CN103012540A - 22-drop-6-hydroxystigmast-3,22-O-dimethyloxime ether and 22-drop-6-oximido-stigmast-3,22-O-dimethyloxime ether and application thereof to preparation of antitumor drugs - Google Patents
22-drop-6-hydroxystigmast-3,22-O-dimethyloxime ether and 22-drop-6-oximido-stigmast-3,22-O-dimethyloxime ether and application thereof to preparation of antitumor drugs Download PDFInfo
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Abstract
The invention discloses 22-drop-6-hydroxystigmast-3,22-O-dimethyloxime ether and 22-drop-6-oximido-stigmast-3,22-O-dimethyloxime ether which have the chemical structure formulas described in the specification. Experiments prove that the 22-drop-6-hydroxystigmast-3,22-O-dimethyloxime ether and the 22-drop-6-oximido-stigmast-3,22-O-dimethyloxime ether have remarkable inhibition functions to various tumor cell strains, and can be applied to the preparation of drugs for treating various kinds of cancers.
Description
One, technical field
The present invention relates to 22-falls-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the two methyloxime ether compounds of 22-O-and synthetic method thereof, with and application in preparation treatment cancer drug.
Two, background technology
Cancer medically calls cancer to the malignant tumour that derives from epithelium, 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.
In the research of antitumor drug, once reported some androstene and estrane oxime ether compound, (Dharam Paul Jindal, Raj a Chattopadhaya, Sheetal Guleria, Ranju Gupta.Synthesis and antineoplastic activity of 2-alkylaminoethyl derivatives of various steroidal oximes, 2003, European Journal of Medicinal Chemistry, 38:1025 – 1034), 4-alkene-6-oxime steroidal compounds (Krstic ' a, N.M.; Bjelakovic ', M.S.; Ziz ˇ akb, Z.; Pavlovic, M.D.; Jurani ' c, Z.D.; Pavlovi ' c, V.D.Synthesis of some steroidal oximes, lactams, thiolactams and their antitumor activities, 2007, steroids, 72:406 – 414), 3-carbonyl-4-alkene-6-oxime steroidal compounds, 3-hydroxyl-4-alkene-6-oxime steroidal compounds (Deive, N.; Rodri ' guez, J.; Jime ' nez, C., Synthesis ofcytotoxic 6E-hydroximino-4-ene steroids:structure/activity studies, J.Med.Chem.2001,44,2612-2618; ), 2-hydroxyl-3-carbonyl-Isosorbide-5-Nitrae-diene-6-oxime steroidal compounds (Poza, J.; Rega, M.; Paz, V.; Alonso, B.; Rodri ' guez, J.; Salvador, N.; Ferna ' ndezb A.; Jime ' nez C.Synthesis and evaluation of new6-hydroximinosteroid analogs as cytotoxic agents, Bioorg.Med.Chem.2007,15:4722 – 4740) and 6-alkyl-4-alkene-3-oxime or 6-alkyl-3-oxime steroidal compounds (Jian-Guo Cui, Lei Fan, Li-Liang Huang, Hong-Li Liu, Ai-Min Zhou.Synthesis and evaluation of some steroidal oximes as cytotoxic agents:Structure/activity studies (I) .Steroids, 2009,74 (1), 62-72; Jianguo Cui, Lei Fan, Yanmin Huang, Yi Xin, Aimin Zhou, " Synthesis and evaluation of some steroidal oximes as cytotoxic agents:Structure/Activity Studies (II) ", Steroids.2009,74 (12), 989-995).In the above-claimed cpd some has cytotoxicity external to some tumour cell.But relevant 3, the two methyloxime ethers steroidal compounds of 22-O-have not yet to see report.
Three, summary of the invention
The purpose of this invention is to provide compound 22-falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the two methyloxime ethers of 22-O-.
Another object of the present invention provides the synthetic method of above-claimed cpd.
Further purpose of the present invention provides the application of above-claimed cpd in the preparation antitumor drug.
