CN103860539B - A kind of Pt(IV with mixing axial part) kind anti-cancer drugs thing and preparation method - Google Patents
A kind of Pt(IV with mixing axial part) kind anti-cancer drugs thing and preparation method Download PDFInfo
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- CN103860539B CN103860539B CN201410148904.9A CN201410148904A CN103860539B CN 103860539 B CN103860539 B CN 103860539B CN 201410148904 A CN201410148904 A CN 201410148904A CN 103860539 B CN103860539 B CN 103860539B
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Abstract
The present invention discloses a kind of Pt (IV) kind anti-cancer drugs thing and the preparation method with mixing axial part; Described Pt (IV) the class medicine with mixing axial part, has octahedral coordination structure, namely by two pairs of plane parts and a pair mixing axial part and Pt
4+bonding is formed, and described axial ligand one is and Pt
4+the part that bonding action is relatively strong, another is and Pt
4+the part that bonding action is relatively weak.Adopt the design of this power collocation, make it compared with existing Pt (IV) medicine Satraplatin JM216 BMS 182751, be relatively easily reduced to Pt (II) species, there is relatively high pharmacologically active.The embodiment of the present invention proves that it is compared with Satraplatin JM216 BMS 182751, in the lucifuge reaction system that ascorbic acid, reduced glutathion and DNA pattern species 5 '-dGMP coexist, more easily generate the product of Pt and guanine N7 position bonding, the anti-cancer targets realizing high-efficiency low-toxicity is with a wide range of applications.
Description
Technical field
The invention belongs to chemosynthesis new drug field, relate to Pt (IV) kind anti-cancer drugs thing with mixing axial part and preparation method thereof.
Background technology
Cancer is very big to the threat of human health, and cancer therapy drug research is subject to extensive concern always.The target molecule of platino anticarcinogen is intracellular DNA (deoxyribonucleic acid) (DNA).In Pt and DNA in platino medicine guanine N7 atomic linkage after, DNA replication dna and cell death inducing can be suppressed, thus reach anticancer effect.Platino anticarcinogen is not only more responsive to normal cell to the cancerous cell ratio of many fast breedings, kills and wounds also comparatively large, can cause toxic and side effects in various degree to the normal cell (medullary cell, hair follicle and epithelial cell) of division fast.
Platino Anti-Cancer Drug Design follows following principle usually: must comprise Pt-N key in coordination structure, and atom N at least should connect a H.This H atom can form H key with the O6 atom of guanine in DNA, is the essential condition of the N7 atom generation bonding impelled in Pt and guanine.
According to the valence state of coordination center, platino anticarcinogen can be divided into Pt (II) and Pt (IV) two type substantially.The configuration with Pt (II) anticarcinogen of monokaryon coordination structure mostly is planar shape, enter clinical stage comprise cisplatin (Cisplatin), carboplatin (Carboplatin), JM-216 (Oxaliplatin), naphthalene reach platinum (Nedaplatin), Eptaplatin (Sunpla), lobaplatin (Lobaplatin), picoplatin (Picoplatin), bicycloplatin (Dicycloplatin) etc.In addition, have dual-core architecture and three nuclear structures Pt (II) medicine also receives publicity; Wherein, three core Pt (II) the coordination ion BBR3464 with 3 positive charges have entered II phase clinical experiment.The pharmacologically active of Pt (II) medicine is usual and hydrolysis dynamics is closely related.For cisplatin, there is the hydrolyzate [Pt (NH of positive charge
3)
2(H
2o) Cl]
+and [Pt (NH
3)
2(H
2o)
2]
2+with the reactivity of DNA far above unhydrolysed cisplatin Pt (NH
3)
2cl
2.
The coordination configuration of Pt (IV) anticarcinogen is octahedra, and molecular structure comprises 6 coordinating groups, makes drug design have larger motility, is considered to the new antitumor drug had a extensive future.As shown in Figure 1, Pt (IV) anticarcinogen entering clinical experiment comprises 1. iproplatins (Iproplatin), 2. ormaplatin (Ormaplatin), 3. Satraplatin JM216 BMS 182751 (Satraplatin) and 4.LA-12.Two adjacent Pt-N coordinate bonds are all comprised in the molecular structure of these medicines.The bond energy of Pt-N key is comparatively strong, and usually will comprise the plane of two Pt-N keys as horizontal plane, the part of the upper and lower both sides of this horizontal plane is called axial ligand.
The activity that substitution reaction directly occurs with DNA Pt (IV) anticarcinogen is usual lower, need react with reproducibility species such as ascorbic acid in physiological environment, lose two axial ligands, generate Pt (II) species, then play active anticancer by hydrolysis.Wherein, axial ligand and Pt
4+bond strength appreciable impact Pt (IV) anticarcinogen be reduced to the reactivity of Pt (II) species.
