CN1727327A - Derivative in hydroxy anthraquinones category and application - Google Patents

Derivative in hydroxy anthraquinones category and application Download PDF

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CN1727327A
CN1727327A CN 200510081655 CN200510081655A CN1727327A CN 1727327 A CN1727327 A CN 1727327A CN 200510081655 CN200510081655 CN 200510081655 CN 200510081655 A CN200510081655 A CN 200510081655A CN 1727327 A CN1727327 A CN 1727327A
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derivative
nhch
cancer
hydroxy anthraquinones
medicine
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古练权
陆豫
符立梧
邓焯安
黄志纾
马林
徐忠宪
陈新滋
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Sun Yat Sen University
National Sun Yat Sen University
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Abstract

A hydroxyl anthraquinone derivative with high suppression action to more kinds of tumor cells and its application in preparing medicine for treating cancers are disclosed.

Description

Derivative in hydroxy anthraquinones category and application thereof
Technical field
The present invention relates to a class derivative in hydroxy anthraquinones category and be used for the treatment of purposes in the medicine of cancer in preparation.
Technical background
Cancer is to one of human health and the dangerous maximum disease of quality of life.Seeking efficient, highly selective and the little cancer therapy drug of side effect is the main direction of cancer therapy drug exploitation.
The contained hydroxyanthraquinone compounds of multiple herbal medicine has been found has certain anti-tumor activity, mainly is that the DNA of anticancer is synthetic.For example, to people's young white corpuscle (HL-60) morning, murine sarcoma, knurl strains such as mouse hepatoma growth has restraining effect, [Huang Taikang chief editor, herbal medicine composition commonly used and pharmacology handbook, P1225,1994, Chinese Medicine science and technology press]. but because the anti-tumor activity of natural hydroxyanthraquinone compounds is not high enough, fail at present to use as cancer therapy drug clinically.
Summary of the invention
The purpose of this invention is to provide new derivative in hydroxy anthraquinones category, this analog derivative synthetic and be used for the treatment of application in the medicine of cancer in preparation.
Hydroxyanthraquinone derivative of the present invention is with shown in the following formula I:
Figure A20051008165500031
Formula I
R among the formula I 1, R 2, R 3The group of representative is one of and the following combination:
(1) R 1Be CH 2N 3Or CH 2NH 2R 2Be OCH 3R 3Be CH 3
(2) R 1Be CH 2N 3Or CH 2NH 2R 2Be OH; R 3Be CH 3
(3) R 1Be CH 2N 3Or CH 2NH 2R 2Be OCH 3R 3Be H.
(4) R 1Be CH 2N 3Or CH 2NH 2R 2Be OH; R 3Be H.
(5) R 1Be CH 3R 2Be NHCH 2CH 2N (CH 3) 2, NHCH 2CH 2CH 2N (CH 3) 2, NHCH 2CH 2N (CH 2CH 2OCH 2CH 2), NHCH 2CH 2N (CH 2CH 3) 2, NHCH 2CH 2CH 3N (CH 2CH 3) 2, NHCH 2CH 2N (CH 2) 4Or NHCH 2CH 2N (CH 2) 5R 3Be CH 3
Derivative in hydroxy anthraquinones category of the present invention can be obtained through chemically modified (promptly 6 and 8 to natural hydroxyanthraquinone compounds transform, and for example 6,8 at natural hydroxyanthraquinone introduce nitrogenous group) by natural hydroxyanthraquinone compounds.
Said natural hydroxyanthraquinone compounds comprises Schuttgelb (emodin) and rheochrysidin (physcion) etc., can hold from tiger, extracts in the herbal medicine such as rheum officinale, through separation and purifying and make.
The reaction for preparing derivative in hydroxy anthraquinones category of the present invention is shown in following reaction formula:
Figure A20051008165500041
