum.Specifically
Synthesis step is as follows:
(1) than pyridine formaldehyde schiff bases copper platinum, the synthesis step of different binuclear complex is azide bridge laminine contracting 2-:
Step A: 40mmol (4.28g) 2-is diluted with 10mL absolute ethyl alcohol than pyridine formaldehyde, is slowly dropped to and is dissolved with
In the 40mL ethanol solution of 40mmol (7.56g) laminine.Dropping finishes rear temperature and is slowly increased to 70 DEG C, continues anti-
Answer 4 hours.Evaporation solution, to remainder about 5mL, adds ice ethanol 20mL, has a large amount of precipitation to generate.Solution is filtered,
Wash repeatedly with ice ethanol, ether respectively, vacuum drying, obtain white object product and be laminine contracting 2-than pyridine formaldehyde
Schiff bases.
Step B: by 40mmol (7.56g) CuCl2·3H2O dilutes with 10mL absolute ethyl alcohol, is slowly dropped to and is dissolved with
In the 40mL ethanol solution of 40mmol (11.08g) laminine contracting 2-pyridine carboxaldehyde schiff bases.Dropping finishes rear temperature
It is slowly increased to 70 DEG C, continue reaction 4 hours.Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of
Precipitation generates.Solution is filtered, washs repeatedly with ice ethanol, ether respectively, vacuum drying, obtain blue target product,
Laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex part.
Step C: method synthesis laminine contracting 2-is than pyridine formaldehyde schiff bases platinum mononuclear complex part as shown in step B,
CuCl2·3H2O K2PtCl4Replace.
Step D:40mmol (2.60g) NaN3It with the dilution of 10mL absolute ethyl alcohol, is added drop-wise to 40mL and is dissolved with 40mmol
(14.98g) laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex and 40mmol (21.88g) laminine contracting 2-
In the ethanol solution of pyridine carboxaldehyde schiff bases platinum mononuclear complex.Dropping finishes rear temperature and is slowly increased to 70 DEG C, continues
Continuous reaction 4 hours.Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of precipitation to generate.By solution
Filter, wash repeatedly with ice ethanol, ether respectively, vacuum drying, obtain dusty blue target product.
Under room temperature, target product is very stable, is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, permissible
It is dissolved in water.
(2) than pyridine formaldehyde schiff bases copper ruthenium, the synthesis step of different binuclear complex is thiocyanate bridging laminine contracting 2-:
Step A: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases as shown in preparation method 1 step A.
Step B: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases copper monokaryon coordinates as shown in preparation method 1 step B
Thing part.
Step C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases ruthenium monokaryon coordinates as shown in preparation method 1 step B
Thing part, by CuCl2·3H2O RuCl2Replace, it is thus achieved that expected product.
Step D:40mmol (3.24g) NaSCN dilutes with 10mL absolute ethyl alcohol, is added drop-wise to 40mL and is dissolved with 40
Mmol (14.98g) laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex and 40mmol (18.04g) kelp ammonia
In the ethanol solution of acid contracting 2-pyridine carboxaldehyde schiff bases ruthenium mononuclear complex.Dropping finishes rear temperature and is slowly increased to 70
DEG C, continue reaction 4 hours.Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of precipitation to generate.
Solution is filtered, washs repeatedly with ice ethanol, ether respectively, vacuum drying, obtain black objects product.
Under room temperature, target product is very stable, is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, permissible
It is dissolved in water.
(3) azide bridge laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases copper platinum is:
Step A: method synthesis laminine contracting 3 as shown in preparation method 1 step A, 5-Dibromosalicylaldehyde schiff bases, by 2-
Pyridine carboxaldehyde is with 3, and 5-Dibromosalicylaldehyde replaces.
Step B: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper monokaryon as shown in preparation method 1 step B
Complex ligand.
Step C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases platinum mononuclear complex part as shown in step B,
CuCl2·3H2O K2PtCl4Replace.
Step D: method synthesis azide bridge laminine contracting 3,5-Dibromosalicylaldehyde Schiff as shown in preparation method 1 step D
The different binuclear complex of alkali copper platinum.
Under room temperature, target product is very stable, is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, permissible
It is dissolved in water.
(4) Bridging oxalate laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases copper platinum
For:
Step A: method synthesis laminine contracting 3 as shown in preparation method 1 step A, 5-Dibromosalicylaldehyde schiff bases, by 2-
Pyridine carboxaldehyde is with 3, and 5-Dibromosalicylaldehyde replaces.
Step B: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper monokaryon as shown in preparation method 1 step B
Complex ligand.
Step C: method synthesis laminine contracting 3 as shown in step B, 5-Dibromosalicylaldehyde schiff bases platinum mononuclear complex is joined
Body, CuCl2·3H2O K2PtCl4Replace.
