CN102603812A - Binuclear platinum (II)-zoledronate complex and preparation and application thereof - Google Patents
Binuclear platinum (II)-zoledronate complex and preparation and application thereof Download PDFInfo
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- CN102603812A CN102603812A CN2012100613196A CN201210061319A CN102603812A CN 102603812 A CN102603812 A CN 102603812A CN 2012100613196 A CN2012100613196 A CN 2012100613196A CN 201210061319 A CN201210061319 A CN 201210061319A CN 102603812 A CN102603812 A CN 102603812A
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Abstract
The invention discloses binuclear platinum (II)-zoledronate complex with a structural general formula (I), and further discloses a preparation method of the binuclear platinum (II)-zoledronate complex, which includes preparation of diiododiammine platinum complex, preparation of sulfate radical ethylenediamine platinum and obtaining of final product. The binuclear platinum (II)-zoledronate complex is used for treating osteosarcoma and lung cancer, and has the advantages of high water solubility, low toxic and side effects, low drug resistance, and excellent bone targeting function and antitumor activity.
Description
Technical field
The present invention relates to a kind of cancer therapy drug, particularly, relate to a kind of double-core platinum (II) – Zoledronic acid title complex and preparation and application.
Background technology
Human beings'health in the cancer serious threat, and the annual whole world has 7,000,000 people to die from cancer approximately.Osteosarcoma is to be difficult to cure one of malignant tumour with pain most, and chemotherapy is one of osteosarcomatous main means of present clinical treatment.First-generation platinum-containing anticancer drug-cis-platinum be one of osteosarcomatous main selection of treatment, but it exists serious resistance and toxic side effect (like renal toxicity, stomach toxicity etc.), and these problems and cis-platinum tumor-selective difference is closely related.Though developed s-generation platinum-containing anticancer drug carboplatin afterwards again, third generation platinum-containing anticancer drug oxaliplatin has overcome the shortcoming of cis-platinum to a certain extent; Reduce like toxic side effect, water-soluble raising also has effect to the tumour cell of some anti-cis-platinums; But because structural similitude, still can not obviously improve with the cis-platinum is the limitation that classical platinum-containing anticancer drug had (Liu Weiping, the Zhang Yongli of representative; Sun Jialin. Future Development of Platinum Anticancer Drugs [J]. precious metal. 2005,26,47-52.).Therefore, we are necessary to break through the classical structure activity relationship of platinum-containing anticancer drug, seek to have optionally cancer therapy drug of good bone target, thereby the curative effect of disease of skeletal system such as raising osteosarcoma reduce the toxic side effect to other organ and tissue.
Two phosphonic acids are the compounds with P-C-P feature structure; This compounds has very high avidity for bone and other calcified tissues; Can be passed to bone metabolism preferentially, apace and enliven the position, thereby absorbed, and then suppress the ripe and effect of osteoclast by osteoclast; Suppress the bone Reabsorption of osteoclast mediation, be applied to treating the various bone photo related disorders that scleromalacia disease, osteoporosis and tumour cause.The bis phosphoric acid salt has experienced the triple-substituted development; Wherein the Zoledronic acid (English name ZL) in the third generation bis phosphoric acid salt medicine is the best bisphosphonate class of drugs of present comprehensive drug; Bone avidity and good therapeutic action (Neville Webbe H with height; Et, al. The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia [J]. Pallia. Med., 2003; 17; 539.), drug effect is stronger 100 times than DClMDP, Pamidronic Acid disodium, than etidronate disodium strong 1000 times (Matthew R.Smith. Osteoclast targeted therapy for prostate cancer:Bisphosphonates and beyond [J]. Urol. Oncol.:Semin. Orig. Investig. 2008; 26,420-425.).The Zoledronic acid dosage is little, and the time is short, and pitch time is long, and is evident in efficacy, untoward reaction few (Li EC, et, al. Zoledronic acid:a new parenteral bisphosphonate [J] .Clin. Ther., 2003,25,2669.).Therefore; Zoledronic acid becomes a kind of medicine that is widely used in treating the bone photo related disorders clinically; Simultaneously the metal complexes of Zoledronic acid and verivate thereof still shows good bone target property, and the diagnosis and treatment medicine that utilizes Zoledronic acid to develop the Skeletal system relative disease as the bone targeting vector has been seen bibliographical information (1. Makbule Asikoglu, et; Al. The rabbit biodistribution of a therapeutic dose of zoledronic acid labeledwith Tc-99m [J]. Appl. Radiat. Isot.; 2009,67,1616-1621; 2. Majkowska A, Neves M, Antunes I, Bilewicz A.. Complexes of low energy beta emitters
47Sc and
177Lu with zoledronic acid for bone pain therapy [J]. Appl. Radiat. Isot., 2009,67,11-13; 3. Jianguo Lin; Et; Al. Preparation and in vivo biological investigations on a novel radioligand for bone scanning:technetium-99m-labeled zoledronic acid derivative [J]. Nucl. Med. Biol.; 2011,38,619-629.).