Show by the cancer cell in vitro inhibition test, derivative in hydroxy anthraquinones category of the present invention to various tumor cell strains such as oral cavity at the bottom of cancer, mammary cancer, nasopharyngeal carcinoma, leukemia etc. significant inhibitory effect is arranged, normal cytotoxicity is then significantly reduced.Especially cancer at the bottom of the oral cavity (KBS) and mammary cancer cancer cells such as (MCF-7/S) had very strong cytotoxicity; Cytotoxicity (IC to cancer at the bottom of the oral cavity (KB) 50) than more than the natural hydroxyanthraquinone chemical combination object height 100 μ g/ml, normal cytotoxicity has then been descended 80%.Therefore derivative in hydroxy anthraquinones category of the present invention can be used for preparing the medicine for the treatment of cancer.
The present invention also provides a kind of medicine that is used for the treatment of cancer, and it contains the derivative in hydroxy anthraquinones category and the pharmaceutically acceptable auxiliary of the invention described above.This medicine can be made the form of injection, tablet, pill, capsule, suspension agent or emulsion and use, and that its route of administration can be is oral, through skin, vein or muscle.
Embodiment
The invention will be further described by the following examples
Embodiment one: the extraction of natural hydroxyanthraquinone compounds Schuttgelb and rheochrysidin, separate and purifying
Take by weighing the battle of 1kg tiger, pulverized 20 mesh sieves, use 95% industrial spirit, refluxing extraction secondary in water-bath, merging filtrate, concentrating under reduced pressure add 3Mol to 500ml.Sulfuric acid 100-500ml adds 1500ml water behind the backflow 0.5-1h, standing over night, and the suction filtration drying gets the 180g pink powder.The red powder that obtains is put into apparatus,Soxhlet's, with ether extraction to the apparatus,Soxhlet's ether near colourless, earlier with 5% (w/w) NaHCO 3Solution (6 * 100ml), the extraction ether layer, water is abandoned.Use 5% (w/w) Na again 2CO 3(8 * 100ml), the extraction ether layer merges preceding 2 * 100ml extraction liquid 5Mol to solution.Hydrochloric acid is transferred PH＜4, filter, dry, through the acetone crystallization, orange crystallization 2.75g compound-Schuttgelb (1).(6 * 100ml) use and handle to such an extent that Schuttgelb and rheochrysidin (1) and (2) mixture extract with apparatus,Soxhlet's with quadrat method again remaining extraction liquid, and (5 * 100ml) extract extraction liquid 5Mol to ether layer with 1%NaOH solution.Hydrochloric acid is transferred PH＜4, filters, drying obtains yellow crystal 0.61g compound rheochrysidin (2), and product structure is through IR, MMR, M 3Determine with the ultimate analysis data.
Schuttgelb, orange red needle-like crystal, m.p.254-256 ℃ of IR (KBr) 3300,1675,1625; 1H NMR (DMSO-d 6/ TMS, 500MHz) δ: 2.351 (s, 3H), 6.503 (d, J=2.5,1H), 7.007 (d, J=2.5,1H), 7.022 (s, 1H), 7.336 (s, 1H), 11.255 (br., 1H), 11.879 (s, 1H), 11.960 (s, 1H); FAB-Ms m/z 271[M+1] +Anal.Calcd for C 15H 10O 5: C 66.67, and H 3.73, found C 66.73, H 3.69.
Rheochrysidin, yellow needle-like crystal m.p.200-202 ℃, IR (KBr): 3400,1674,1635; 1H NMR (DMSO-d 6/ TMS, 500MHz) δ: 2.412 (s, 3H), 3.923 (s, 3H), 6.825 (d, J=2.5,1H), 7.140 (d, J=2.5,1H), 7.16 (s, 1H), 7.48 (s, 1H), 11.91 (s, 1H), 12.11 (s, 1H); FAB-Ms m/z285[M+1] +Anal.Calcd forC 16H 12O 5: C 67.60, and H 4.26, found C 67.53, H 4.22.
Figure A20051008165500051
Embodiment two: the preparation of intermediate product (3)
Take by weighing 4.2g (15.6mmol) Schuttgelb, the anhydrous K after grinding 2CO 316g (28.6mmol) adds Me 2SO 45ml (50mmol), acetone 380ml, stirring and refluxing 5-20h concentrates, and adds the water stirring, filters, and with a small amount of cold third cave washing, gets pale yellow powder (3) 4.4g, productive rate 90.5%.Product structure is through IR, MMR, M 3Determine with the ultimate analysis data.m.p.225-227℃，IR(KBr)υ：1661，1600，1564，1321，1245。 1H?NMR(CDCl 3/TMS，500MHz)δ：2.467(s，3H)，3.950(s，3H)，3.962(s，3H)，3.984(s，3H)，6.763(d，J＝2.5，1H)，7.094(s，1H)，7.320(d，J＝2.5，1H)，7.640(s，1H)；FAB-Ms?m/z?313[M+1] +；Anal.Calcd?for?C 18H 16O 5：C?69.22，H?5.16，found?C?69.31，H?5.12.