The axial ligand of ormaplatin and iproplatin is respectively two and Pt
4+the Cl that bonding is more weak
-and OH
-, these two kinds of medicines are eliminated in the I phase of clinical experiment and III stage phase respectively.Satraplatin JM216 BMS 182751 is similar to the structure of LA-12, and two axial ligands are and Pt
4+the OAc that bonding is stronger
-; Be in the Cl all comprising two cis in the part of horizontal plane
-with a NH
3, difference is that another part is respectively cyclohexylamine and amantadine (amantadine).It is more late that LA-12 enters clinical experiment, and related data is comparatively limited.Satraplatin JM216 BMS 182751 is the oral Pt of the first (IV) anticarcinogen entering clinical treatment, impassivity toxicity and nephrotoxicity.Ascorbic acid (Vc) is reproducibility species important in physiological environment, but the reduced glutathion (GSH) extensively existed in physiological environment can suppress redox reaction between Satraplatin JM216 BMS 182751 and ascorbic acid.This redox reaction be attributable between ascorbic acid and Satraplatin JM216 BMS 182751 relates to the step generating AFR, and GSH has the function of scavenging free radicals, and AFR concentration can be caused to reduce.On the other hand, the activity of GSH self reduction Satraplatin JM216 BMS 182751 is not high yet.Therefore, compared with cisplatin, the pharmacologically active of Satraplatin JM216 BMS 182751 still has larger gap.
Can find out, no matter be the ormaplatin and iproplatin that have been eliminated, two axial ligands of the Satraplatin JM216 BMS 182751 and LA-12, Pt (IV) coordination structure that are still in clinical stage are made up of the group of identical type respectively.This design weak point is adopted to be relatively limited to the Modulatory character of Pt (IV) coordination compound redox active.When two axial ligands are and Pt
4+(such as, Cl during the more weak group of bonding
-), the speed that Pt (IV) coordination compound is reduced to Pt (II) species in physiological environment is relatively too fast, easily causes stronger toxic and side effects; Namely the ormaplatin be eliminated in clinical experiment belongs to this kind of situation.On the other hand, when two axial ligands are and Pt
4+(such as, OAc during the stronger group of bonding
-), the speed being reduced to Pt (II) species in physiological environment is relatively slow, causes pharmacologically active not high; This just Satraplatin JM216 BMS 182751 at Clinical practice institute problems faced.
In sum, Pt (IV) anticancer drug design of same item type axial ligand is adopted easily to cause toxic and side effects to cross strong or that pharmacologically active is not high problem.Undoubtedly, axial ligand design is a key link of regulation and control Pt (IV) medicine active anticancer.Clinical research shows, Pt (IV) anticarcinogen Satraplatin JM216 BMS 182751 has the lower advantage of toxic and side effects, but the problems demand solution that pharmacologically active is not high.
The present invention utilizes Pt (IV) anticancer drug design feature comparatively flexibly, will with Pt
4+the different part of bond strength combines, and the pharmacologically active of regulation and control Pt (IV) coordination compound, designs and prepare novel Pt (IV) kind anti-cancer drugs with mixed type axial ligand.Compared with Satraplatin JM216 BMS 182751, in the lucifuge reaction system that novel Pt (IV) medicine with mixed type axial ligand coexists at ascorbic acid, reduced glutathion and DNA pattern species 5 '-dGMP, relatively more easily generate the product of Pt and guanine N7 position bonding, significant for the lower problem of solution existing Pt (IV) anticarcinogen Satraplatin JM216 BMS 182751 pharmacologically active.
Summary of the invention
The object of the invention is, for the lower problem of existing Pt (IV) clinical anti-cancer medicine Satraplatin JM216 BMS 182751 pharmacologically active, to propose a kind of novel Pt (IV) kind anti-cancer drugs thing structural design and the preparation method with mixing axial part.Compared with Satraplatin JM216 BMS 182751, in the lucifuge reaction system that Pt (IV) the class medicine with mixing axial part of the designed and preparation of the present invention coexists at ascorbic acid, reduced glutathion and 5 '-dGMP, the activity generating Pt and guanine N7 position bonding product obviously strengthens, the significant and application prospect widely for the anti-cancer targets realizing high-efficiency low-toxicity.
Pt (IV) the class medicine with mixing axial part of the present invention, has octahedral coordination structure, namely by two pairs of plane parts and a pair mixing axial part and Pt
4+bonding is formed, and it has the feature of high-efficiency low-toxicity, is achieved through the following technical solutions: a pair namely described mixing axial part is respectively part I and part II, and part and Pt
4+bond strength order be: ammonia > part I > part II.
Described Pt(IV) axial ligand one of kind anti-cancer drugs thing is and Pt
4+the part that bonding action is relatively strong, another is and Pt
4+the part that bonding action is relatively weak, adopt the design of this power collocation, make it compared with Satraplatin JM216 BMS 182751, the activation energy losing two axial ligands in reduction reaction process decreases, and is relatively easily reduced to Pt (II) species.
For Pt (IV) the class medicine with mixing axial part described in technical scheme mentioned above, in preferred situation, described part I is OAc
-, part II is H
2o, OH
-or Cl
-.That is: OAc
-for with Pt
4+the part that bonding action is relatively strong, H
2o, OH
-or Cl
-for with Pt
4+the part that bonding action is relatively weak.
For Pt (IV) the class medicine with mixing axial part described in technical scheme mentioned above, in preferred situation, in two pairs of described plane parts, it is for a pair wherein ammonia/the amido at ortho position; In other a pair part, one is H
2o, Cl
-or OH
-, another part is Cl
-or OH
-.When these two plane parts comprise electroneutral H
2during O, the positive charge of Pt (IV) coordination structure is relatively strong, also relatively high with the reactivity of Vitamin C acid radical anion.
