CN103479613A - Application of fluoro taxane derivative in preparation of liver cancer treating drugs - Google Patents
Application of fluoro taxane derivative in preparation of liver cancer treating drugs Download PDFInfo
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- CN103479613A CN103479613A CN201210193416.0A CN201210193416A CN103479613A CN 103479613 A CN103479613 A CN 103479613A CN 201210193416 A CN201210193416 A CN 201210193416A CN 103479613 A CN103479613 A CN 103479613A
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Abstract
The invention belongs to the field of medicinal chemistry, and relates to an application of a fluoro taxane derivative represented by the formula (1) in preparation of liver cancer treating drugs, wherein R1 is hydrogen or fluorine, R2 is hydrogen or fluorine, R3 is hydrogen or fluorine, R4 is hydrogen or fluorine, and R5 is hydrogen or fluorine. In vitro pharmacological studies show that the fluoro taxane derivative has an obvious anti-tumor effect and a good dose-dependent relationship; test results related to human cancer cytotoxic activity show that the anti-tumor effect of the fluoro taxane derivative is equal to that of docetaxel activity, even better than that of docetaxel; and in vivo pharmacological experiment results show that the fluoro taxane derivative can inhibit division and proliferation of liver cancer cells, and has an obvious effect of treating liver cancer. The fluoro taxane derivative can further be made into liver cancer treating medicinal preparations with medicinal carriers.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the new purposes of fluoro taxane derivatives in pharmacy, be specifically related to the purposes of fluoro taxane derivatives in preparing the Hepatoma therapy medicine.
Background technology
Paclitaxel (taxol) and Docetaxel (docetaxel) are two representational medicines in bearing taxanes family.(the J.Am.Chem.Soc.1971 such as Wall, 93,2325) extracted and separate the diterpene-kind compound obtained from the bark of America Chinese yew genus plants yewtree (Taxus breviolia) first in 1971, be mainly used in treating ovarian cancer, breast carcinoma and nonsmall-cell lung cancer.French Rhone-Poulenc Rorer in 1985 and French National Nature research establishment carry out the semi-synthetic Docetaxel that obtains by 10-DAB, show that after deliberation its water solublity is better than paclitaxel, the antitumor spectrum is wider, all effective to other solid tumors except renal carcinoma, knot, rectal cancer.Under suitable toxicity dose, its antitumor action is higher 1 times than paclitaxel.Studies show that, the Anticancer Effect and Mechanism of paclitaxel analog compound is by inducing and impelling tubulin polymerization to become microtubule, suppress the depolymerization of the microtubule that forms simultaneously, produce stable microtubule fasolculus, the normal dynamic regeneration of microtubule fasolculus is obstructed, cell can not form normal mitosis spindle when mitosis, thereby has suppressed cell division and propagation.Researcher thinks, the reason that the Docetaxel anti-tumor activity strengthens is that the tertbutyloxycarbonyl on C-13 side chain N has substituted benzoyl.The fluoro Docetaxel derivant that development has new pharmaceutically active is to become the focus of attention of this area research worker, as Chinese invention patent ZL 200510027537.8(paclitaxel derivant) a series of fluoro Docetaxel derivants are disclosed.
Summary of the invention
An object of the present invention is to provide the new purposes of fluoro taxane derivatives in pharmacy, be specifically related to the purposes of fluoro taxane derivatives in preparing the Hepatoma therapy medicine shown in formula (1).
In formula, R
1for hydrogen atom or fluorine, R
2for hydrogen atom or fluorine, R
3for hydrogen atom or fluorine, R
4for hydrogen atom or fluorine, R
5for hydrogen atom or fluorine.
More specifically, fluoro taxane derivatives of the present invention is following compound,
The present invention studies show that through external pharmacology, and described fluoro taxane derivatives has obvious antitumor action and good dose-dependence.To two kinds of human cancer cell strain human mouth epidermal carcinoma cell strains (KB-0528) and human promyelocytic leukemia strain (HL60-0607-2), three kinds of multidrug resistances (MDR) cell strain (KBR-0530, KBR-0602, and HL60OR-0604-2) carried out the cytotoxic activity test, result shows, described its antitumor action of fluoro taxane derivatives and Docetaxel are quite active, even are better than Docetaxel; ICR mice H22 hepatocarcinoma has been carried out to pharmacological evaluation and experimental therapy in the body, the result demonstration, described fluoro taxane derivatives can suppress division and the propagation of hepatoma carcinoma cell, has the effect of obvious Hepatoma therapy.
Fluoro taxane derivatives of the present invention can be used as effective ingredient and makes the various preparations that comprise safe and effective amount fluoro taxane derivatives and pharmaceutical carrier, is used for the treatment of especially Hepatoma therapy of liver tumor.