The present invention is achieved through the following technical solutions above-mentioned purpose: 22-falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, and the two methyloxime ethers of 22-O-have following structural:
22-falls-6-hydroxyl beans steroid-3, and the two methyloxime ether 22-of 22-O-fall-6-oximido beans steroid-3, the two methyloxime ethers of 22-O-
22-of the present invention falls-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, and the two methyloxime ether compounds of 22-O-are oxidized to 4-alkene-3 by Stigmasterol through PCC, the 6-diketone, then with the reduction of 3-position carbonyl and 4-position thiazolinyl, product is further oxidized to beans steroid-3, and the 6-diketone is with beans steroid-3, in the 6-diketone side chain 22, the two key ozonize cracking in 23-position obtain 3,6-dioxo beans steroid-22-aldehyde.Then with 3, in 6-dioxo beans steroid-22-aldehyde 3,22-position carbonyl selectivity first oxime etherificate, obtaining 22-falls-6-oxo beans steroid-3, and the two methyloxime ethers of 22-O-, 22-falls-6-oxo beans steroid-3,6-position carbonyl in the two methyloxime ethers of 22-O-is by reduction and oximate, obtaining respectively target compound 22-falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the two methyloxime ethers of 22-O-.
From Stigmasterol, press following chemical equation synthesising target compound:
Reagent and condition: a:PCC/CH
2Cl
2; B:NaBH
4/ NiCl
26H
2O, CH
3OH; C:Jones reagent/acetone/0 ℃; D:1) O
3/-78 ℃, CH
2Cl
2/ CH
3OH (4:1), 2) Me
2S; E:NH
2OCH
3.HCl/95%EtOH/NaOAc.3H
2O; F:NaBH
4, CH
3OH; G:NH
2OH.HCl/95%EtOH/NaOAc.3H
2O.
Suppressing activity test by cancer cell in vitro shows, 22-of the present invention falls-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, and the two methyloxime ethers of 22-O-have significant restraining effect to cancer cell strains such as various tumor cell strains such as liver cancer, cancer of the stomach.22-of the present invention falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, and the two methyloxime ethers of 22-O-can be used in the medicine of preparation treatment cancer.
The present invention also provides a kind of medicine that is used for the treatment of cancer, and it contains above-mentioned 22-and falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the two methyloxime ether steroidal compounds of 22-O-and pharmaceutically acceptable auxiliary.This medicine can be made the form of injection, tablet, pill, capsule, suspension agent or emulsion and use, and its route of administration can be oral, or through subcutaneous, vein or intramuscular injection.
Four, embodiment
In the invention will be further described by the following examples.
Embodiment 1
22-falls-6-hydroxyl beans steroid-3, the preparation of the two methyloxime ethers 8 of 22-O-
The beans Gona-4-ene-3,6-diketone 2 synthetic
In the reaction flask of 100mL, add Stigmasterol 1200mg, use 15mL CH
2Cl
2After the dissolving, property adding PCC600mg again, the rapid blackening of solution colour.Reaction is at room temperature stirred and is carried out.The TLC monitoring reaction is behind the reaction 48h, without raw material point, stopped reaction.Reactant impouring one silica gel short column is used ethyl acetate drip washing, collects liquid and removes solvent under reduced pressure, column chromatography for separation (eluent: V
Sherwood oil: V
Ethyl acetate=6:1), get faint yellow solid product 2133mg, productive rate 65%, m.p.153 ~ 154 ℃.The spectroscopic data of compound 2: IR (KBr) ν/cm
-1: 2953,2868,1687,1679,1458,1384,1245,1221,1119,972;
1H NMR (500MHz, CDCl
3) δ: 0.758 (s, 3H, 18-CH
3), 0.814 (d, 3H, J=7.0,26-CH
3), 0.822, (t, 3H, J=7.4,29-CH
3), 0.863 (d, 3H, J=6.5,27-CH
3), 1.051 (d, 3H, J=6.5,21-CH
3), 1.183 (s, 3H, 19-CH
3), 2.168 (m, 1H, 7-C
βH), 2.496 (m, 1H, 2-C
αH), 2.590 ~ 2.516 (m, 1H, 2-C
βH), 2.690 (dd, 1H, J=16.0,4.5Hz, 7-C
αH), 5.057 (dd, 1H, J=15.1,8.6,22-CH), 5.167 (dd, 1H, J=15.1,8.6,23-CH), 6.183 (s, 1H, 4-CH).