For Pt (IV) the class medicine with mixing axial part described in technical scheme mentioned above, in preferred situation, described ammonia/amido is respectively the NH at ortho position
3and cyclohexylamine.Ammonia/amido in this plane part continues to use NH adjacent in Satraplatin JM216 BMS 182751
3with cyclohexylamine design, to make Pt (IV) coordination structure, there is fat-soluble and cell membrane penetration preferably.
The present invention figure 2 shows axial ligand by OAc
-and H
2four kinds of isomerss 5,6 of Pt (IV) the class medicine of O composition, the schematic diagram of 7,8.Wherein, in plane part ammonia/amido by the NH at ortho position
3with cyclohexylamine composition, all the other two plane parts are by a H
2o and one Cl
-composition.The total charge of coordination structure is 2+.Under GSH concurrent conditions, this Pt (IV) class medicine and the ascorbic acid generation redox reaction with mixing axial part, loses the activity of two axial ligands apparently higher than Satraplatin JM216 BMS 182751.Remain unchanged at other part, the H in axial ligand
2o is replaced by Cl
-(or OH
-) time, Pt (IV) coordination compound with mixing axial part obtained and the speed of ascorbic acid generation redox reaction also apparently higher than Satraplatin JM216 BMS 182751, but lower than 5 in Fig. 2,6,7,8.
Another aspect of the present invention is: the preparation method disclosing Pt (IV) the class medicine with mixing axial part mentioned above, it comprises following operating procedure: under lucifuge and room temperature condition, prepare Satraplatin JM216 BMS 182751 aqueous solution, its concentration range between 10 μMs to saturated concentration; And adopt the light of wavelength 390 ~ 450nm to carry out irradiation to it; When detecting the OAc participating in coordination
-with the OAc dissociated
-between ratio between 1.3 ~ 1.0 time, stop irradiation, solution is kept in Dark Place.
Obtain comprising axial ligand of the present invention by OAc
-and H
2the solution of Pt (IV) the class medicine with mixing axial part of O composition.The too short meeting of exposure time causes the conversion ratio of Satraplatin JM216 BMS 182751 lower, and the long meeting of exposure time causes OAc
-with H
2the ligand exchange degree of O is excessive.
For the method described in technical scheme mentioned above, detect the OAc participating in coordination
-with the OAc dissociated
-between concentration ratio can pass through
1the methods such as H NMR (Nuclear Magnetic Resonance) spectrum, chromatography of ions, capillary electrophoresis, high performance liquid chromatography.Wherein, use
1h nuclear magnetic resonance spectroscopy, directly can pass through OAc
- bondingand OAc
- dissociatecorresponding spectrum peak integral area ratio asks the concentration ratio of both calculations; When adopting chromatography of ions, capillary electrophoresis, high performance liquid chromatography to detect, can according to OAc
-standard curve and OAc
- dissociatespectrum peak area measure OAc in solution
- dissociateconcentration, then at known OAc
-under total amount (2 times of Satraplatin JM216 BMS 182751 solution original concentration) condition, pass through OAc
- bonding/ OAc
- dissociate=(OAc
- total amount-OAc
- dissociate)/OAc
- dissociaterelational expression ask calculation.
For the method described in technical scheme mentioned above, in preferred situation, described Satraplatin JM216 BMS 182751 concentration of aqueous solution be 100 μMs to saturated concentration.In most preferred situation, Satraplatin JM216 BMS 182751 concentration of aqueous solution is saturated concentration.
For the method described in technical scheme mentioned above, in preferred situation, the wave-length coverage that described Satraplatin JM216 BMS 182751 aqueous solution carries out irradiation is 415 ~ 450nm.
For the method described in technical scheme mentioned above, in preferred situation, the described OAc when detection participation coordination
-with the OAc dissociated
-between ratio between 1.1 ~ 1.0 time, stop irradiation.
The pharmacologically active characterization result of Pt (IV) the class medicine with mixing axial part mentioned above is:
Under the lucifuge condition that GSH, ascorbic acid and DNA pattern species 5 '-dGMP coexist, mixing axial part of the present invention will be comprised by OAc
-and H
2the Satraplatin JM216 BMS 182751 solution that the solution of Pt (IV) the class medicine of O composition is identical with total platinum concentration carries out reactivity contrast.
1h NMR (Nuclear Magnetic Resonance) spectrum shows, compared with adding the control systems of Satraplatin JM216 BMS 182751, adding has in the reaction system of Pt (IV) class medicine of mixing axial part, in Pt and 5 '-dGMP, the bonding action of guanine N7 position significantly strengthens, the pharmacologically active that confirmation has Pt (IV) class coordination compound of mixing axial part is obviously better than Satraplatin JM216 BMS 182751, for improving the anticancer effect of Pt (IV) medicine and to enrich therapeutic scheme significant.