Step D: method synthesis of oxalic acid root bridging laminine contracting 3 as shown in preparation method 1 step D, 5-Dibromosalicylaldehyde is wished
Sodium azide sodium oxalate is replaced by the different binuclear complex of husband's alkali copper.
Under room temperature, target product is very stable, is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, permissible
It is dissolved in water.
(5) Bridging oxalate laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases ruthenium platinum
For:
Step A: method synthesis laminine contracting 3 as shown in preparation method 1 step A, 5-Dibromosalicylaldehyde schiff bases, by 2-
Pyridine carboxaldehyde is with 3, and 5-Dibromosalicylaldehyde replaces.
Step B: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper monokaryon as shown in preparation method 1 step B
Complex ligand.
Step C: method synthesis laminine contracting 3 as shown in step B, 5-Dibromosalicylaldehyde schiff bases platinum mononuclear complex is joined
Body, CuCl2·3H2O K2PtCl4Replace.
Step D: method synthesis of oxalic acid root bridging laminine contracting 3 as shown in preparation method 1 step D, 5-Dibromosalicylaldehyde is wished
Sodium azide sodium oxalate is replaced by the different binuclear complex of husband's alkali copper.
Under room temperature, target product is very stable, is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, permissible
It is dissolved in water.
Carry out Pharmacological Analysis research for above-claimed cpd, specifically include:
(1) research that compound interacts with DNA, application catfish milt DNA (HS-DNA) is as research object.
Catfish milt DNA (HS-DNA) becomes 10 by NaCl/Tris-HCl (pH=7.16) buffer preparation-4The solution of M, surveys
Absorbance (A) at amount 260nm and 280nm, A260/A280, in the range of 1.8～1.9, illustrates HS-DNA
Solution meets requirement of experiment.Measurement absorbance at 260nm for the HS-DNA, calculates DNA according to Lang Mu-Beer law
Concentration (with the molar concentration meter of DNA base pair, ε 260=6600L mol-1·cm-1)。
Ultra-violet absorption spectrum titrates: compound NaCl/Tris-HCl cushioning liquid is made into 10-3The solution of M is then dilute
Release 10-5The concentration of M；Using NaCl/Tris-HCl cushioning liquid as blank liquid, measure 200～800nm wavelength
In the range of ultraviolet spectra.Sample-adding every time, molten to blank and that addition equivalent in ligand sample prepares HS-DNA respectively
Liquid (10-3M), it is sufficiently mixed and be then scanned after static 10min again.Binding constants is determined by below equation:
[DNA]/(εa-εf)=[DNA]/(εa-εf)+1/Kb(εa-εf)
The wherein concentration of [DNA] representation DNA, εa, εfAnd εbRepresent respectively under each DNA concentration, free and with
The molar absorption coefficient of the saturated part of DNA bonding.With [DNA]/(εa-εf) [DNA] is mapped, binding constants KbFor directly
The slope of line and the ratio of intercept.
Fluorescence quenching spectrum titrates: the preparation of EB-DNA compound system: by 5 μ L EB (1 × 10-3mol·L-1) solution adds
Enter to 1mL HS-DNA (10-3M) being placed in solution in 10mL colorimetric cylinder, keep in Dark Place under normal temperature 2h.Then add
Enter NaCl/Tris-HCl cushioning liquid and be diluted to 5mL, after mixing.Excite with the wavelength of 522nm, record
Fluorescence emission wavelengths at 584nm for the EB-DNA compound system and intensity.Sample-adding every time, adds equivalent in sample
The ligand sample solution (10 preparing-3M), the fluorescent quenching light to EB-DNA compound system for the variable concentrations part is recorded
Spectrum.
Quencher coefficient is determined by Stern-Volmer formula:
I0/ I=1+Ksv[Q]
Wherein I0Represent respectively with I be not added with compound and when adding compound EB-DNA compound system fluorescence intensity；[Q] table
Show the concentration of quencher (compound).With I0[Q] is mapped by/I, and slope is quenching constant Ksv。
(2) research that compound interacts with BSA: application bovine serum albumin(BSA) (BSA) is as research object.Ultraviolet
Absorption spectrum titrates: the BSA storing solution (100 μM) preparing is diluted to 10 μM, with NaCl/Tris-HCl buffering
Solution as blank, measures the ultraviolet spectra in 200～350nm wave-length coverage, every time sample-adding respectively to blank and
BSA sample adds the compound solution (10 that equivalent prepares-3M), it is sufficiently mixed and then carry out after static 10min again
Scanning.
Tryptophan fluorescence quencher spectral derivative: the BSA storing solution (100 μM) preparing is diluted to 10 μM, with 295
The wavelength of nm excites, and records fluorescence emission wavelengths at 584nm for the BSA solution and intensity.Sample-adding every time, to sample
Product add the compound sample solution (10 that equivalent prepares-3M), glimmering to BSA solution of variable concentrations compound is recorded
Optical quenching spectrum.