In the present invention, " safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce serious side effect; Safe and effective amount is according to determining age for the treatment of target, the state of an illness, the course for the treatment of etc.
In the present invention, " pharmaceutical carrier " refers to: one or more compatibility solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." compatibility " referred to herein as each component energy and compound of the present invention and blending mutually between them in compositions, and the drug effect of not obvious reduction compound.
In the present invention, pharmaceutically the acceptable carrier can be selected from sugar (as glucose, sucrose, lactose etc.), starch (as corn starch, potato starch etc.), cellulose and derivant thereof (as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, Talcum, kollag (as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods), polyhydric alcohol (as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent is (as tween
), wetting agent (as sodium lauryl sulphate), coloring agent, flavoring agent, stabilizing agent, antioxidant, antiseptic, apirogen water etc.
The invention provides the fluoro Docetaxel derivant with new pharmaceutically active, described fluoro taxane derivatives can be used as effective ingredient make new comprise safe and effective amount fluoro taxane derivatives and pharmaceutical carrier be used for the treatment of the especially various preparations of Hepatoma therapy of liver tumor.
The accompanying drawing explanation
Fig. 1 is the impact of fluoro taxane derivatives on H22 liver cancer mouse transplanted tumor volume.
The specific embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiment are never any limitation of the invention.
Embodiment 1 anti tumor activity in vitro experiment
1) material
1.1 cell strain: two kinds of human cancer cell strain human mouth epidermal carcinoma cell strains (KB-0528) and human promyelocytic leukemia strain (HL60-0607-2), three kinds of multidrug resistances (MDR) cell strain (KBR-0530, KBR-0602, and HL60OR-0604-2).
1.2 positive control: Docetaxel.
1.3 reagent: HyQR modified form RPMI 1640 culture medium, DMEN culture medium, GIBCO; MTT; Pancreatin; Three solubilising reagents;
1.4 the configuration of three joint-trial agent: 20%SDS, 10% isobutanol, 0.024mol/LHCL, distilled water dissolves.
1.5 equipment: CO2 incubator, aseptic operating platform, microplate reader, centrifuge etc., liquid-transfering gun, pipet, centrifuge tube, 96 orifice plates etc.
Cell strain and reagent that the present invention's test adopts, be those skilled in the art and know, can be by commercial acquisition.
2) experimental technique step
2.1 cell culture: two kinds of human cancer cell strain human mouth epidermal carcinoma cell strains (KB-0528) and human promyelocytic leukemia strain (HL60-0607-2), three kinds of multidrug resistances (MDR) cell strain (KBR-0530, KBR-0602, and HL60OR-0604-2): by RPMI 1640 culture medium containing 10% hyclone, in 37 ℃, in the incubator of 5%CO2, cultivate.
2.2 cell is processed: get in exponential phase of growth, cell in good condition, add appropriate trypsin digestion cell, and collecting cell is centrifugal, abandons supernatant.With the culture fluid containing serum suspendible cell again, then count, and cell density is diluted to 2 * 104/ml density.
2.3 the cell inoculation: obtained cell suspension is inoculated on 96 orifice plates, 150ul/ hole (containing 3000/hole of tumor cell).Culture plate is proceeded in constant temperature CO2 incubator, at 37 ℃, cultivate 24 hours under 5%CO2 and saturated humidity condition.
2.4 compound configuration: planted experimentally compound and first with DMSO, be mixed with the storage liquid of 0.01M, then dilute sample as required.
2.5 add test-compound: the 50ul/ hole, cultivate 72 hours, establish 3 parallel holes for every group, and repeated experiments.
2.6 result is measured: compound effects, after 72 hours, adds the MTT of 5mg/ml in 96 orifice plates, and 20 μ L/ holes are placed in incubator and hatch 4 hours, then add three joint-trial agent, light absorption value is surveyed in 50 μ L/ holes at the 570nm place after spending the night.
2.7 try to achieve suppression ratio according to following formula:
2.8 the calculating of IC50: suppression ratio is higher than 50% compound, by SPSS computed in software IC50 value.
3) experimental result
Table 1 is the in vitro cytotoxic effect (IC of fluoro Docetaxel analog to multidrug resistance cell
50μ M) experimental result.
Table 1
Embodiment 2 compound F 17-hydroxy-corticosterone DT(1i) in vitro cytotoxic effect
According to a conventional method, adopt FDT to carry out the test of cell in vitro poison, result shows, HCT116 (human colon cancer cell), Pc3 (Human Prostate Cancer Cells), SGC (people's gastric cancer), the IC of four kinds of tumor cell lines of A2780 (Proliferation of Human Ovarian Cell)
50value reduces by 1 order of magnitude than Docetaxel; And FDT is to the IC of KB multidrug resistance cell strain
50for 23.9nm, the IC of Docetaxel
50for 743.5nm.