The invention has the beneficial effects as follows:
The present invention utilizes the advantage of structure control compared with horn of plenty of Pt (IV) coordination compound, takes strong and weak part arranging scheme, will with Pt
4+the different part of bond strength combines, and the pharmacologically active of regulation and control Pt (IV) coordination compound, designs and prepare Pt (IV) kind anti-cancer drugs with mixed type axial ligand.With Pt
4+axial ligand (the such as H that binding ability is more weak
2o or OH
-, Cl
-deng) introducing, the reduction process that Satraplatin JM216 BMS 182751 can be avoided to face the easily lower problem of suppressed caused pharmacologically active; With Pt
4+the axial ligand OAc that binding ability is stronger
-introducing, can avoid Pt (IV) coordination structure in physiological environment, reduce the stronger problem of very fast caused toxic and side effects.A H is introduced in the plane part of Pt (IV) coordination structure
2o, can strengthen the electropositive of coordination structure, improves the reactivity of itself and ascorbate ions.Containing in N coordinating group, continue to use NH in Satraplatin JM216 BMS 182751
3with the mixed amine design of cyclohexylamine, retain the fat-soluble feature such as better.
In the lucifuge reaction system that GSH, ascorbic acid, DNA pattern species 5 '-dGMP coexist, mixing axial part of the present invention will be comprised by OAc
-and H
2the Satraplatin JM216 BMS 182751 that the solution of Pt (IV) the class medicine of O composition is identical with total platinum concentration carries out active contrast experiment.Compared with adding the control systems of Satraplatin JM216 BMS 182751, add and of the present inventionly have in Pt (IV) the class drug reaction system of mixing axial part, in Pt and 5 '-dGMP, the bonding action of guanine N7 position significantly strengthens, the pharmacologically active that confirmation has Pt (IV) class coordination compound of mixing axial part is obviously better than Satraplatin JM216 BMS 182751, for improving the anticancer effect of Pt (IV) medicine and to enrich therapeutic scheme significant.
Accompanying drawing explanation
Fig. 1: four kinds of Pt (IV) the anticarcinogen structural representations entering clinical experiment.
Fig. 2: four kinds of isomers structure charts with Pt (IV) anticarcinogen of mixing axial part.
Fig. 3: the structure chart of four kinds of main metabolites of Satraplatin JM216 BMS 182751 in clinical experiment.
Fig. 4: excite d-d transition to cause the coordinate bond activation schematic diagram of octahedral coordination structure.
Fig. 5: the ultraviolet-visible absorption spectroscopy of Satraplatin JM216 BMS 182751.
Fig. 6: the PL spectrum of different wave length exposure light.
Fig. 7: HPLC spectrogram contrast.A () newly prepares, (b) lucifuge heats, the Satraplatin JM216 BMS 182751 solution after (c) irradiation.
Fig. 8: Satraplatin JM216 BMS 182751 conversion ratio is with the change of exposure time.
Fig. 9: OAc
- coordination/ OAc
- dissociatewith the change of exposure time.
Figure 10:
1h NMR (Nuclear Magnetic Resonance) spectrum.A (), without the Satraplatin JM216 BMS 182751 solution of irradiation, prepared by (b) comprises Pt (IV) the kind anti-cancer drugs solution with mixing axial part, OAc
- coordination/ OAc
- dissociate=1.3:1.0.
Figure 11:
1h NMR (Nuclear Magnetic Resonance) spectrum.The lucifuge reactivity of Satraplatin JM216 BMS 182751 in 5 '-dGMP, ascorbic acid and GSH mixed system.A (), after 2 days, is 3% with 5 '-dGMP of Pt bonding; B (), after 1 week, is 6% with 5 '-dGMP of Pt bonding; C () after 2 days, OAc
- coordination/ OAc
- dissociatefor 24:1; D () after 1 week, OAc
- join position/ OAc
- dissociatefor 10:1.
Figure 12:
1h NMR (Nuclear Magnetic Resonance) spectrum.There is the lucifuge reactivity of Pt (IV) kind anti-cancer drugs in 5 '-dGMP, ascorbic acid and GSH mixed system of mixing axial part.A (), after 2 days, is 20% with 5 '-dGMP of Pt bonding; B (), after 1 week, is 51% with 5 '-dGMP of Pt bonding; C () after 2 days, OAc
- coordination/ OAc
- dissociatefor 1:1; D () after 1 week, OAc
- coordination/ OAc
- dissociatefor 2:3.
Detailed description of the invention
Following non-limiting example can make the present invention of those of ordinary skill in the art's comprehend, but does not limit the present invention in any way.
Pt (IV) the kind anti-cancer drugs thing design with mixing axial part of the present invention, carry out based on following principle:
(1) the easy downtrod analysis of causes of the reduction reaction of Satraplatin JM216 BMS 182751 in physiological environment
Pt (IV) cancer therapy drug reacts with the reproducibility species such as ascorbic acid in physiological environment, loses two axial ligands, and the step generating Pt (II) species is the important step playing pharmacologically active.The axial ligand of Satraplatin JM216 BMS 182751 is two acetate (OAc
-).OAc
-there is π type unoccupied orbital, not only OAc
-lone pair electrons can occupy Pt
4+unoccupied orbital generate σ coordinate bond, Pt
4+d track also can with OAc
-the π * antibonding orbital do not occupied in part is overlapping, generates anti-coordination π key.This σ coordinate bond and anti-coordination π bonding claim σ-π to join key, make axial ligand OAc
-with Pt
4+bonding action relatively strong; In addition, OAc
-can with the NH in plane part
3and C
6h
11-NH
2form intramolecular hydrogen bond, make Pt
4+with OAc
-bonding action strengthen further.