Quencher coefficient is determined by Stern-Volmer formula:
I0/ I=1+Ksv[Q]=1+Kqτ0[Q]
Wherein I0Represent fluorescence intensity when being not added with compound (complex) and add compound (complex) with I respectively；[Q]
Represent the concentration of compound (complex)；KsvFor dynamic quenching constant；KqFor dynamic quenching speed constant；τ0For without quencher
Agent is the average life span (10 of fluorescence molecule-8s-1).With I0[Q] is mapped by/I, and slope is Ksv.All kinds of fluorescence quenchers
2.0 × 10 are about to the maximum Dynamic Fluorescence quencher speed constant of large biological molecule10L·mol-1·s-1.Pass through Ksv=Kqτ0,
Can be in the hope of Kq。
During static quenching, it is assumed that have two to three similar binding sites independent of each other again on large biological molecule,
Then the relation between fluorescence intensity and quencher is represented by formula:
nQ+B→Qn...B
Wherein B represents the large biological molecule fluorescing, and Q is quencher molecule, Qn... B represents the unstressed configuration intensity of generation
Biomolecule, its formation constant is represented by:
K=[Qn... B]/[Q] n [B]
If the total concentration of large biological molecule is B0, then [B0]=[Qn... B]+[B], [B] represents that unconjugated biology divides greatly
The concentration of son, then the relation of the concentration of fluorescence intensity and unconjugated large biological molecule is [B]/[B0]=F/F0, F0Divide with F
Do not represent the fluorescence intensity of large biological molecule when not adding quencher and add quencher.Formula can be released from relation above:
log[(F0-F)/F]=logK+nlog [Q]
Wherein K represents the binding constant of quencher and large biological molecule, and n represents the binding site number of quencher and large biological molecule,
With log [(F0-F)/F] log [Q] to be mapped, slope is n, can be in the hope of binding constant K by cutting evidence.
(3) the cell in vitro poison test of the compounds of this invention uses SRB detection method, determines addition and obtains from the present invention
Compound after, OD reading at 515nm for the culture medium, by the OD value recording, calculated by equation below and treat
Test sample product are to human hepatoma cell strain (SMMC-7721), lung adenocarcinoma cell line (A549) cell, people's acute promyelocytic leukemic
And the inhibiting rate of normal mouse horn cell (Pam212) (HL-60):
With sample concentration, linear regression is done to inhibiting rate, obtain the half-inhibition concentration (IC in its 48h50).Make with cis-platinum
For positive control.
This beneficial effect of the invention is: the invention provides a kind of laminine schiff bases isodigeranyl caryogamy with anticancer activity
The synthesis of compound and the synthetic method of pharmaceutical composition thereof, and carried out Pharmacological Analysis, it was demonstrated that the tool of this compound is anticancer
Active function, is suitable in anti-cancer field using.The inventive method have found a kind of new pharmaceutical synthesis method, has relatively
Big medical science and pharmacy value, be that research and development and the application of cancer therapy drug provides an important foundation.
Brief description
The azide bridge laminine contracting 2-pyridine carboxaldehyde schiff bases copper platinum that Fig. 1 is synthesized in the embodiment of the present invention 1 is different
Binuclear complex structural formula.
The thiocyanate bridging laminine contracting 2-pyridine carboxaldehyde schiff bases copper ruthenium that Fig. 2 is synthesized in the embodiment of the present invention 2 is different
The structural formula of binuclear complex.
Fig. 3 is azide bridge laminine contracting 3 synthesized in the embodiment of the present invention 3,5-Dibromosalicylaldehyde schiff bases copper
Platinum different binuclear complex structural formula.
Fig. 4 is Bridging oxalate laminine contracting 3 synthesized in the embodiment of the present invention 4,5-Dibromosalicylaldehyde schiff bases
Copper platinum different binuclear complex structural formula.
Fig. 5 is Bridging oxalate laminine contracting 3 synthesized in the embodiment of the present invention 5,5-Dibromosalicylaldehyde schiff bases
Ruthenium platinum different binuclear complex structural formula.
Detailed description of the invention
It is described with the detailed description of the invention to the present invention for the embodiment below in conjunction with the accompanying drawings, in order to be better understood from this
Bright.
Embodiment 1:
The synthesis step of the different binuclear complex of azide bridge laminine contracting 2-pyridine carboxaldehyde schiff bases copper platinum is:
Step A: 40mmol (4.28g) 2-pyridine carboxaldehyde is diluted by 10mL absolute ethyl alcohol, is slowly dropped to and is dissolved with
In the 40mL ethanol solution of 40mmol (7.56g) laminine.Dropping finishes rear temperature and is slowly increased to 70 DEG C, continues anti-
Answer 4 hours.Evaporation solution, to remainder about 5mL, adds ice ethanol 20mL, has a large amount of precipitation to generate.Solution is filtered,
Wash repeatedly with ice ethanol, ether respectively, vacuum drying, obtain white object product and be laminine contracting 2-than pyridine formaldehyde
Schiff bases.