In order the bone target property of bis-phosphonic acids compounds and the antitumous effect of platinum complexes effectively to be combined, improve the curative effect of relative disease such as osteosarcoma, Chinese scholars has been launched extensive studies in this respect, and has made fruitful work.2010, people such as Zuqin Xue have reported a series of platinum, and (preparation of II) – diphosphonic acid complex, some of them title complex had good inhibitory effect (Zuqin Xue to HOS, ovarian cancer cell; Et; Al. Platinum (II) compounds bearing bone-targeting group:synthesis, crystal structure and antitumor activity [J]. Chem. Commun., 2010; 46,1212-1214.).In addition; Nicola Margiotta seminar has since two thousand seven reported an eka-platinium (research of the synthetic and biological property of II) – diphosphonic acid complex; Experimental result shows that this dinuclear platinum complex all has stronger restraining effect to tumour cells such as people's lung cancer; Human tumor cell line to some anti-cis-platinums also has restraining effect; And this dinuclear platinum complex can reach 96% to the adsorption rate of Win 40350 (major ingredient of bone); Explain the existing good antineoplastic activity of this platinum complex have again stronger bone target property (1. Nicola Margiotta, et, al. Bisphosphonate complexation and calcium doping in silica xerogels as a combined strategy for local and controlled release of active platinum antitumor compounds [J]. Dalton Trans.; 2007,3131-3139; 2. Nicola Margiotta; Et; Al. Synthesis, characterization, and cytotoxicity of dinuclear platinum-bisphosphonate complexes to be used as prodrugs in the local treatment of bone tumours [J]. Dalton Trans; 2009,10904-10913; 3. Michele Iafisco; Et, al. Smart delivery of antitumoral platinum complexes from biomimetic hydroxyapatite nanocrystals [J]. J. Mater. Chem., 2009; 19,8385-8392.).
In a word, prior art also do not find with Zoledronic acid (high close bone property, dosage is little; Time is short; Pitch time is long, and is evident in efficacy, and untoward reaction is few etc.) be incorporated in platinum (II) title complex; Bring into play the dual function of its bone target property and treatment, strengthen the application of platinum-bis-phosphonic acids title complex anticancer function.
Summary of the invention
The technical problem that the present invention will solve is to overcome existing defective, and a kind of novel double-core platinum (II) – Zoledronic acid title complex, the advantage that it has, and good water solubility, toxic side effect and resistance are low, bone target function and antitumour activity are excellent are provided.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
A kind of double-core platinum (II) – Zoledronic acid title complex has following structural formula (I):
（I）
The double-core platinum that the present invention proposes (preparation method of II) – Zoledronic acid title complex may further comprise the steps:
(1) preparation of diiodo-quadrol platinum complex: 40 ℃ of low-grade fevers of potassium chloroplatinite and excessive potassiumiodide, the reaction after-filtration is removed insolubles, adds reacting ethylenediamine in the gained solution, and it is dry to leave and take the throw out washing; Prepared diiodo-quadrol platinum complex is a cis-compound, also can be expressed as cis-Pt (en) I
2
(2) sulfate radical quadrol platinum complex [Pt (en) (OSO
3) (H
2O)] preparation: under the lucifuge condition, step (1) products therefrom and Sulfuric acid disilver salt reaction are spent the night, and remove deposition, and evaporate to dryness makes [Pt (en) (OSO
3) (H
2O)];
(3) double-core platinum (making of II) – Zoledronic acid title complex: step (2) gained [Pt (en) (OSO
3) (H
2O)] with Zoledronic acid barium reaction after, Ba (OH)
2Regulate PH to 5.0, remove deposition, add H again
2SO
4Regulate pH to 1.5-2.0, make double-core platinum (II) – Zoledronic acid title complex.