Embodiment three: the preparation of intermediate product (4)
Take by weighing 4.0g (6.4mmol) and 2.0g (3.5mmol), 1,3-two bromo-5,5-dimethyl hydantoin (BDH) adds 200-500ml CCl 44, behind the thermosol, adding the 0.6g Benzoyl Peroxide again, stirring and refluxing 6-15h filters, and solid separates (ethyl acetate: benzene=10: 90) get pale yellow powder (4) 2.8g, productive rate 56.0% with hot wash 2 times, dry, silica gel column chromatography.Product structure is through IR, MMR, M 3Determine with the ultimate analysis data.m.p?250-252℃，IR(KBr)υ：1665，1597，1334，1245； 1HNMR(CDCl 3/TMS，500MHz)δ：3.962(s，3H)，3.971(s，3H)，4.023(s，3H)，4.523(s，2H)，6.779(d，J＝2.5，1H)，7.309(s，1H)，7.328(d，J＝2.5，1H)，7.832(s，1H)；FAB-Ms?m/z?391[M+1] +；Calcd?forC 18H 15BrO 5：C?55.26，H?3.86，found?C?55.38，H?3.83.
Embodiment four: intermediate product (5-1) and (5-2) preparation of mixed isomers
Take by weighing 2.0g (5.1mmol) (4) and add 100-400ml exsiccant methylene dichloride, in ice-water-bath, add 6ml 1molBBr 3/ H 2CCl 2Solution, stirring reaction 2-6h under the room temperature, reactant are poured in the 200g ice, treat that ice dissolves after, with chloroform 200ml * 2 extractions, MgSO 44Dry, filter, concentrate, silica gel column chromatography separates (chloroform), pale yellow powder product (5-1) and (5-2) mixed isomers 1.64g, productive rate 85.0%.Product structure is through IR, MMR, M 3Determine .m.p.200-202 ℃ with the ultimate analysis data, IR (KBr) υ: 3400,1624,1564,1344,1303. 1H NMR (CDCl 3/ TMS, 500MHz) δ: 3.926 (s, 3H), 4.087 (s, 3H), 4.535 (s, 2H), 6.728 (d .J=2.5,1H), 7.261 (d, J=2.5,1H), 7.291 (s, 1H), 7.987 (s, 1H); δ: 4.004 (s, 3H), 4.037 (s, 3H), 4.464 (s, 2H), 6.803 (d, J=2.5,1H), 7.259 (s, 1H), 7.478 (d, J=2.5,1H), 7.763 (s, 1H), FAB-Ms m/z 377[M+1] +Calcd for C 17H 13BrO 5: C 54.13, and H 3.47, found C 54.21, H 3.50.
Embodiment five: the preparation of intermediate product (6)
Take by weighing 2.4g (6.1mmol) (4) and add 100-200ml CH 3COOH and 16ml 33% HBr/CH 3COOH, reflux 3-66h, cooling is filtered, wash with water, dry, silica gel column chromatography separates (chloroform), pale yellow powder product (6) 1.84g, productive rate 82.1%.Product structure is through IR, MMR, M 3Determine .m.p 247-249 ℃ with the ultimate analysis data, IR (KBr) υ: 3400,1631,1620. 1H NMR (DMSO-d 6/ TMS, 500MHz) δ: 3.951 (s, 1H), 4.751 (s, 2H), 6.863 (d .J=2.5,1H), 7.190 (d .J=2.5,1H), 7.431 (s .1H), 7.748 (s, 1H), 11.990 (s, 1H), 12.083 (s, 1H); FAB-Ms m/z363[M+1] +Calcd for C 16H 11BrO 5: C 52.92, and H 3.05, found C 52.85, H 3.02.
Embodiment six: 6-azido-methyl 1,3, the preparation of 8-trimethoxy-9,10 anthraquinone (7)
Take by weighing 0.18g (1.2mmol) AgN of 400mg (1mmol) (4) and new system 3, add 200-500ml acetone, reflux 5h, filtering and concentrating is separated (chloroform) with silica gel column chromatography, gets pale yellow powder product (7) 340mg, productive rate 94.0%.Product structure is through IR, MMR, M 3Determine .m.p.179～180 ℃, IR (KBr) υ: 3430,2107,1667,1600 with the ultimate analysis data; 1H NMR (CDCl 3/ TMS, 500MHz) δ: 3.961 (s, 3H), 3.973 (s, 3H), 4.026 (s, 3H), 4.494 (s, 2H), 6.781 (d, J=2.5,1H), 7.251 (s, 1H), 7.331 (d, J=2.5,1H), 7.754 (s, 1H); FAB-MS m/z (%) 354 ([M+1] +Anal.Calcd for C 18H 15N 3O 5: C 61.19, and H 4.28, and N 11.89; Found C 61.25, H 4.32, and N 11.82.
Can prepare (8) and (9) with quadrat method
Embodiment seven: 6-aminomethyl-1,2,3, the preparation of 8-trimethoxy-9.10 anthraquinone (10)
Take by weighing 100mg (0.28mmol) (7) and add 40ml ethyl acetate and 5mg 10% Pd/C, normal temperature and pressure hydrogenation 48h, filtering and concentrating, separate (chloroform: methyl alcohol=98: 2) with silica gel column chromatography, get pale yellow powder (10) 71mg, productive rate 76.6% is transformed into hydrochloride, m.p.228.5～230.5 ℃ d.IR(KBr)υ：3420，3122，1645，1596； 1H?NMR(D 2O/TMS，500MHz)δ：3.693(s，3H)，3.707(s，3H)，3.861(s，3H)，4.320(s，2H)，6.685(d，J＝2.5，1H)，6.794(s，1H)，7.530(d，.J＝2.5，1H)，7.829(s，1H)；FAB-MS?m/z(％)328([M+1] +；Anal?Calcd?for?C 18H 18NO 5ClC?59.43?H?5.00?N?3.85；found?C?59.50?H.5.04?N3.89