Step B: by 40mmol (7.56g) CuCl2·3H2O dilutes with 10mL absolute ethyl alcohol, is slowly dropped to and is dissolved with
In the 40mL ethanol solution than pyridine formaldehyde schiff bases for 40mmol (11.08g) the laminine contracting 2-.Dropping finishes rear temperature
It is slowly increased to 70 DEG C, continue reaction 4 hours.Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of
Precipitation generates.Solution is filtered, washs repeatedly with ice ethanol, ether respectively, vacuum drying, obtain blue target product,
Laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex part.
Step C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases platinum mononuclear complex part as shown in step B,
CuCl2·3H2O K2PtCl4Replace.
Step D:40mmol (2.60g) NaN3It with the dilution of 10mL absolute ethyl alcohol, is added drop-wise to 40mL and is dissolved with 40mmol
(14.98g) laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex and 40mmol (21.88g) laminine contracting 2-
In the ethanol solution of pyridine carboxaldehyde schiff bases platinum mononuclear complex.Dropping finishes rear temperature and is slowly increased to 70 DEG C, continues
Continuous reaction 4 hours.Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of precipitation to generate.By solution
Filter, wash repeatedly with ice ethanol, ether respectively, vacuum drying, obtain dusty blue target product.
The azide bridge laminine contracting 2-pyridine carboxaldehyde schiff bases copper platinum that Fig. 1 is synthesized in the embodiment of the present invention 1 is different
Binuclear complex structural formula.IR peak position and elemental microanalysis the results are shown in Table 1 and table 2.Under room temperature, target product is very stable,
It is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, water can be dissolved in.
Table 1: embodiment 1 object IR peak position
Table 2: embodiment 1 object elemental microanalysis
| Elemental microanalysis: | C% | H% | N% |
| Calculated value | 42.03 | 5.64 | 14.70 |
| Measured value | 41.98 | 5.85 | 14.51 |
Implement: 2:
The synthesis step of the different binuclear complex of thiocyanate bridging laminine contracting 2-pyridine carboxaldehyde schiff bases copper ruthenium is:
Step A: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases as shown in embodiment 1 step A.
Step B: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex as shown in embodiment 1 step B
Part.
Step C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases ruthenium mononuclear complex as shown in the present embodiment step B
Part, by CuCl2·3H2O RuCl2Replace, it is thus achieved that expected product.
Step D:40mmol (3.24g) NaSCN dilutes with 10mL absolute ethyl alcohol, is added drop-wise to 40mL and is dissolved with 40
Mmol (14.98g) laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex and 40mmol (18.04g) kelp ammonia
In the ethanol solution of acid contracting 2-pyridine carboxaldehyde schiff bases ruthenium mononuclear complex.Dropping finishes rear temperature and is slowly increased to 70
DEG C, continue reaction 4 hours.Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of precipitation to generate.
Solution is filtered, washs repeatedly with ice ethanol, ether respectively, vacuum drying, obtain black objects product.
The thiocyanate bridging laminine contracting 2-pyridine carboxaldehyde schiff bases copper ruthenium that Fig. 2 is synthesized in the embodiment of the present invention 2 is different
The structural formula of binuclear complex.IR peak position and elemental microanalysis the results are shown in Table 3 and table 4.Under room temperature, target product is very stable,
It is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, water can be dissolved in.
Table 3: embodiment 2 object IR peak position
Table 4: embodiment 2 object elemental microanalysis
| Elemental microanalysis: | C% | H% | N% |
| Calculated value | 47.77 | 6.21 | 12.58 |
| Measured value | 47.96 | 6.45 | 12.47 |
Implement: 3:
Azide bridge laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases copper platinum is:
Step A: method synthesis laminine contracting 3 as shown in embodiment 1 step A, 5-Dibromosalicylaldehyde schiff bases, by 2-
Pyridine carboxaldehyde is with 3, and 5-Dibromosalicylaldehyde replaces.
Step B: method synthesis laminine contracting 3 as shown in embodiment 1 step B, 5-Dibromosalicylaldehyde schiff bases copper monokaryon is joined
Compound part.
Step C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases platinum mononuclear complex as shown in the present embodiment step B
Part, CuCl2·3H2O K2PtCl4Replace.
Step D: method synthesis azide bridge laminine contracting 3,5-Dibromosalicylaldehyde schiff bases as shown in embodiment 1 step D
The different binuclear complex of copper platinum.
Fig. 3 is azide bridge laminine contracting 3 synthesized in the embodiment of the present invention 3,5-Dibromosalicylaldehyde schiff bases copper
Platinum different binuclear complex structural formula.IR peak position and elemental microanalysis the results are shown in Table 5 and table 6.Under room temperature, target product is very
Stable, it is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, water can be dissolved in.