The reaction formula of step (3) is:
The double-core platinum that the present invention proposes (application of II) – Zoledronic acid title complex in preparation treatment osteosarcoma and lung-cancer medicament.
In sum, its total reaction route is:
Wherein, being abbreviated as in the above-mentioned reaction formula:
Double-core platinum (II) – Zoledronic acid title complex: [{ Pt (en) }
2ZL];
Quadrol: en;
Zoledronic acid: ZL;
Zoledronic acid barium: Ba-ZL;
Potassium chloroplatinite: K
2PtCl
4
Sulfate radical quadrol platinum complex: [Pt (en) (OSO
3) (H
2O)];
Diiodo-quadrol platinum complex (cis): cis-Pt (en) I
2
The present invention has following beneficial effect:
The advantage of comprehensive Zoledronic acid part and the characteristics of platinum complex, we have designed and synthesized a kind of novel double-core platinum, and (II) – Zoledronic acid title complex, the Zoledronic acid that will have outstanding clinical value first is incorporated in such medicine as part.Expect that this dinuclear platinum complex on the one hand owing to the existence of Zoledronic acid has high bone avidity, can be passed to bone metabolism fast and enliven the position, thereby have the bone target function and the result of treatment of excellent performance; Has good anti-cancer activity on the other hand again; This platinum complex can combine with target molecule DNA, produces in the chain afterwards or interchain linkage, and then disturbs the DNA normal replication; Finally cause cancer cell death, and lower toxic side effect and resistance are arranged than cis-platinum.Through preliminary extracorporeal biology experiment; We have screened two kinds of human tumor cell line: osteosarcoma U2-OS and lung cancer A549 cell; Find that this compound all has the obvious suppression effect for the propagation of these two kinds of cells, thereby can be used as a kind of potential bone targeted anticancer medicine.
Embodiment
Product and preparation embodiment:
Double-core platinum (II) – Zoledronic acid title complex and preparation thereof:
(1) diiodo-quadrol platinum complex cis-Pt (en) I
2Preparation:
(0.415 g, 1 mmol) is water-soluble with potassium chloroplatinite, and under agitation condition, (1.328 g 8mmol), reacted 20-40 minute the elimination insolubles down at 40 ℃ dropwise to add excessive liquor kalii iodide.Under agitation condition, dropwise in filtrating, add quadrol (0.057 g, 0.95 mmol), reaction is 4-6 hour under 40 ℃, crosses and filters throw out, uses frozen water, the washing of ice ether, vacuum-drying gets dark yellow solid 0.4736 g, and productive rate is 94.94%.
(2) intermediate product [Pt (en) (OSO
3) (H
2O)] preparation:
With cis-[Pt (en) I
2] (0.509 g, 1 mmol) be suspended in the 20 ml water, adds Sulfuric acid disilver salt (0.3058 g0.98 mmol), under 25 ℃; Stirred overnight removes by filter deposition, and it is half that the filtrate decompression distillation is concentrated into original volume; Filter with millipore filter (0.22 μ m), remove insolubles, underpressure distillation is closely dried again; Vacuum-drying then gets glassy yellow pressed powder 0.3297 g, and productive rate is 91.17%.
(3) double-core platinum (producing of II) – Zoledronic acid title complex:
(0.0272 g, 0.1 mmol) is dissolved in the 5 ml water with the Zoledronic acid solid, and 25 ℃, N
2Protection splashes into baryta water (0.0171 g, 0.1 mmol) under the agitation condition, produce white opacity immediately, keeps and stirs 10-20 minute, gets white solid and is the Zoledronic acid barium salt, without other processing.
