CN105037427B - Tanshinone IIA ethylenimine phosphate derivative and preparation method and application - Google Patents
Tanshinone IIA ethylenimine phosphate derivative and preparation method and application Download PDFInfo
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- CN105037427B CN105037427B CN201510344170.6A CN201510344170A CN105037427B CN 105037427 B CN105037427 B CN 105037427B CN 201510344170 A CN201510344170 A CN 201510344170A CN 105037427 B CN105037427 B CN 105037427B
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- ethylenimine
- tanshinone iia
- phosphate derivative
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- compound
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Abstract
The present invention discloses a kind of tanshinone IIA ethylenimine phosphate derivative.The structure such as formula of tanshinone IIA ethylenimine phosphate derivative of the invention（I）、（II）With（III）It is shown.In formula, X is O, S.Purposes the invention further relates to the preparation method of such compound and in oncotherapy.
Description
Technical field
The present invention relates to tanshinone IIA ethylenimine phosphate derivative and preparation method thereof and answering as anticarcinogen
With.
Background technology
The red sage root is using one of earliest and widest medicine, its liposoluble constituent red sage root in China's traditional medicine pharmacy
Ketone IIA has phenanthrenequione structure, and its phenanthrene ring can be combined with DNA, and furan nucleus and quinones structure may result from, by base, causing DNA damage,
Suppress DNA of tumor cell synthesis.Tanshinone IIA can also be shown by inducing apoptosis of tumour cell, research, the red sage root of 5 μ g/mL
Ketone IIA, the inhibiting rate to P388 lymphocytic leukemia cells is 50.05%（Nicholson DW. Nature, 2001,
410:33-34）, can induce HL60 cell DNAs and be cracked into small fragment.
To being found in the chlormethine series pharmaceuticals with antitumaous effect in vivo bioconversion research, such medicine is by transformation
Alkylating is played for ethylenimine reactive intermediate, thus, the ethylenimine phosphamide of low toxicity is have developed
Derivative is mainly used in the treatment of breast cancer, oophoroma, liver cancer, carcinoma of urinary bladder for group and phosphinothioylidynetrisaziridine on both clinical drugs.
The present invention the phenanthrene ring of tanshinone IIA, furan nucleus and quinones structure it is constant on the premise of, using principle of hybridization, will
Ethylenimine reactive intermediate with alkylation function is spliced in the structure of tanshinone IIA, has obtained anticancer effect good
, the tanshinone IIA ethylenimine phosphate derivative that toxicity is low.
The content of the invention
It is an object of the invention to provide a kind of tanshinone IIA ethylenimine phosphate derivative, it has good
Active anticancer, and toxicity is relatively low.
Preparation side another object of the present invention is to provide above-mentioned tanshinone IIA ethylenimine phosphate derivative
Method.
It is still another object of the present invention to provide the purposes of above-mentioned tanshinone IIA ethylenimine phosphate derivative.
The present invention will be described in detail below.
The present invention provides formula（I）、（II）With（III）Tanshinone IIA ethylenimine phosphate derivative, structure is such as
Shown in lower：
In formula, X is O, S.
Preferably, tanshinone IIA ethylenimine phosphate derivative of the invention is selected from following compound.
Present invention also offers above-mentioned formula（I）、（II）With（III）Compound preparation method, step includes：
In formula, X is O, S.
Tanshinone IIA ethylenimine phosphate derivative of the invention has significant active anticancer and low toxicity.
The present invention is further illustrated by following examples, but should be noted that the scope of the present invention is not implemented by these
Any limitation of example.
Specific embodiment
Embodiment 1
Compound（1）Preparation：
By 0.95g (0.022mol) Ethylenimines and 2.22g (0.022mol) Et3N is dissolved in 15mL dichloromethane, is cooled to
0 DEG C, the POCl of 1.52g (0.01mol) is added dropwise3Or the PSCl of 1.68g (0.01mol)3With the solution of 5mL dichloromethane, drip
Finish, room temperature reaction 3 hours, filtering, concentration, vacuum distillation obtains diethylene imines phosphoryl chloride phosphorus oxychloride or diethylene phosmet acyl chlorides,
Yield is respectively 79% and 81%.