Table 5: embodiment 3 object IR peak position
Table 6: embodiment 3 object elemental microanalysis
| Elemental microanalysis: | C% | H% | N% |
| Calculated value | 30.22 | 3.49 | 7.71 |
| Measured value | 30.18 | 3.61 | 7.62 |
Enforcement 4:
Bridging oxalate laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases copper platinum is:
Step A: method synthesis laminine contracting 3 as shown in embodiment 1 step A, 5-Dibromosalicylaldehyde schiff bases, by 2-
Pyridine carboxaldehyde is with 3, and 5-Dibromosalicylaldehyde replaces.
Step B: method synthesis laminine contracting 3 as shown in embodiment 1 step B, 5-Dibromosalicylaldehyde schiff bases copper monokaryon is joined
Compound part.
Step C: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases platinum monokaryon as shown in the present embodiment step B
Complex ligand, CuCl2·3H2O K2PtCl4Replace.
Step D: method synthesis of oxalic acid root bridging laminine contracting 3,5-Dibromosalicylaldehyde Schiff as shown in embodiment 1 step D
Sodium azide sodium oxalate is replaced by the different binuclear complex of alkali copper.
Fig. 4 is Bridging oxalate laminine contracting 3 synthesized in the embodiment of the present invention 4,5-Dibromosalicylaldehyde schiff bases copper
The structural formula of the different binuclear complex of platinum.IR peak position and elemental microanalysis the results are shown in Table 7 and table 8.Under room temperature, target product is very
Stable, it is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, water can be dissolved in.
Table 7: embodiment 4 object IR peak position
Table 8: embodiment 4 object elemental microanalysis
| Elemental microanalysis: | C% | H% | N% |
| Calculated value | 32.75 | 3.56 | 4.49 |
| Measured value | 32.64 | 3.71 | 4.39 |
Embodiment 5:
Bridging oxalate laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases ruthenium platinum is:
Step A: method synthesis laminine contracting 3 as shown in embodiment 1 step A, 5-Dibromosalicylaldehyde schiff bases, by 2-
Pyridine carboxaldehyde is with 3, and 5-Dibromosalicylaldehyde replaces.
Step B: method synthesis laminine contracting 3 as shown in embodiment 1 step B, 5-Dibromosalicylaldehyde schiff bases copper monokaryon is joined
Compound part.
Step C: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases platinum monokaryon as shown in the present embodiment step B
Complex ligand, CuCl2·3H2O K2PtCl4Replace.
Step D: method synthesis of oxalic acid root bridging laminine contracting 3,5-Dibromosalicylaldehyde Schiff as shown in embodiment 1 step D
Sodium azide sodium oxalate is replaced by the different binuclear complex of alkali copper.
Fig. 5 is Bridging oxalate laminine contracting 3 synthesized in the embodiment of the present invention 5,5-Dibromosalicylaldehyde schiff bases
The structural formula of the different binuclear complex of ruthenium platinum.IR peak position and elemental microanalysis the results are shown in Table 9 and table 10.Target under room temperature
Product is very stable, is all insoluble in carbon tetrachloride, chloroform and benzene, is slightly soluble in methyl alcohol, ethanol, can be dissolved in water.
Table 9: embodiment 5 object IR peak position
Table 10: embodiment 5 object elemental microanalysis
| Elemental microanalysis: | C% | H% | N% |
| Calculated value | 29.35 | 3.39 | 7.49 |
| Measured value | 29.44 | 3.51 | 7.37 |
Embodiment 6:
Carry out Pharmacological Analysis research for above-claimed cpd, specifically include:
(1) research that compound interacts with DNA: application catfish milt DNA (HS-DNA) is as research object.
Catfish milt DNA (HS-DNA) becomes 10 by NaCl/Tris-HCl (pH=7.16) buffer preparation-4The solution of M, surveys
Absorbance (A) at amount 260nm and 280nm, A260/A280, in the range of 1.8～1.9, illustrates HS-DNA
Solution meets requirement of experiment.Measurement absorbance at 260nm for the HS-DNA, calculates DNA according to Lang Mu-Beer law
Concentration (with the molar concentration meter of DNA base pair, ε 260=6600L mol-1·cm-1)。
Ultra-violet absorption spectrum titrates: compound NaCl/Tris-HCl cushioning liquid is made into 10-3The solution of M is then dilute
Release 10-5The concentration of M；Using NaCl/Tris-HCl cushioning liquid as blank liquid, measure 200～800nm wavelength
In the range of ultraviolet spectra.Sample-adding every time, molten to blank and that addition equivalent in ligand sample prepares HS-DNA respectively
Liquid (10-3M), it is sufficiently mixed and be then scanned after static 10min again.Binding constants is determined by below equation:
[DNA]/(εa-εf)=[DNA]/(εa-εf)+1/Kb(εa-εf)
The wherein concentration of [DNA] representation DNA, εa, εfAnd εbRepresent respectively under each DNA concentration, free and with
The molar absorption coefficient of the saturated part of DNA bonding.With [DNA]/(εa-εf) [DNA] is mapped, binding constants KbFor directly
The slope of line and the ratio of intercept.
