CN1298727C - Novel liposoluble platinum (II) anti-tumor ligand - Google Patents
Novel liposoluble platinum (II) anti-tumor ligand Download PDFInfo
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- CN1298727C CN1298727C CNB2005100106632A CN200510010663A CN1298727C CN 1298727 C CN1298727 C CN 1298727C CN B2005100106632 A CNB2005100106632 A CN B2005100106632A CN 200510010663 A CN200510010663 A CN 200510010663A CN 1298727 C CN1298727 C CN 1298727C
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Abstract
The present invention discloses two new fat soluble platinum (II) antitumor coordination compounds of cis-[3, 5-diisopropyl salicylate radical. Diamino platinum (II)] and cis-[3, 5-diisopropyl salicylate radical. (1R, 2R-cyclohexanediamine) platinum (II)]. Both of the two compounds of the present invention can be prepared by a conventional preparation method of platinum anticancer coordination compounds. The compounds of the present invention have anticancer activity which are higher than that of carboplatin, have good fat solubility and can be prepared into liposomes for clinic cancer targeted therapy, the structural formulas of the compounds are respectively shown as the figures.
Description
Technical field
The present invention relates to a class and have fat-soluble novel platinum (II) anti-tumor complex, particularly relate to 3,5-di-isopropyl salicylate is to dissociate liposoluble platinum (II) anti-tumor complex of group
Background technology
Chemotherapy is that the present mankind tackle one of three big means of cancer, is used widely clinically.The main medicine of chemotherapy use now all belongs to cytotoxic compound, cancer cells is lacked selectivity and specificity, in kill cancer cell, also greatly injure normal histocyte, cause serious toxic side effect [the Han Rui chief editor. chemoprevention of cancer and pharmacological agent. combined publication society of China Concord Medical Science University of Beijing Medical University. Beijing, 1991].Therefore, the toxic side effect of reduction chemotherapeutics is a great research topic of cancer therapy always.Target administration is considered to subtract the light toxic side effect of medicine, improves the effective means of curative effect.Liposome is the most sophisticated now target administration system, and the liposome of organic anticarcinogens such as 5 FU 5 fluorouracil, Zorubicin has been succeeded in developing, and clinical efficacy is remarkable.The platinum kind anti-cancer drugs be the multiple cancer of clinical treatment such as ovarian cancer, lung cancer, prostate cancer, tumor of testis etc. choice drug [Li Yixin translates. the choice drug of cancer chemotherapeutic. the external medicine-biochemical medicine preparation of synthetic drug fascicle, 1998,19 (2): 89-101; Ernest Wong, Christen M G.Current Status of Platinum-based AntitumorDrugs.Chem.Rev., 1999,99:2451-2466], the history in existing more than 20 year of the development of their lipid targeted drug delivery system, but all do not achieve success.Tracing it to its cause, we think that mainly to be that the platinum kind anti-cancer drugs has as cis-platinum, carboplatin, oxaliplatin do not resemble organic anticarcinogen good fat-soluble, cause that lipid encapsulated rate is low, do not reach the meaning [Liu Weiping of clinical application, Gao Wengui. the platinum metals title complex [J] of treatment cancer. the pharmacy progress, 2001,25 (1): 27-31].Therefore, design and synthetic a kind of to have fat-soluble platinum kind anti-cancer drugs be the key that solves the lipid targeted administration of platinum kind anti-cancer drugs.Simultaneously, chemical sproof problem usually appears in clinical use platinum kind anti-cancer drugs, causes that curative effect obviously reduces.Studies show that recently cancer cells produces the change that one of drug-fast principal element is the cancer cell membrane structure to the platinum kind anti-cancer drugs, make medicine stride film running difficulty, accumulation is less than the effective concentration that suppresses dna replication dna in cancer cells.Increase the fat-soluble permeability that can improve medicine of platinum kind anti-cancer drugs, be the effective way that overcomes this resistance mechanism [Liu Weiping, Zhang Yongli, Sun Jialin. Future Development of Platinum Anticancer Drugs [J]. precious metal, 2005,26 (1), 45-51].
Now liposoluble platinum (II) anti-tumor complex of abroad studying has cis-two (new certain herbaceous plants with big flowers acid group) (1R, the 2R-cyclohexanediamine) closes platinum (II) and cis-two (tetradecane acid group) (1R, the 2R-cyclohexanediamine) closes platinum (II) [Long Qidong, Gou Shaohua. the progress of antitumor platinum complexes, pharmaceutical chemistry progress .2003,2:161-187], but their molecular volume is huge, stride film running difficulty, antitumour activity is not high; Simultaneously be the part that dissociates with the monocarboxylic acid root, a little less than the coordination ability, complexes stability is poor, influences the preparation and the storage of liposome.