Get (11) with quadrat method, (12) and (13) compound.
Embodiment eight: intermediate product 8-hydroxyl-1,3-dimethoxy-6-methyl-9,10 anthraquinone (14)) preparation
Take by weighing 4.0g (14.8mmol) Schuttgelb, the anhydrous K after grinding 2CO 38g (14.3mmol) adds Me 2SO 43ml (30mmol), acetone 100-600ml, 40 ℃ are stirred 8-24h, filter, and concentrate, and separate (chloroform) with silica gel column chromatography, and recrystallization gets pink powder (3) 3.2g, productive rate 72.56%.Product structure is through IR, MMR, M 3Determine .m.p.215-217 ℃ with the ultimate analysis data, IR (KBr) υ: 3314,1630,1610; 1H NMR (CDCl 3/ TMS, 500MHz) δ: 2.433 (s, 3H), 3.994 (s, 3H), 4.032 (s, 3H), 6.791 (d, J=2.5,1H), 7.080 (s, 1H), 7.468 (d, J=2.5,1H), 7.573 (s, 1H); FAB-MS m/z (%) 299 ([M+1] +Anal.Calcd for C 17H 14O 5: C 68.45, and H 4.73, found C 68.51, and H 4.70.
Embodiment nine: intermediate product 8-p-toluenesulfonyl-1.3-dimethoxy, the preparation of-6-methyl-9.10 anthraquinone (15)
Take by weighing 0.53g (14) and (1.8gmmol) add 0.3g (1.6mmol) Tosyl chloride and 350ml acetone and 2.5g K 2CO 3Backflow 5h, filtering and concentrating is with silica gel column chromatography (hexanaphthene: ethyl acetate=7: 3) separate, get pale yellow powder 0.72g, productive rate 90%.Product structure is through IR, MMR, M 3Determine .m.p.215～217 ℃, IR (KBr) υ: 1678,1600 with the ultimate analysis data; 1351,1311,1193,1176, 1H NMR (CDCl 3/ TMS, 500MHz) δ: 2.385 (s, 3H), 2.446 (s, 1H), 3.922 (s, 3H), 3.958 (s, 3H), 6.745 (d, J=2.5,1H), 7.274 (d, J=8.5,2H), 7.306 (d, J=2.5,1H), 7.423 (s, 1H), 7.901 (d, J=8.5,2H), 7.962 (s, 1H); FAB-MS m/z452[M+1] +Anal.Calcd for C 24H 20O 5S:C 63.71, and H 4.46; Found C63.62, H 4.43.
Embodiment ten: 8-[2-(N.N-dimethylamino) ethyl] preparation of amino-1.3-dimethoxy-6-methyl-9.10 anthraquinone (16)
Take by weighing 200mg (0.44ml) (16) and add 20-50ml DMSO (dimethyl sulfoxide (DMSO)) and 0.12g (1.4mmol) N, N-dimethyl aminoethyl amine is at N 2Under the gas shiled, heat 150 ℃ of stirring reaction 5h, add 200g ice, treat ice-out, use ethyl acetate extraction three times, the combined ethyl acetate layer washes secondary with water, anhydrous Na 2SO 4Dry, silica gel column chromatography (chloroform: methyl alcohol=95: 5) separate, get 90mg product (16), productive rate 56.3%.Product structure is through IR, MMR, M 3Determine .m.p.158～160 ℃, IR (KBr) υ: 3265,1629,1596,1319,1238 with the ultimate analysis data; 1H NMR (CDCl 3/ TMS, 500MHz) δ: 2.340 (s.6H), 2.395 (s .3H), 2.659 (t, J=7.0,2H), 3.415 (m .J=7.0,5.0,2H), 3.957 (s, 3H), 3.996 (s, 3H), 6.776 (d, J=2.5., 1H), 6.849 (s, 1H), 7.349 (s, 1H), 7.403 (d, J=2.5,1H), 9.716 (t, J=5.0,1H); FAB-MS m/z (%) 369 ([M+1] +Anal.Calcd for C 21H 24N 2O 4: C 68.46, and H 6.57, and N 7.60; Found C 68.52, H 6.52, and N 7.65.
Can prepare (17) with quadrat method, (18), (19), (20), (21), compounds such as (22).
Embodiment 11: hydroxyanthraquinone and derivative thereof are to the restraining effect of tumor cell line growth
JEG-3 (KB) at the bottom of selecting part derivative in hydroxy anthraquinones category of the present invention and natural hydroxyl quinone to human oral, human breast cancer cell strain (MFC-7), (MDA-MB231) and the cytotoxicity of human nasopharyngeal carcinoma cell line (CNE-2).Adopt mtt assay, carry out the cell in vitro poison and measure.The logarithmic phase cell adds the derivative in hydroxy anthraquinones category of different concns, behind the effect 72h, measures its absorbancy.Calculate cell growth inhibiting respectively and reach 50% o'clock compound concentration, with IC 50Value representation, the result is as shown in table 1.
Table 1: natural hydroxy anthraquinones deutero-of part and natural hydroxyanthraquinone be to KB, MCF-7, the cytotoxicity of CNE-2 and MDA-MB231
IC 50(μg/ml)
Figure A20051008165500081