On the other hand, Pt (IV) cancer therapy drug relates in the process of physiological environment and ascorbic acid generation redox reaction the step generating AFR; Because the GSH extensively existed in physiological environment has the function of scavenging free radicals, certain inhibitory action is produced to Pt (IV) redox reaction between cancer therapy drug and ascorbic acid.Two axial ligands of Satraplatin JM216 BMS 182751 are and Pt
4+the OAc that bonding is stronger
-, in physiological environment, therefore lose two axial ligands, the speed generating Pt (II) species is relatively slow, causes its pharmacologically active compared with cisplatin, still has larger gap.
As shown in Figure 3, in the clinical experiment of Satraplatin JM216 BMS 182751, the metabolite that can detect mainly comprises: the reduzate 9.JM118 losing two axial ligands, two Cl
-part is all by OH
-replace 10.JM383 and only have a Cl
-part is by OH
-isomers 11.JM518 and 12.JM559 replaced.These results show, the reduction reaction of Satraplatin JM216 BMS 182751 relates generally to the departure proess of two axial ligands, have also confirmed axial ligand OAc simultaneously
-with Pt
4+between there is stronger bonding action.
In sum, the structure activity relationship of Reasonable Regulation And Control platino medicine, designs novel Pt (IV) coordination structure, and appropriateness strengthens the activity of itself and ascorbic acid generation redox reaction, significant for the anti-cancer targets realizing high-efficiency low-toxicity.
(2) there is Pt (IV) the class coordination structure design of mixing axial part
Pt in Pt (IV) coordination structure
4+there is stronger positive charge.Under coordination atom the same terms, Pt
4+to electric neutrality part (such as, H
2o) captivation is obviously weaker than monoanionic ligand (such as, OAc
-) captivation; In particular, H
2o can not with Pt
4+σ-the π generating bond strength higher joins key.Therefore, for the reduction reaction of Pt (IV) coordination structure, axial ligand is H
2during O, it departs from Pt
4+needed for the activation energy that overcomes can significantly lower than axial OAc
-part.On the other hand, ascorbic acid is main under physiological ph conditions exists with monoacid radical ion form.Electroneutral H is introduced in Pt (IV) coordination structure
2o, can strengthen the electropositive of coordination structure, is conducive to the interaction of itself and Vitamin C acid radical anion.
Pt (IV) class medicine designed by the present invention, the axial ligand described in it by with Pt
4+the part I that bond strength is different and part II form, and part and Pt
4+bond strength order be: ammonia > part I > part II; In preferred situation, described part I is OAc
-, part II is H
2o, OH
-or Cl
-.That is: OAc
-for with Pt
4+the part that bonding action is relatively strong, H
2o, OH
-or Cl
-for with Pt
4+the part that bonding action is relatively weak.OAc is with two axial ligands
-satraplatin JM216 BMS 182751 compare, this there is mixed type axial ligand Pt (IV) class medicine and the activity of ascorbic acid generation redox reaction relatively strong, its pharmacologically active is obviously better than Satraplatin JM216 BMS 182751; On the other hand, owing to comprising one and Pt in axial ligand
4+the OAc that coordination ability is stronger
-, too fast the caused toxic and side effects problem of rate of reduction in physiological environment can be avoided.
Pt (IV) class medicine designed by the present invention, in two pairs of plane parts described in it, is for a pair ammonia/amido; In preferred situation, described a pair ammonia/amido part is the NH at ortho position
3and cyclohexylamine, make Pt (IV) the class medical instrument with mixing axial part designed by the present invention have the fat-soluble and Cell permeable similar with Satraplatin JM216 BMS 182751.In addition in pair of planar part, one is H
2o, Cl
-or OH
-, another part is Cl
-or OH
-.
When mixing axial part is OAc
-and H
2o, pair of planar part is the NH at ortho position
3and cyclohexylamine, other two plane parts are respectively Cl
-and H
2during O, obtain four kinds of isomerss as shown in Figure 2.
(3) axial ligand of the present invention is by OAc
-and H
2the preparation of Pt (IV) the class medicine of O composition, carry out based on following principle:
Adopt Satraplatin JM216 BMS 182751 as raw materials, use the exposure light of specific wavelength to excite its d-d transition in water solution system, by controlling irradiation intensity and time, the axial ligand obtained as shown in Figure 2 comprises an OAc
-with a H
2pt (IV) kind anti-cancer drugs of O.Relative theory is as follows:
The Pt of Pt (IV) anticarcinogen coordination center
4+pass through d
2sp
3orbital hybridization and part form octahedral coordination structure, and highest occupied molecular orbital (HOMO) and the minimum track (LUMO) that do not occupy are respectively 2t2
g(xy, xz, yz) and 2e
g(z
2, x
2-y
2).When being in ground state, Pt
4+5d
6low spinning electron occupies 2t
2g(xy, xz, yz) track, just staggering of electron cloud direction of extension and 6 coordinate bonds, energy is lower.