Beans steroid-3,6-diketone (5) synthetic
At ambient temperature, get 4.12mmol compound 2 and be dissolved in fully in the 100mL anhydrous methanol for 1.75g, wherein add approximately 5mL methylene dichloride hydrotropy, then add the NiCl of 4.12mmol
26H
2O979mg, behind the dissolve complete, the NaBH of disposable adding 13.0mmol
4492mg.The TLC monitoring reaction, react about half an hour after, without raw material point, stopped reaction.With 6M HCl cancellation reaction, the most of methyl alcohol of pressure reducing and steaming is used 30mL ethyl acetate extraction three times, merges organic layer, and organic layer is respectively washed once with distilled water, saturated aqueous common salt successively, anhydrous sodium sulfate drying.Filter, the pressure reducing and steaming solvent obtains solid mixture 3 and 4.Solid mixture 3 and 4 does not need further to separate, and directly uses approximately 100mL acetone solution gained solid, wherein adds approximately 5mL methylene dichloride hydrotropy, then reaction flask is placed ice-water bath, maintains the temperature between 0 to 5 ℃.Dropwise be added dropwise to Jones reagent, and constantly stir, when solution shows orange, stop to add Jones reagent, continue approximately 20min of reaction, the TLC monitoring reaction, without the raw material point, stopped reaction, the pressure reducing and steaming solvent adds little water, with 30mL ethyl acetate extraction three times, merge organic layer, water, saturated aqueous common salt are respectively washed once successively, anhydrous sodium sulfate drying.Filter the pressure reducing and steaming solvent.Column chromatography for separation, eluent: V
Sherwood oil: V
Ethyl acetate=4:1 obtains compound 51.32g, productive rate: 75%; M.p.190 ~ 192 ℃; The spectroscopic data of compound 5: IR (KBr) ν/cm
-1: 2962,2864,1731,1718,1682,1609,972;
1H NMR (500MHz, CDCl
3) δ: 0.736 (s, 3H, 18-CH
3), 0.823 (d, 3H, J=7.5,26-or27-CH
3), 0.829 (t, 3H, J=7.5,29-CH
3), 0.870 (d, 3H, J=6.5,26-or27-CH
3), 0.984 (s, 3H, 19-CH
3), 1.052 (d, 3H, J=6.5,21-CH
3), 2.579 ~ 2.661 (m, 2H, 2-CH
2), 5.058 (dd, 1H, J=15.0,9.022-CH), 5.172 (dd, 1H, J=15.0,8.5,23-CH).
22-falls-3,6-dioxo beans steroid-22-aldehyde (6) synthetic
In the round-bottomed flask of 500mg compound 5 addings with arm, add 16mL methylene dichloride and 4mL methyl alcohol, dissolve complete is placed in the ethyl acetate vacuum flask of cooled with liquid nitrogen, after system temperature is cooled to-78 ℃, passes into and has been rich in O
3Oxygen Flow, the TLC plate is followed the tracks of reaction, developping agent: V
Sherwood oil: V
Ethyl acetate=4:1, solution become and stop to pass into O after light blue
3, continuing to pass into oxygen 20min, the system for the treatment of rises to room temperature, then adds the 3mL dimethyl sulphide, and stirring is spent the night.The most of solvent of pressure reducing and steaming obtains the mixing oily matter of white solid, and this oily matter is with the methylene dichloride dissolving of 60mL, and water, saturated sodium-chloride water solution are washed successively, the organic layer anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains water white oily matter.Rapid column chromatography separates, eluent: V
Sherwood oil: V
Ethyl acetate=4:1 obtains solid chemical compound 6242mg, productive rate 60%.m.p.168~169℃。The spectroscopic data of compound 6: IR(KBr) v/cm
-1: 2931,2871,2734,1709,1463,1386,1265,1227,920.
1H NMR (300MHz, CDCl
3) δ: 0.656 (s, 3H, 18-CH
3), 0.873 (s, 3H, 19-CH
3), 1.039 (d, 3H, J=6.6,21-CH
3), 9.478 (d, 1H, J=3.0,22-CHO);
13C NMR (75MHz, CDCl
3) δ: 12.3,12.5,13.3,21.5,24.3,26.8,36.9,37.3,37.8,37.9,38.9,41.1,43.4,46.4,49.3,50.8,53.2,55.7,57.3,204.6,208.7,211.0.