Summary of the invention
The object of the invention provides two kinds and has antitumour activity height, stable liposoluble platinum (II) title complex.It is huge simultaneously can to solve molecular volume, strides film running difficulty, and antitumour activity is not high; While can solve with the monocarboxylic acid root and be the part that dissociates, and a little less than the coordination ability, complexes stability is poor, influences the problem of the preparation and the storage of liposome.
The chemistry of a kind of title complex of the present invention is called cis-[3,5-di-isopropyl salicylate two ammino platinum (II)] (be called for short LSPt-NH
3), its molecular formula C
13H
22N
2O
3Pt, its molecular weight FW=449.41, its chemical structure is as shown in Figure 1.
Fig. 1 .C
13H
22N
2O
3The structural formula of Pt
The chemistry of another kind of title complex of the present invention is called cis-[3, and 5-di-isopropyl salicylate (1R, 2R-cyclohexanediamine) closes platinum (II)] (being called for short LSPt-DACH), its molecular formula C
19H
30N
2O
3Pt, its molecular weight FW=529.54, its chemical structure is as shown in Figure 2.
Fig. 2 .C
19H
30N
2O
3The structural formula of Pt
The preparation method's preparation that all can adopt the platinum genus against cancer complexes routine of two kinds of compounds of the present invention.With cis-[Pt (NH3) 2I2] or cis-[Pt (1R, the 2R-cyclohexanediamine) I2] be raw material, in water with the Silver Nitrate quantitative reaction, the after-filtration that reacts completely separates AgI, mother liquor adds 3,5-di-isopropyl Whitfield's ointment disodium salt is separated out the precipitation of compound of the present invention, purifies and to obtain elaboration through the anti-method of analysing of chemistry.
Title complex of the present invention has good fat-soluble, is dissolved in ethanol, ether, the acetone and other organic solvent, also is dissolved in peanut oil, Camellia oil, the olive wet goods lipoid substance, can be prepared into the liposome of target administration.
Platinum complex of the present invention has a powerful antitumour activity external, to the IC of the strain of HT-29 human colon cancer cell, 3AO human oophoroma cell line, A549 human lung carcinoma cell line
50All, be better than clinical widely used platinum kind anti-cancer drugs carboplatin (Carboplatin) at present less than 10g/ml.
Antitumour activity for the compound of this invention, can DMSO be solvent, carboplatin is contrast, and the restraining effect that the compound that adopts srb assay mensuration to be invented is grown to the strain of HT-29 human colon cancer cell, 3AO human oophoroma cell line, A549 human lung carcinoma cell line is calculated IC
50Two kinds of compounds being invented have very high antitumour activity, IC
50All little than carboplatin, be better than carboplatin.Shown in table 1, table 2.Fat-soluble, as shown in table 3 for the compound of this invention.
The concentration IC of table 1 compound anticancer growth 50%
50(μ g/ml)
| The HT-29 human colon cancer cell | The 3AO Proliferation of Human Ovarian Cell | The A549 human lung carcinoma cell | |
| LSPt-NH 3 | 6.4 | 1.8 | 0.15 |
| LSPt-DACH | 2.7 | 0.65 | 0.15 |
| Carboplatin | 58.5 | 5.3 | 5.27 |
Table 2: the concentration IC of compound anticancer growth 50%
50(g/ml)
| BGC-823 people's adenocarcinoma of stomach | The DU145 human prostata cancer | The MDA-MB-231 human breast carcinoma | |
| LSPt-NH 3 | 5.6 | 14.8 | 6.2 |
| LSPt-DACH | 12.7 | 12.6 | 14.1 |
| Carboplatin | ＞100 | 50.3 | ＞100 |
For compound fat-soluble of invention,, measure 25 ℃ of solubleness in organic solvent and lipid of compound of being invented according to the solubility test method of 2005 editions two appendix of Chinese Pharmacopoeia.The result shows that the solubleness of two kinds of compounds in organic solvent and lipid of being invented all is higher than 10mg/ml, and is fat-soluble good, can be prepared into the liposome of target administration.