Above-mentioned suspension liquid is placed ice bath, and temperature is 0-5 ℃ in the control reaction vessel, gets [Pt (en) (OSO
3) (H
2O)] (0.0738 g, 0.2 mmol) is dissolved in the 2 ml water, at N fully
2Splash in the above-mentioned reaction solution under the protection, stirred stopped reaction 4-5 hour.Centrifugal (15min 2000rpm) isolates supernatant liquid, half of 30-35 ℃ of underpressure distillation to original volume, and (0.22 μ m) removes insolubles with millipore filter, and underpressure distillation is concentrated into 1-2 mL solution.
In above-mentioned solution, add Ba (OH)
2(0.5 M) regulates pH=5.0, and spinning adds H again
2SO
4Regulate pH=1.5-2.0, get 65.3 mg yellow-green colour solids, productive rate is 83.93%.
In above-mentioned steps (3), add Ba (OH)
2Regulate the pH value, both can let Zoledronic acid exist with anionic form, again can with [Pt (en) (OSO
3) (H
2O)] sulfate radical in forms deposition, impels coordination reaction to carry out smoothly, generates stable title product [{ Pt (en) }
2ZL].Add an amount of H afterwards
2SO
4In order to removing excessive barium ion, thereby separate out the higher pure target compound of productive rate.
Product detects:
Title product has passed through the affirmation of ultimate analysis, mass spectrum, ir spectra and proton nmr spectra respectively.
1, [{ Pt (en) }
2ZL] ultimate analysis (C
9H
22N
6O
7P
2Pt
2, Elementar Vario EL III analyzer, Germany):
2、[{Pt(en)}
2ZL]ESI-MS（Waters?Platform?ZMD4000,?U.S.A.）：[M-H]=776.8(100%)
3, [{ Pt (en) }
2ZL] ir spectra (cm
-1, the KBr compressing tablet, Nicolet Nexus 470, Thermo): 3406 (υ O-H); 3280,3205 (υ N-H), 3153 (υ N=C-H), 2959 (υ C-H); 1629 (υ C=N), 1566 (υ C=C), 1466 (δ C-H), 1288 (υ P=O); 1128,1052 (υ P-O), 570 (υ Pt-O);
4、[{Pt(en)}
2ZL]
1H-NMR（D
2O,?TMS,?400MHz,?Bruker?DRX-500?spectrometer,?Germany）：
The application implementation example
Curative effect of medication is estimated:
Experimental technique: MTT colourimetry
Cell strain: HOS U2-OS cell, people's lung cancer A549 cell
Experimental design:
The cultivation of cell: U2-OS cell (A549 cell) in 37 ℃, contains 5%CO with the DMEM nutrient solution (RPMI-1640) that contains 100,000 U/L penicillium mould, 100,000 U/L Streptomycin sulphates, 10% foetal calf serum
2Incubator in cultivate.
The mensuration of cell inhibitory rate: use trypsin digestion cell, be made into cell suspension, add 96 orifice plates (for preventing fringing effect, peripheral hole does not add cell), return to zero with only adding the blank well that nutrient solution do not add cell, as blank with conventional substratum.Remain every hole and add 100 μ L U2-OS, A549 cell suspension, cell inoculation concentration is 7 * 10
7/ L.At 37 ℃, contain 5%CO
2Incubator in cultivate after 24 hours, test group and control group add [{ Pt (en) } of 100 μ L respectively
2ZL] 5 ~ 100 μ M) and 100 μ L nutrient solutions (concentration is divided into 8 groups:, every group is provided with 8 parallel holes to solution.Continue to cultivate after 72 hours, add 20 μ L MTT (concentration is 5 mg/mL) solution, put into incubator and continue to cultivate after 4 hours, stop cultivating, carefully absorb supernatant, add 100 μ L methyl-sulphoxides (DMSO), concussion 10min is to dissolving fully.Measure every hole absorbance A value with the enzyme linked immunological ELIASA at 490 nm, calculate [{ Pt (en) } with return law of the straight line
2ZL] half-inhibition concentration (IC
50) value (SPSS software), test repetition 3 times for every group.
Experimental analysis:
1, [{ Pt (en) }
2ZL] to the extracorporeal inhibiting rate (%) of HOS U2-OS cell (72h):
2, [{ Pt (en) }
2ZL] to the extracorporeal inhibiting rate (%) of people's lung cancer A549 cell (72h):
The result shows:
[{ Pt (en) }
2ZL] to the IC of U2-OS and A549 cell
50Value is respectively 22.98 μ M and 34.63 μ M.Adding dose is 100 μ M, during effect 72h, is 88.17% to U2-OS cell inhibiting rate, is 94.57% to A549 cell inhibiting rate, and [{ Pt (en) } is described
2ZL] these two kinds of human tumor cell lines are had the obvious suppression effect, be expected to become a kind of bone targeting anti-tumor medicine with better application prospect.