The ultra-violet absorption spectrum titration exercising result of the representation compound that the present invention is obtained is shown in Table 11.
Table 11: the ultra-violet absorption spectrum titration exercising result of the representation compound that the present invention is obtained
| Compound | Kb×10-4(M-1) |
| Preparation method 1 | 9.22 |
| Preparation method 2 | 8.17 |
| Preparation method 3 | 9.54 |
| Preparation method 4 | 12.02 |
| Preparation method 5 | 11.77 |
Fluorescence quenching spectrum titrates: the preparation of EB-DNA compound system: by 5 μ LEB (1 × 10-3 mol·L-1) solution adds
Enter to 1mL HS-DNA (10-3M) being placed in solution in 10mL colorimetric cylinder, keep in Dark Place under normal temperature 2h.Then add
Enter NaCl/Tris-HCl cushioning liquid and be diluted to 5mL, after mixing.Excite with the wavelength of 522nm, record
Fluorescence emission wavelengths at 584nm for the EB-DNA compound system and intensity.Sample-adding every time, adds equivalent in sample
The ligand sample solution (10 preparing-3M), variable concentrations part is recorded sudden to the fluorescence of EB-DNA compound system
Go out spectrum.
Quencher coefficient is determined by Stem-Volmer formula:
I0/ I=1+Ksv[Q]
Wherein I0Represent respectively with I be not added with compound and when adding compound EB-DNA compound system fluorescence intensity；
[Q] represents the concentration of quencher (compound).With I0[Q] is mapped by/I, and slope is quenching constant Ksv。
The fluorescence quenching spectrum titration exercising result of the representation compound that the present invention is obtained is shown in Table 12.
Table 12: the fluorescence quenching spectrum titration exercising result of the representation compound that the present invention is obtained
| Compound | Ksv×10-4 |
| Preparation method 1 | 11.24 |
| Preparation method 2 | 8.75 |
| Preparation method 3 | 9.01 |
| Preparation method 4 | 13.22 |
| Preparation method 5 | 12.11 |
(2) research that compound interacts with BSA: application bovine serum albumin(BSA) (BSA) is as research object.Purple
Outer absorption spectrum titrates: the BSA storing solution (100 μM) preparing is diluted to 10 μM, delays with NaCl/Tris-HCl
Dissolved liquid, as blank, measures the ultraviolet spectra in 200～350nm wave-length coverage, and sample-adding is respectively to blank every time
With the compound solution (10 adding equivalent to prepare in BSA sample-3M), it is sufficiently mixed and then enter after static 10min again
Row scanning.
Tryptophan fluorescence quencher spectral derivative: the BSA storing solution (100 μM) preparing is diluted to 10 μM, with 295
The wavelength of nm excites, and records fluorescence emission wavelengths at 584nm for the BSA solution and intensity.Sample-adding every time, to sample
Product add the compound sample solution (10 that equivalent prepares-3M), glimmering to BSA solution of variable concentrations compound is recorded
Optical quenching spectrum.
Quencher coefficient is determined by Stem-Volmer formula:
I0/ I=1+Ksv[Q]=1+Kqτ0[Q]
Wherein I0Represent fluorescence intensity when being not added with compound (complex) and add compound (complex) with I respectively；[Q]
Represent the concentration of compound (complex)；KsvFor dynamic quenching constant；KqFor dynamic quenching speed constant；τ0For without quencher
Agent is the average life span (10 of fluorescence molecule-8s-1).With I0[Q] is mapped by/I, and slope is Ksv.All kinds of fluorescence quenchers
2.0 × 10 are about to the maximum Dynamic Fluorescence quencher speed constant of large biological molecule10L·mol-1·s-1.Pass through Ksv=Kqτ0,
Can be in the hope of Kq。
During static quenching, it is assumed that have two to three similar binding sites independent of each other again on large biological molecule,
Then the relation between fluorescence intensity and quencher is represented by formula:
nQ+B→Qn...B
Wherein B represents the large biological molecule fluorescing, and Q is quencher molecule, Qn... B represents the unstressed configuration intensity of generation
Biomolecule, its formation constant is represented by:
K=[Qn... B]/[Q] n [B]
If the total concentration of large biological molecule is B0, then [B0]=[Qn... B]+[B], [B] represents unconjugated large biological molecule
Concentration, then the relation of the concentration of fluorescence intensity and unconjugated large biological molecule is [B]/[B0]=F/F0, F0With F table respectively
Show the fluorescence intensity of large biological molecule when not adding quencher and add quencher.Formula can be released from relation above:
log[(F0-F)/F]=logK+nlog [Q]
Wherein K represents the binding constant of quencher and large biological molecule, and n represents the binding site number of quencher and large biological molecule,
With log [(F0-F)/F] log [Q] to be mapped, slope is n, can be in the hope of binding constant K by cutting evidence.