3.10g (0.01mol) 1- hydroxyl tanshinone IIAs are dissolved in 15mL dichloromethane, 1.11g is added
(0.011mol)Et3N, is cooled to 0 DEG C, and the diethylene imines phosphoryl chloride phosphorus oxychloride that 1.83g (0.011mol) is added dropwise is molten with 8mL dichloromethane
Liquid, completion of dropping, room temperature reaction 7 hours, filtering, concentration, column chromatography purifying obtains compound（1）, yield 81%.1H NMR
（300MHz, CDCl3）δ7.70-7.60(m,2H), 7.22(s,1H), 5.01(m,1H), 2.07(m,1H), 1.94(s,
3H),1.84(m,1H), 1.66(m,1H), 1.63(t,J = 4.2Hz,8H), 1.40(m,1H), 1.38(s,6H)。
Embodiment 2
Compound（2）Preparation：
By the diethylene imines phosphoryl chloride phosphorus oxychloride of 1.83g (0.011mol) in embodiment 1 diethylene of 2.00g (0.011mol)
Phosmet acyl chlorides replaces, and other operations obtain compound with embodiment 1（2）, yield 83%.1H NMR（300MHz, CDCl3）δ
7.70- 7.60(m,2H), 7.22(s,1H), 4.97(m,1H), 2.07(s, 3H), 1.90(m,1H),1.63-1.65
(m,2H),1.63(t,J= 4.2Hz,8H),1.40(m,1H), 1.38(s, 6H)。
Embodiment 3
Compound（3）Preparation：
3.10g (0.01mol) 17- hydroxyl tanshinone IIAs are dissolved in 15mL dichloromethane, 1.11g is added
(0.011mol)Et3N, is cooled to 0 DEG C, and the diethylene imines phosphoryl chloride phosphorus oxychloride that 1.83g (0.011mol) is added dropwise is molten with 7mL dichloromethane
Liquid, completion of dropping, room temperature reaction 7 hours, filtering, concentration, column chromatography purifying obtains compound（3）, yield 78%.1H NMR
（300MHz, CDCl3）δ7.69-7.56(m,2H), 7.24(s,1H), 5.29(s,2H), 3.05(m,2H), 1.67(t,J=
4.2Hz,8H), 1.63(m,2H),1.57(m,2H), 1.30(s,6H)。
Embodiment 4
Compound（4）Preparation：
By the diethylene imines phosphoryl chloride phosphorus oxychloride of 1.83g (0.011mol) in embodiment 3 diethylene of 2.00g (0.011mol)
Phosmet acyl chlorides replaces, and other operations obtain compound with embodiment 3（4）, yield 80%.1H NMR（300MHz, CDCl3）δ
7.69-7.55(m,2H), 7.24(s,1H), 5.11(s,2H), 3.05(m,2H), 1.67(t,J= 4.2Hz,8H),
1.63(m,2H),1.56(m,2H), 1.30(s,6H)。
Embodiment 5
Compound（5）Preparation：
3.24g (0.01mol) 15- methylene hydroxyl tanshinone IIAs are dissolved in 15mL dichloromethane, 1.11g is added
(0.011mol)Et3N, is cooled to 0 DEG C, and the diethylene imines phosphoryl chloride phosphorus oxychloride that 1.83g (0.011mol) is added dropwise is molten with 7mL dichloromethane
Liquid, completion of dropping, room temperature reaction 8 hours, filtering, concentration, column chromatography purifying obtains compound（5）, yield 81%.1H NMR
（300MHz,CDCl3）δ7.62-7.53(m,2H), 5.17(s,2H), 2.95(m,2H), 2.09(s,3H), 1.67(t,J=
4.2Hz,8H), 1.64(m,2H), 1.56(m,2H),1.30(s,6H)。
Embodiment 6
Compound（6）Preparation：
By the diethylene imines phosphoryl chloride phosphorus oxychloride of 1.83g (0.011mol) in embodiment 5 diethylene of 2.00g (0.011mol)
Phosmet acyl chlorides replaces, and other operations obtain compound with embodiment 5（6）, yield 78%.1H NMR（300MHz, CDCl3）δ
7.62-7.53(m,2H), 4.97(s,2H), 2.95(m,2H), 2.09(s,3H), 1.67(t,J= 4.2Hz,8H),1.63
(m,2H), 1.56(m,2H),1.30(s,6H)。
Embodiment 7
Inhibitory action of the tanshinone IIA ethylenimine phosphate derivative to Lewis lung cancer
C57BL/6 mouse, male and female half and half, 18-20g.Right fore oxter subcutaneous vaccination Lewis lung cancer entity tumors.Inoculation
First day afterwards, animal was randomly divided into 5 groups, every group 10.Model group intraperitoneal injection 0.4mL/ physiological saline, the positives only is given respectively
The cis-platinum of control group intraperitoneal injection 1mg/kg, tanshinone IIA ethylenimine phosphate derivative group intraperitoneal injection 20mg/kg
Ethylenimine phosphate derivative.Continuous injection 5 days, takes each group animal tumor on the 11st day, weighs quality, calculates tumor suppression
Rate.Result shows, each administration group compared with control group, average knurl gum fraction（Table 1）.
Embodiment 8
Inhibitory action of the tanshinone IIA ethylenimine phosphate derivative to breast cancer MDA-MB-231 cells
MDA-MB-231 cells are selected in experiment, and its cell concentration is 5 × 105/ mL exponential phase tumour cells, by every hole
100 μ L are inoculated in 96 well culture plates.Put 37 DEG C, 5%CO2In incubator after culture 24h, 0.25 μ g/mL concentration is separately added into
Tanshinone IIA and tanshinone IIA ethylenimine phosphate derivative, it is every kind of if the μ g/mL of tanshinone IIA 0 are blank
Compound sets 4 each multiple holes, after effect 48h, adds the MTT liquid of new configuration, puts 37 DEG C, 5%CO2Added after culture 6h in incubator
DMSO, acts on 15min, puts in ELIASA, selects wavelength 570nm, measures the absorbance A of each group570.Calculate cell inhibitory rate.Suppression
Rate processed（%）=（1- experimental groups A570/ control group A570）×100%.Result shows that blank control group increases in normal logarithm, each reality
Test group tanshinone IIA and tanshinone IIA ethylenimine phosphate derivative has to breast cancer MDA-MB-231 cell growths
Significant inhibitory action（Table 2）.
Claims (2)
1. a kind of tanshinone IIA ethylenimine phosphate derivative, it is characterised in that：The compound is for lung cancer and mammary gland
Cancer cell has active anticancer, and it has the structure of following formula,
。
2. application of the compound described in claim 1 in anti-lung cancer and anti-breast cancer medicines are prepared.
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| CN101974068B (en) * | 2005-10-25 | 2011-08-10 | 秦引林 | Tanshinon IIA crylic acid or sodium salt thereof, preparation method and application thereof |
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