Table 2 is inhibited proliferations of 72 hours of FDT tumor cell interaction in vitro.
Table 2
The treatment experiment of embodiment 3 FDT to ICR mice H22 hepatocarcinoma
1. experiment material
1.1 tested material: pharmaceutical college of FDT Fudan University provides;
Pharmaceutical college of Taxol Zhejiang University experimental teaching of medicinal chemistry chamber provides.
1.2 laboratory animal
SPF level ICR kind mice, female, 30, body weight 29 ± 2g.By Si Laike laboratory animal company limited, provided.Laboratory animal production licence: SCXK (Shanghai) 2007-0008.Laboratory animal occupancy permit number: SCXK (Zhejiang) 2007-0098
The animal feeding condition: meet the requirement of SPF level animal facility, 20 ~ 25 ℃ of temperature, humidity 40 ~ 70%, each 12h of illumination light and shade, rate of ventilation is 10 ~ 20 times/hour, freely drink water (urban drinking water), illumination replaces 12h/12h for light and shade round the clock
2. experimental procedure
2.1 inoculation H22 cell
By 5 * 10
6individual H22 cell lumbar injection ICR mice, extract mouse ascites in after inoculation the 7th day, and every mice is in right fore oxter inoculation 0.2mL, and next day, random packet, started administration.
2.2 grouping and administration
30 mices of inoculation H22 tumor strain, be divided into 5 groups at random, is respectively negative control group, FDT 2.5mg/kg group, FDT 5mg/kg group, FDT 10mg/kg group, positive controls Taxol 5mg/kg, and each treated animal is 6.The negative control group lumbar injection is given solvent 0.1ml/10g, FDT 2.5mg/kg group, FDT 5mg/kg group, FDT 10mg/kg group mice give respectively the medicinal liquid 0.1ml/10g of corresponding dosage, the Taxol group is given 0.5mg/ml medicinal liquid 0.1ml/10g, the rear drug withdrawal that is administered twice of each group, within the 8th day, put to death mice, get the tumor piece and weigh, calculate the tumor suppression percentage rate.
3. experimental result shows,
Experimental session, each organizes Mouse Weight without significant change, without animal dead; FDT 2.5mg/kg group has function of tumor inhibition, and tumor is heavily 1.49 ± 0.59g, and tumour inhibiting rate is 27.4%; FDT 5mg/kg group, FDT 10mg/kg group have obvious function of tumor inhibition, and tumor heavily is respectively 1.02 ± 0.48g, 0.95 ± 0.17g, and tumour inhibiting rate is respectively 50.6%, 53.6%, and result is as shown in table 3, Fig. 1.
Table 3 is FDT(i.p.) the growth inhibited effect of mice H22 is treated to experimental result.
Table 3
With matched group, compare,
*p<0.01,
* *p<0.001,
* * * *p<0.00001.
Claims (4)
1. the purposes of fluoro taxane derivatives in preparing the Hepatoma therapy medicine of formula (1),
In formula, R
1for hydrogen atom or fluorine,
R
2for hydrogen atom or fluorine,
R
3for hydrogen atom or fluorine,
R
4for hydrogen atom or fluorine,
R
5for hydrogen atom or fluorine.
2. by purposes claimed in claim 1, it is characterized in that, described fluoro taxane derivatives is following compound,
3. by purposes claimed in claim 1, it is characterized in that, described medicine is the various preparations that comprise safe and effective amount fluoro taxane derivatives and pharmaceutical carrier.
4. by purposes claimed in claim 3, it is characterized in that, described pharmaceutically acceptable carrier is selected from sugar, starch, cellulose and derivant thereof, gelatin, Talcum, kollag, calcium sulfate, vegetable oil, polyhydric alcohol, emulsifying agent, wetting agent, coloring agent, flavoring agent, stabilizing agent, antioxidant, antiseptic or apirogen water.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102851740A (en) * | 2011-06-30 | 2013-01-02 | 复旦大学 | Fluorinated docetaxel crystal and its preparation method |
-
2012
- 2012-06-10 CN CN201210193416.0A patent/CN103479613A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| HONG-FU LU ET AL.: "Synthesis, cytotoxicity, metabolic stability and pharmacokinetic evaluation of fluorinated docetaxel analogs", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 雷景根: "多烯紫杉醇抑制SMMC-7721肝癌细胞的研究", 《实用肿瘤学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102851740A (en) * | 2011-06-30 | 2013-01-02 | 复旦大学 | Fluorinated docetaxel crystal and its preparation method |
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