As shown in Figure 4, there is e
gthe dz of feature
2and dx
2-y
2track direction of extension overlapping with coordinate bond.When there is d-d transition, 2t
2gthe electronics of (xy, xz, yz) track is excited to 2e
g(z
2, x
2-y
2) track, producing repulsive interaction with coordinate bond electronics, causing the energy of coordinate bond to raise (by activating).Wherein, 2e is occupied
g(x
2-y
2) effect of raising energy that causes of the excitation electron of track disperse by four coordinate bonds of xy plane; Occupy 2e
g(z
2) two axial coordination keys on the effect of raising energy quilt ± z direction that causes of the excitation electron of track disperse.Therefore, for Satraplatin JM216 BMS 182751, d-d transition is relatively more remarkable to the activation of axial coordinate bond, is more conducive to promoting axial ligand OAc
-with H in solution
2the ligand exchange of O.
In the coordinated planar of Satraplatin JM216 BMS 182751, Pt-Cl bond strength is obviously weaker than Pt-N key.In the water solution system of lucifuge, can there is Cl slowly in Satraplatin JM216 BMS 182751
-/ H
2o ligand exchange.When there is d-d transition, be excited to 2e
g(x
2-y
2) activation of electron pair Pt-Cl key of track, cause Cl
-/ H
2o ligand exchange speed increases.Stability due to Pt-N key is significantly higher than Pt-Cl key, occupies 2e
g(x
2-y
2) excitation electron of track is more weak to the activation of Pt-N key in Satraplatin JM216 BMS 182751.
Excited the radiation parameter of d-d transition by regulation and control, make an axial OAc in Satraplatin JM216 BMS 182751 molecule
-with water generation ligand exchange, retain an OAc simultaneously
-with Pt
4+bonding, can prepare the platino anticarcinogen with mixing axial part of the present invention.
Embodiment one
The preparation condition with the platino cancer therapy drug of mixing axial part of the present invention controls, and carries out based on under type:
(1) under lucifuge and room temperature condition, prepare Satraplatin JM216 BMS 182751 saturated aqueous solution, and measure its ultraviolet-visible absorption spectroscopy.Test instrunment is JASCO550 ultraviolet-visible absorption spectroscopy instrument.As shown in Figure 5, when wavelength is less than 450nm, start the absorption to incident illumination to be detected, along with the reduction of lambda1-wavelength, photon absorbing intensity increases gradually; When lambda1-wavelength is greater than 450nm, Satraplatin JM216 BMS 182751 aqueous solution, shows to excite the wavelength upper limit of the exposure light of Satraplatin JM216 BMS 182751 d-d transition to be 450nm without obvious absorption to incident illumination.
(2) the Satraplatin JM216 BMS 182751 aqueous solution that purple light (415nm, half-peak breadth 12nm), blue light (477nm, half-peak breadth 22nm), green glow (528nm, half-peak breadth 32nm) and gold-tinted (610nm, half-peak breadth 32nm) irradiation are prepared is adopted respectively.The PL spectrum of exposure light is provided by Fig. 6, and test instrunment is Beijing Chinese light 500 spectrogrph.When adopting blue light, green glow and gold-tinted irradiation, the ultraviolet-visible absorption spectroscopy of Satraplatin JM216 BMS 182751 solution does not all change.When adopting purple light irradiation, observe ultraviolet-visible absorption spectra strength reduction and the peak position blue shift of Satraplatin JM216 BMS 182751 solution; Stop absorption spectra after irradiation no longer to change, show that absorption spectra change is closely related with purple light irradiation, confirmation wavelength is that the purple light of 415nm is as the exposure light of d-d transition exciting Satraplatin JM216 BMS 182751.Choose 390-450nm as the exposure light wave-length coverage being applicable to exciting Satraplatin JM216 BMS 182751 d-d transition.According to the activate mechanism of d-d transition to coordinate bond in Satraplatin JM216 BMS 182751, under the prerequisite that d-d transition can be excited, the exciting light adopting wavelength relatively to grow (energy is relatively low) is conducive to protecting the Pt-N key in Pt (IV) coordination structure.Therefore, wave-length coverage is that the exposure light of 415-450nm is more preferred.When wavelength is less than 390nm, the d-d transition of Satraplatin JM216 BMS 182751 also can be excited, but relatively strong to the activating effect of Pt-N.
(3) NH dissociated in Satraplatin JM216 BMS 182751 solution after measuring different exposure time
3, OAc
-and Cl
-concentration.Result shows, free OAc in irradiation process
-, Cl
-and NH
3molar concentration advance the speed than being about 11:10:2, show that d-d transition significantly promotes the axial ligand OAc of Satraplatin JM216 BMS 182751
-with the ligand exchange of water; Meanwhile, Cl
-/ H
2o ligand exchange is also more remarkable.In contrast, under lucifuge and 60 DEG C of conditions, after Satraplatin JM216 BMS 182751 aqueous solution heating 24h, free Cl in solution
-concentration obviously increases, and shows that lucifuge heating can promote Cl
-/ H
2o ligand exchange, does not detect free OAc
-and NH
3, confirmation Satraplatin JM216 BMS 182751 in Pt-N key and Pt-O key more stable under lucifuge heating condition.Test instrunment is the DIONEXICS90 ion chromatograph being equipped with electric conductivity detector.IonPacAS23 post is adopted to measure Cl
-and OAc
-, mobile phase is 4.5mMNa
2cO
3and 0.8mMNaHCO
3, flow velocity is 1ml/min; Cs-12 post is adopted to measure free NH
3, mobile phase is 20mM pyrovinic acid, and flow velocity is 1ml/min.