The Tryptophan fluorescence quencher spectral derivative exercising result of the representation compound that the present invention is obtained is shown in Table 13.
Table 13: the Tryptophan fluorescence quencher spectral derivative exercising result of the representation compound that the present invention is obtained
| Compound | Ksv×10-4(M-1) | Kq×10-12(L·mol-1·s-1) | n | K×10-4(M-1) |
| Preparation method 1 | 5.72 | 5.72 | 1.14 | 27.3 |
| Preparation method 2 | 6.54 | 6.54 | 1.15 | 38.2 |
| Preparation method 3 | 6.22 | 6.22 | 1.14 | 30.4 |
| Preparation method 4 | 9.56 | 9.56 | 1.20 | 67.1 |
| Preparation method 5 | 10.13 | 10.13 | 1.20 | 70.2 |
(3) the cell in vitro poison test of the compounds of this invention uses SRB detection method, determines addition and obtains from embodiment
After the compound arriving, OD reading at 515nm for the culture medium, by the OD value recording, calculated by equation below
Testing sample is to human hepatoma cell strain (SMMC-7721), lung adenocarcinoma cell line (A549) cell, people's children's acute morning white blood of grain
Sick (HL-60) and the inhibiting rate of normal mouse horn cell (Pam212):
With sample concentration, linear regression is done to inhibiting rate, obtain the half-inhibition concentration (IC in its 48h50).Make with cis-platinum
For positive control.
The IC of the representation compound that the present invention is obtained50The results are shown in Table 14.
Table 14: the IC of the representation compound that the present invention is obtained50Result
The above is the preferred embodiment of the present invention, it is noted that come for those skilled in the art
Saying, under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modifications also regard
For protection scope of the present invention.
Claims (1)
1. a synthetic method for the different binuclear complex of laminine schiff bases with anticancer activity, specifically includes: (1)
The synthesis of the different binuclear complex of azide bridge laminine contracting 2-pyridine carboxaldehyde schiff bases copper platinum；(2) thiocyanate bridging kelp
The synthesis of the different binuclear complex of propylhomoserin contracting 2-pyridine carboxaldehyde schiff bases copper ruthenium；(3) azide bridge laminine contracting 3,5-bis-
The synthesis of the different binuclear complex of bromosalicylaldehyde schiff bases copper platinum；(4) Bridging oxalate laminine contracting 3,5-dibromo bigcatkin willow
The synthesis of the different binuclear complex of aldehyde schiff bases copper platinum；(5) Bridging oxalate laminine contracting 3,5-Dibromosalicylaldehyde Schiff
The synthesis of the different binuclear complex of alkali ruthenium platinum；It is characterized in that: azide bridge laminine contracting 2-pyridine carboxaldehyde schiff bases copper platinum
The synthesis step of different binuclear complex is:
Step 1A: 40mmol (4.28g) 2-pyridine carboxaldehyde is diluted by 10mL absolute ethyl alcohol, is slowly dropped to and is dissolved with
In the 40mL ethanol solution of 40mmol (7.56g) laminine；Dropping finishes rear temperature and is slowly increased to 70 DEG C, continues anti-
Answer 4 hours；Evaporation solution, to remainder about 5mL, adds ice ethanol 20mL, has a large amount of precipitation to generate；Solution is filtered,
Wash repeatedly with ice ethanol, ether respectively, vacuum drying, obtain white object product and be laminine contracting 2-pyridine carboxaldehyde
Schiff bases；
Step 1B: by 40mmol (7.56g) CuCl2·3H2O dilutes with 10mL absolute ethyl alcohol, is slowly dropped to and is dissolved with
In the 40mL ethanol solution of 40mmol (11.08g) laminine contracting 2-pyridine carboxaldehyde schiff bases；Dropping finishes rear temperature
It is slowly increased to 70 DEG C, continue reaction 4 hours；Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of
Precipitation generates；Solution is filtered, washs repeatedly with ice ethanol, ether respectively, vacuum drying, obtain blue target product,
Laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex part；
Step 1C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases platinum mononuclear complex part as shown in step 1B,
CuCl2·3H2O K2PtCl4Replace；
Step 1D:40mmol (2.60g) NaN3It with the dilution of 10mL absolute ethyl alcohol, is added drop-wise to 40mL and is dissolved with 40mmol
(14.98g) laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex and 40mmol (21.88g) laminine contracting 2-
In the ethanol solution of pyridine carboxaldehyde schiff bases platinum mononuclear complex；Dropping finishes rear temperature and is slowly increased to 70 DEG C, continues
Continuous reaction 4 hours；Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of precipitation to generate；By solution