Table 3: the dissolubility data of compound (25 ℃, mg/ml)
| Acetone | Ethyl acetate | Peanut oil | Camellia oil | Sweet oil | |
| LSPt-NH 3 | 50 | 40 | ＞10 | ＞10 | ＞10 |
| LSPt-DACH | 25 | 20 | ＞10 | ＞10 | ＞10 |
| Carboplatin | ＜0.01 | ＜0.01 | ＜0.01 | ＜0.01 | ＜0.01 |
Embodiment
The preparation of first kind of compound of embodiment 1 the present invention
Get cis-[Pt (NH3) 2I2 of 10g], in the suspension 200ml water, add the Silver Nitrate 7.0g of equivalent, 45 ℃ of following stirring reactions 5 hours, the inspection after-filtration that reacts completely is removed AgI precipitation, mother liquor adds 3, and 5-di-isopropyl Whitfield's ointment disodium salt 5.51g separates out white precipitate, filter and collect, wash the back with water 65 ℃ of oven dry down, get the crude product of 3.9g, productive rate 42%.Crude product 3.9g is dissolved in the ethanol of 30ml, removes by filter insoluble slag, and filtrate adds counter the analysing of water 50ml of PH=10, separates out white crystals, filters and collects, and washes back oven dry under 65 ℃ with water and obtains elaboration 2.53g, productive rate 65%.The feature structure parameter is:＜1〉ultimate analysis C 34.6%; N 6.1%; H 4.8%; Pt 43.2%, with theoretical value C 34.74%; N 6.23%; H 4.93%; Pt 43.4% unanimity.<2>FAB
+-MS m/e＝450(M
+)。＜3〉IR (cm
-1, the KBr compressing tablet) and 3423-3298 (s vNH
3), 2953 (w vCH
2), 1642[vs vas (COO)], 1611 (s vC=C), 1461 (s vC=C), 1392[svs (COO)], 1102 (m, v C-OH) 536 (s vPt-N).These parameters meet the chemical structure of the compound of being invented.
The preparation of second kind of compound of embodiment 2 the present invention
Get cis-[Pt (1R, the 2R-cyclohexanediamine) I2 of 10g], in the suspension 200ml water, the Silver Nitrate 6.0g that adds equivalent, 45 ℃ of following stirring reactions 5 hours, check that the after-filtration that reacts completely removes the AgI precipitation, mother liquor adds 3,5-di-isopropyl Whitfield's ointment disodium salt 4.73g, separate out white precipitate, filter and collect, wash the back with water 65 ℃ of oven dry down, get the crude product of 4.7g, productive rate 50%.Crude product 4.7g is dissolved in the ethanol of 55ml, removes by filter insoluble slag, and filtrate adds counter the analysing of water 70ml of PH=10, separates out white crystals, filters and collects, and washes back oven dry under 65 ℃ with water and obtains elaboration 3.1g, productive rate 65%.The feature structure parameter is:＜1〉ultimate analysis C 43.1%; N 5.2%; H 5.6%; Pt 36.7%, with theoretical value C 43.09%; N5.29%; H 5.71%; Pt 36.8% unanimity.<2>FAB
+-MS m/e＝530(M
+)。＜3〉IR (cm
-1, the KBr compressing tablet) and 3423-3298 (s vNH3) 2953 (w vCH2), 1642[vs vas (COO)], 1611 (s vC=C), 1461 (s vC=C), 1392[s vs (COO)] and, 1102 (m, v C-OH), 514 (s vPt-N).These parameters meet the chemical structure of the compound of being invented.
Claims (3)
1, a kind of liposoluble platinum (II) anti-tumor complex is characterized in that its molecular formula is C
13H
22N
2O
3Pt, its structural formula is:
Its molecular weight FW=449.41.
2, a kind of liposoluble platinum (II) anti-tumor complex is characterized in that its molecular formula is C
19H
30N
2O
3Pt, its structural formula is:
Its molecular weight FW=529.54.
3, liposoluble platinum according to claim 1 and 2 (II) anti-tumor complex can be prepared into liposome, treats the application of the liposome medicament of the clinical target administration of cancer as preparation.
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|---|---|---|---|---|
| CN102603805A (en) * | 2012-02-14 | 2012-07-25 | 昆明贵研药业有限公司 | Platinum (II) complex with antineoplastic activity and preparation method of platinum (II) complex |
| CN104230997B (en) * | 2013-06-13 | 2017-01-04 | 上海医药工业研究院 | A kind of platinum (II) coordination compound, its preparation method, pharmaceutical composition and application |
| CN109678910B (en) * | 2016-01-25 | 2021-09-07 | 沈阳药科大学 | Compound and application thereof, platinum complex and liposome thereof |
| CN113801167A (en) * | 2020-06-17 | 2021-12-17 | 沈阳药科大学 | Platinum complex, liposome thereof and application thereof |
| CN115677785A (en) * | 2022-11-07 | 2023-02-03 | 盐城师范学院 | Diflunisal platinum complex, preparation thereof and application thereof in preparation of anti-cancer drugs |
Citations (2)
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|---|---|---|---|---|
| CN1557825A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anticancer activity |
| CN1557822A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anti-tumor activity |
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| CN1557825A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anticancer activity |
| CN1557822A (en) * | 2004-02-11 | 2004-12-29 | 昆明贵金属研究所 | Platinum complex having anti-tumor activity |
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