Claims (4)

1. the derivative in hydroxy anthraquinones category shown in the formula I:
Figure A2005100816550002C1
Formula I
R among the formula I 1Be CH 3R 2Be NHCH 2CH 2N (CH 3) 2, NHCH 2CH 2CH 2N (CH 3) 2, NHCH 2CH 2N (CH 2CH 2OCH 2CH 2), NHCH 2CH 2N (CH 2CH 3) 2, NHCH 2CH 2CH 2N (CH 2CH 3) 2, NHCH 2CH 2N (CH 2) 4Or NHCH 2CH 2N (CH 2) 5R 3Be CH 3
2. the described derivative in hydroxy anthraquinones category of claim 1 is used for the treatment of application in the medicine of cancer in preparation.
3. medicine that is used for the treatment of cancer, it contains described derivative in hydroxy anthraquinones category of claim 1 and pharmaceutically acceptable auxiliary.
4. medicine according to claim 3 is characterized in that this medicine is injection, tablet, pill, capsule, suspension agent or emulsion.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478399A (en) * 2016-08-31 2017-03-08 中国科学院海洋研究所 Derivative in hydroxy anthraquinones category and its application
CN107213144A (en) * 2017-05-31 2017-09-29 潘小平 The purposes of Physcion and its derivative in antineoplastic is prepared
CN109608369A (en) * 2018-12-24 2019-04-12 广西大学 Sulphonyl ester group anthraquinone derivatives and its preparation method and application

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* Cited by examiner, † Cited by third party
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CN1014526B (en) * 1988-01-15 1991-10-30 广东省农业科学院经济作物研究所 Biotechnology for fleshen transformation of starch and its application

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478399A (en) * 2016-08-31 2017-03-08 中国科学院海洋研究所 Derivative in hydroxy anthraquinones category and its application
CN106478399B (en) * 2016-08-31 2019-01-08 中国科学院海洋研究所 Derivative in hydroxy anthraquinones category and its application
CN107213144A (en) * 2017-05-31 2017-09-29 潘小平 The purposes of Physcion and its derivative in antineoplastic is prepared
CN109608369A (en) * 2018-12-24 2019-04-12 广西大学 Sulphonyl ester group anthraquinone derivatives and its preparation method and application

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