Filter, wash repeatedly with ice ethanol, ether respectively, vacuum drying, obtain dusty blue target product；
The synthesis step of the different binuclear complex of thiocyanate bridging laminine contracting 2-pyridine carboxaldehyde schiff bases copper ruthenium is:
Step 2A: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases as shown in step 1A；
Step 2B: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex part as shown in step 1B；
Step 2C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases ruthenium mononuclear complex part as shown in step 1B,
By CuCl2·3H2O RuCl2Replace, it is thus achieved that expected product；
Step 2D:40mmol (3.24g) NaSCN dilutes with 10mL absolute ethyl alcohol, is added drop-wise to 40mL and is dissolved with 40
Mmol (14.98g) laminine contracting 2-pyridine carboxaldehyde schiff bases copper mononuclear complex and 40mmol (18.04g) kelp ammonia
In the ethanol solution of acid contracting 2-pyridine carboxaldehyde schiff bases ruthenium mononuclear complex；Dropping finishes rear temperature and is slowly increased to
70 DEG C, continue reaction 4 hours；Evaporation solution, to remainder about 10mL, adds ice ethanol 20mL, has a large amount of precipitation to generate；
Solution is filtered, washs repeatedly with ice ethanol, ether respectively, vacuum drying, obtain black objects product；
Azide bridge laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases copper platinum is:
Step 3A: method synthesis laminine contracting 3 as shown in step 1A, 5-Dibromosalicylaldehyde schiff bases, by 2-pyridine first
Aldehyde is with 3, and 5-Dibromosalicylaldehyde replaces；
Step 3B: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper mononuclear complex as shown in step 1B
Part；
Step 3C: method synthesis laminine contracting 2-pyridine carboxaldehyde schiff bases platinum mononuclear complex part as shown in step 3B,
CuCl2·3H2O K2PtCl4Replace；
Step 3D: method synthesis azide bridge laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper platinum as shown in step 1D
Different binuclear complex；
Bridging oxalate laminine contracting 3, the synthesis step of the different binuclear complex of 5-Dibromosalicylaldehyde schiff bases copper platinum is:
Step 4A: method synthesis laminine contracting 3 as shown in step 1A, 5-Dibromosalicylaldehyde schiff bases, by 2-pyridine first
Aldehyde is with 3, and 5-Dibromosalicylaldehyde replaces；
Step 4B: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper mononuclear complex as shown in step 1B
Part；
Step 4C: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases platinum mononuclear complex as shown in step 4B
Part, CuCl2·3H2O K2PtCl4Replace；
Step 4D: method synthesis of oxalic acid root bridging laminine contracting 3,5-Dibromosalicylaldehyde as shown in preparation method 1 step D
Sodium azide sodium oxalate is replaced by the different binuclear complex of schiff bases copper；Bridging oxalate laminine contracting 3,5-dibromo
The synthesis step of the different binuclear complex of salicylide schiff bases ruthenium platinum is:
Step 5A: method synthesis laminine contracting 3 as shown in step 1A, 5-Dibromosalicylaldehyde schiff bases, by 2-pyridine first
Aldehyde is with 3, and 5-Dibromosalicylaldehyde replaces；
Step 5B: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper mononuclear complex as shown in step 1B
Part；
Step 5C: method synthesis laminine contracting 3,5-Dibromosalicylaldehyde schiff bases platinum mononuclear complex as shown in step 5B
Part, CuCl2·3H2O K2PtCl4Replace；
Step 5D: method synthesis of oxalic acid root bridging laminine contracting 3,5-Dibromosalicylaldehyde schiff bases copper as shown in step 1D
Sodium azide sodium oxalate is replaced by different binuclear complex.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696240A (en) * | 1991-03-15 | 1997-12-09 | Vallarino; Lidia M. | Macrocyclic complexes of yttrium, the lanthanides and the actinides having peripheral coupling functionalities |
| US6890754B2 (en) * | 1999-04-20 | 2005-05-10 | L'oreal | Epidermis/dermis equivalents and aged skin equivalents shaped therefrom |
| CN1951905A (en) * | 2006-11-04 | 2007-04-25 | 青岛大学 | Clean method for producing high-purity laminine |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696240A (en) * | 1991-03-15 | 1997-12-09 | Vallarino; Lidia M. | Macrocyclic complexes of yttrium, the lanthanides and the actinides having peripheral coupling functionalities |
| US6890754B2 (en) * | 1999-04-20 | 2005-05-10 | L'oreal | Epidermis/dermis equivalents and aged skin equivalents shaped therefrom |
| CN1951905A (en) * | 2006-11-04 | 2007-04-25 | 青岛大学 | Clean method for producing high-purity laminine |
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