(4) adopt high performance liquid chromatograph, measure the Satraplatin JM216 BMS 182751 solution after lucifuge heating and purple light irradiation respectively; As shown in Figure 7, detect in the Satraplatin JM216 BMS 182751 solution after lucifuge heating and only Cl occurs
-/ H
2the product (retention time 2.78min) of O ligand exchange and still unreacted Satraplatin JM216 BMS 182751 (retention time 4.89min); At Cl
-/ H
2o and OAc
-/ H
2in solution after all more significant purple light irradiation of O ligand exchange, do not detect that Satraplatin JM216 BMS 182751 only Cl occurs
-/ H
2the product of O ligand exchange, shows that Satraplatin JM216 BMS 182751 Cl occurs in purple light irradiation process simultaneously
-/ H
2o and OAc
-/ H
2the process of O ligand exchange is more remarkable.Test instrunment is Waters600 high performance liquid chromatograph.Adopt SunFire
tMc
18reversed-phase column, column temperature 30 DEG C; 2489 UV-detector, determined wavelength 220nm; Mobile phase is methanol (500 μ lmin
-1), high purity water (150 μ lmin
-1) and 0.05% trifluoroacetic acid aqueous solution (350 μ lmin
-1).
(5) draw the corresponding relation of Satraplatin JM216 BMS 182751 conversion ratio and exposure time according to the integral area of high performance liquid chromatography, result is provided by Fig. 8, and observing that Saite uncle conversion ratio extends with exposure time increases gradually, does not occur obvious flex point.
(6) in Satraplatin JM216 BMS 182751 Pt-OAc coordinate bond dissociation degree with the change of exposure time.Relative theory is as follows: with Pt
4+the OAc of coordination
-middle CH
3corresponding to the Dan Qiangfeng at chemical shift 2.11ppm place.Work as Pt-OAc
-after coordinate bond is dissociated, the Dan Qiangfeng at 2.11ppm place weakens; Meanwhile, the OAc dissociated
-adjacent high field area is caused to occur a new Dan Qiangfeng.Due to OAc
-the integral area of middle methyl signals is directly proportional to content, passes through OAc
- coordinationand OAc
- dissociatecorresponding Dan Qiangfeng integral area ratio, can measure the concentration ratio of the two.Test instrunment is JeolJNM-ECA600M nuclear magnetic resonance chemical analyser.
As shown in Figure 9, the OAc of coordination is participated in
-with the OAc dissociated
-between concentration ratio with exposure time increase and decline.After the two concentration proportion is down to 1.1, continue to extend exposure time, further ratio change is not remarkable, shows two axial OAc in the Satraplatin JM216 BMS 182751 that purple light irradiation causes
-being dissociated into of part is carried out successively.As first OAc
-after axial ligand dissociates, Pt (IV) coordination structure overall positive charge increases, and to the corresponding increase of the sucking action of elecrtonegativity anion ligand, causes second OAc
-axial ligand departs from the activation energy of Pt (IV) coordination structure apparently higher than first axial OAc
-part.When participating in the OAc of coordination
-with the OAc dissociated
-between concentration proportion when being down to 1.1-1.0 scope, stop irradiation also being kept in Dark Place by solution, the solution with Pt (IV) the class medicine of mixing axial part of the present invention can be obtained.When participating in the OAc of coordination
-with the OAc dissociated
-between ratio when being 1.3, also can obtain Pt (IV) the class medicine with mixing axial part, but the conversion ratio of Satraplatin JM216 BMS 182751 is slightly low.
(7) adopt
1the contrast of H NMR (Nuclear Magnetic Resonance) spectrum has Pt (IV) coordination compound of mixing axial part and the pharmacologically active of Satraplatin JM216 BMS 182751: choose 5 '-deoxyguanylic acid (5 '-dGMP) as the DNA pattern species containing guanine, under ascorbic acid (1.00mM) and reduced glutathion (0.25mM) concurrent conditions, Pt (IV) coordination compound with mixing axial part that 5 '-deoxyguanylic acid (1.00mM) is identical with Satraplatin JM216 BMS 182751 saturated solution and total platinum concentration respectively carries out lucifuge reaction, contrast the activity of guanine N7 position bonding in Pt and 5 '-dGMP in two kinds of reaction systems.
Relevant pharmacology activity characterization principle is:
1in H-NMR spectrum, not corresponding to chemical shift with the H8 atom of the guanine of Pt bonding is the unimodal of 8.14ppm place; After the N7 atom generation bonding of guanine in Pt and 5 '-dGMP, the H8 signal weakening at 8.14ppm place; Meanwhile, cause with the guanine of Pt bonding occurring new H8 signal in adjacent low field areas.Therefore, by the change of H8 signal, N7 position in Pt and guanine can be contrasted the percent of bonding occurs.
Satraplatin JM216 BMS 182751 saturated solution
1h NMR (Nuclear Magnetic Resonance) spectrum, as shown in Figure 10 (a), can observe OAc
- coordinationcorresponding Dan Qiangfeng, does not detect OAc
- dissociatesignal.Use purple light to after above-mentioned Satraplatin JM216 BMS 182751 saturated solution irradiation, OAc
- coordinationspectrum peak weaken; Meanwhile, there is OAc in adjacent high field area
- dissociatesingle strong peak-to-peak signal; As shown in Figure 10 (b), work as OAc
- coordinationwith OAc
- dissociatebetween concentration ratio when being down to 1.3:1.0, stop irradiation, obtain comprising the solution of Pt (IV) coordination compound with mixing axial part.