What should explain at last is: the above is merely the preferred embodiments of the present invention; Be not limited to the present invention; Although the present invention has been carried out detailed explanation with reference to previous embodiment; For a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. a double-core platinum (II) – Zoledronic acid title complex has following structural formula (I):
（I）。
The described double-core platinum of claim 1 (preparation method of II) – Zoledronic acid title complex may further comprise the steps:
(1) preparation of diiodo-quadrol platinum complex: 40 ℃ of low-grade fevers of potassium chloroplatinite and excessive potassiumiodide, the reaction after-filtration is removed insolubles, adds reacting ethylenediamine in the gained solution, and it is dry to leave and take the throw out washing;
(2) preparation of sulfate radical quadrol platinum complex: under the lucifuge condition, step (1) products therefrom and Sulfuric acid disilver salt reaction are spent the night, and remove deposition, and evaporate to dryness makes sulfate radical quadrol platinum complex;
(3) double-core platinum (making of II) – Zoledronic acid title complex: after the reaction of step (2) gained sulfate radical quadrol platinum complex and Zoledronic acid barium, Ba (OH)
2Regulate PH to 5.0, remove deposition, add H again
2SO
4Regulate pH to 1.5-2.0, make double-core platinum (II) – Zoledronic acid title complex.
3. the described double-core platinum of the claim 1 (application of II) – Zoledronic acid title complex in preparation treatment osteosarcoma and lung-cancer medicament.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875606A (en) * | 2012-09-29 | 2013-01-16 | 江苏省原子医学研究所 | Copper diphosphonate complex and preparation method and application thereof |
Citations (3)
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| US5288887A (en) * | 1988-11-22 | 1994-02-22 | Board Of Regents, The University Texas System | Diamine platinum(IV) complexes having mixed carboxylate ligands as antitumor agents |
| US20060173185A1 (en) * | 2003-06-27 | 2006-08-03 | Akira Odani | Bisphosphonate complexes |
| CN101985456A (en) * | 2010-07-02 | 2011-03-16 | 江苏省原子医学研究所 | Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof |
-
2012
- 2012-03-09 CN CN201210061319.6A patent/CN102603812B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5288887A (en) * | 1988-11-22 | 1994-02-22 | Board Of Regents, The University Texas System | Diamine platinum(IV) complexes having mixed carboxylate ligands as antitumor agents |
| US5288887B1 (en) * | 1988-11-22 | 1996-03-12 | Reagents The University Of Tex | Diamine platinum(iv) complexes having mixed carboxylate ligands as antitumor agents |
| US20060173185A1 (en) * | 2003-06-27 | 2006-08-03 | Akira Odani | Bisphosphonate complexes |
| CN101985456A (en) * | 2010-07-02 | 2011-03-16 | 江苏省原子医学研究所 | Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| NICOLA MARGIOTTA等,: "A new dinuclear platinum complex with a nitrogen-containing geminal bisphosphonate as potential anticancer compound specifically targeted to bone tissues", 《JOURNAL OF INORGANIC BIOCHEMISTRY》 * |
| NICOLA MARGIOTTA等,: "Bisphosphonate complexation and calcium doping in silica xerogels as a combined strategy for local and controlled release of active platinum antitumor compounds", 《DALTON TRANSACTIONS》 * |
| NICOLA MARGIOTTA等,: "Synthesis, characterization, and cytotoxicity of dinuclear platinum-bisphosphonate complexes to be used as prodrugs in the local treatment of bone tumours", 《DALTON TRANSACTIONS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875606A (en) * | 2012-09-29 | 2013-01-16 | 江苏省原子医学研究所 | Copper diphosphonate complex and preparation method and application thereof |
| CN102875606B (en) * | 2012-09-29 | 2015-03-25 | 江苏省原子医学研究所 | Copper diphosphonate complex and preparation method and application thereof |
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