As the H8 in Figure 11 (a) and (b) composes shown in peak-to-peak signal, Satraplatin JM216 BMS 182751 saturated solution and 5 '-dGMP (1.00mM), ascorbic acid (1.00mM), GSH(0.25mM) after lucifuge reacts 2 days and one week, be about 3% and 6% respectively with the ratio of 5 '-dGMP of Pt bonding; As OAc in spectrogram (c) in Figure 11 and (d)
-shown in spectrum peak-to-peak signal, after lucifuge reacts 2 days and one week, OAc
- coordination: OAc
- dissociatebe respectively 24:1 and 10:1.
As the H8 in Figure 12 (a) and (b) composes shown in peak-to-peak signal, comprise the solution (OAc of Pt (IV) the class medicine with mixing axial part
- coordination: OAc
- dissociate=1.3:1.0) with 5 '-dGMP (1.00mM), ascorbic acid (1.00mM), GSH(0.25mM) after lucifuge reacts 2 days and one week, reach 20% and 51% respectively with the ratio of 5 '-dGMP of Pt bonding; As OAc in spectrogram (c) in Figure 12 and (d)
-shown in spectrum peak-to-peak signal, after lucifuge reacts 2 days and one week, OAc
- coordination: OAc
- dissociatebe respectively 1:1 and 2:3.
The comparing result of Figure 11 and 12 shows, compared with Satraplatin JM216 BMS 182751, in the lucifuge reaction system that prepared Pt (IV) the class medicine with mixing axial part coexists at ascorbic acid, reduced glutathion and 5 ' dGMP, comparatively easily axial OAc occurs
-dissociating of part, be reduced to Pt (II) species, pharmacologically active is also obviously better than Satraplatin JM216 BMS 182751.
Test instrunment is JeolJNM-ECA600M nuclear magnetic resonance chemical analyser.In pharmacologically active comparative study, for improving
1the signal to noise ratio that H NMR (Nuclear Magnetic Resonance) spectrum detects, and avoid the interference that in reaction system, in GSH, active H may produce guanine H8 signal measuring, use heavy water is solvent, carry out the preparation of Satraplatin JM216 BMS 182751,5 '-dGMP, ascorbic acid and GSH solution, relevant d-d transition to the influencing mechanism of Satraplatin JM216 BMS 182751 ligand exchange in heavy aqueous solution with use water as identical during solvent.
Above-described embodiment only in order to technical scheme of the present invention to be described, is not intended to limit; Although with reference to foregoing embodiments to invention has been detailed description, those of ordinary skill in the art is to be understood that: it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein some or all of technical characteristic; And these amendments or replacement, do not make the essence of appropriate technical solution depart from the scope of various embodiments of the present invention technical scheme.
Claims (2)
1. there is Pt (IV) class medicine for mixing axial part, by two pairs of plane parts and a pair mixing axial part and Pt
4+bonding is formed, and it is characterized in that, a pair described mixing axial part is respectively part I and part II, and described part I is OAc
-, part II is H
2o, OH
-or Cl
-; In two pairs of described plane parts, be for a pair wherein the NH at ortho position
3and cyclohexylamine; In other a pair part, one is H
2o, Cl
-or OH
-, another part is Cl
-or OH
-;
The preparation method of above-mentioned Pt (IV) the class medicine with mixing axial part, it comprises following operating procedure: under lucifuge and room temperature condition, prepare Satraplatin JM216 BMS 182751 aqueous solution, its concentration range between 100 μMs to saturated concentration; And adopt the light of wavelength 415 ~ 450nm to carry out irradiation to it; When detecting the OAc participating in coordination
-with the OAc dissociated
-between ratio between 1.3 ~ 1.0 time, stop irradiation, solution is kept in Dark Place.
2. Pt (IV) the class medicine with mixing axial part according to claim 1, is characterized in that, when described detection participates in the OAc of coordination
-with the OAc dissociated
-between ratio between 1.1 ~ 1.0 time, stop irradiation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5244919A (en) * | 1988-02-02 | 1993-09-14 | Johnson Matthey, Inc. | Pt(IV) complexes as anti-tumor agents |
| CN1350540A (en) * | 1999-04-13 | 2002-05-22 | 阿诺麦德股份有限公司 | Process for preparing amine platinum complexes |
-
2014
- 2014-04-14 CN CN201410148904.9A patent/CN103860539B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5244919A (en) * | 1988-02-02 | 1993-09-14 | Johnson Matthey, Inc. | Pt(IV) complexes as anti-tumor agents |
| CN1350540A (en) * | 1999-04-13 | 2002-05-22 | 阿诺麦德股份有限公司 | Process for preparing amine platinum complexes |
Non-Patent Citations (2)
| Title |
|---|
| A potent cytotoxic photoactivated platinum complex;Fiona S. Mackay et al.;《The National Academy of Sciences of the USA》;20071226;第104卷(第52期);20743–20748 * |
| Photochemotherapy: Targeted Activation of Metal Anticancer Complexes;Nicola J. Farrer et al.;《Aust. J. Chem.》;20081231;第61卷;669–674 * |
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