22-falls-6-oxo beans steroid-3,22-O-dimethyl oxime ether (7) synthetic
100mg compound 6 is dissolved in 20mL95% ethanol, then add sodium acetate trihydrate 79mg (0.58mmol), the heated and stirred dissolving, after dissolving, slowly add methoxy amine hydrochlorate 51mg in batches, approximately add in 10 minutes, the control temperature of reaction is about 65 ℃, and TLC follows the tracks of reaction, stopped reaction after one hour, decompression extracts most of ethanol, a large amount of white solids occur, then adds a little distilled water, the adularescent precipitation generates, with 20mL ethyl acetate extraction three times, merge organic layer, organic layer washes with water successively, saturated aqueous common salt is respectively washed once, then uses anhydrous sodium sulfate drying.Filter, the pressure reducing and steaming solvent obtains white solid.This solid is adopted column chromatography for separation, eluent: V
Sherwood oil: V
Ethyl acetate=8:1 obtains compound 7200mg, productive rate: 67.1%; M.p.170 ~ 122 ℃.The spectroscopic data of compound 7: IR (KBr) ν/cm
-1: 3407,2933,2864,1711,1634,1458,1433,1380,1303,1241,1041;
1H NMR (300MHz, CDCl
3) δ: 0.728 (s, 3H, 18-CH
3), 0.850 (s, 3H, 19-CH
3), 1.047 (d, 3H, J=6.9,21-CH
3), 3.095-3.216 (m, 2H, C
2-β H), 3.818 (s, 3H, 22-=NO-CH
3), 3.839 (s, 3H, 3=NO-CH
3), 6.425 (d, 1H, J=8.1,22-CH);
13C NMR (75MHz, CDCl
3) δ: 12.3,12.4,17.2,20.4,21.4,24.1,26.8,29.6,32.2,37.1,37.8,39.2,41.8,43.1,46.6,53.6,53.8,56.5,57.9,61.2,61.5,155.7,158.3,209.9; HREIMS:m/z403.2959[M+H]
+(calcd for C
24H
39N
2O
3, 403.2961).
-6 hydroxyl beans steroids-3 fall in 22-, 22-O-dimethyl oxime ether (8) synthetic
At ambient temperature, 200mg compound 7 is dissolved in the 20mL anhydrous methanol, wherein adds 2mL methylene dichloride hydrotropy, behind dissolve complete, adds 31mgNaBH in the 20min in batches
4The TLC monitoring reaction, immediately with 1M HCl cancellation reaction, the most of methyl alcohol of pressure reducing and steaming is used 20mL ethyl acetate extraction three times, merges organic layer without raw material point.Organic layer is respectively washed once with distilled water, saturated aqueous common salt, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains white solid, and this solid is adopted column chromatography for separation, eluent: V
Sherwood oil: V
Ethyl acetate=6:1 obtains compound 8126mg, productive rate: 63%; M.p.149 ~ 150 ℃.The spectroscopic data of compound 8: IR (KBr) ν/cm
-1: 3440,2933,2868,2806,1638,1560,1417,1045,886;
1HNMR (300MHz, CDCl
3) δ: 0.742 (s, 3H, 18-CH
3), 1.094 (s, 3H, 19-CH
3), 1.108 (d, 3H, J=8.1,21-CH
3), 2.928 (dd, 1H, J=15.0,3.3, C
2-H), 3.792 (s, 3H, 22-NOCH
3), 3.813 (s, 3H, 3-NO-CH
3), 3.803 ~ 3.831 (m, 1H, 6-CH), 6.420 (d, 1H, J=8.4,22-CH), 7.179 (d, 1H, J=8.4,22-CH);
13CNMR (75MHz, CDCl
3) δ: 12.4,14.9,18.1,20.9,24.3,25.2,27.6,27.8,30.2,32.4,36.1,37.1,39.6,39.8,42.8,42.9,47.8,53.9,55.9,61.0,61.1,61.4,70.9,155.5,160.2.
Embodiment 2
22-falls-6-oximido beans steroid-3, the preparation of the two methyloxime ethers (9) of 22-O-
22-falls-beans steroid-6-oximido-3,22-O-dimethyl oxime ether (9) synthetic
100mg compound 7 is dissolved in 15mL95% ethanol, then adds sodium acetate trihydrate 34mg, the heated and stirred dissolving, disposable adding oxammonium hydrochloride 26mg after the dissolving, the control temperature of reaction is about 65 ℃, and TLC follows the tracks of reaction, stopped reaction after two hours, decompression extracts most of ethanol, a large amount of white solids occur, then adds a little distilled water, the adularescent precipitation generates, add immediately acetic acid ethyl dissolution, use 20mL ethyl acetate extraction three times, merge organic layer.Organic layer washes with water successively, and saturated aqueous common salt is respectively washed once, then uses anhydrous sodium sulfate drying.Filter, decompression extracts solvent, obtains colorless oil.This solid is adopted column chromatography for separation (eluent: V
Sherwood oil: V
Ethyl acetate=6:1) obtain white solid compound 951mg, productive rate: 49.3.%.The spectroscopic data of compound 9: IR (KBr) ν/cm
-1: 3411,2933,2868,1643,1458,1384,1045,906;
1HNMR (300MHz, CDCl
3) δ: 0.713 (s, 3H, 18-CH
3), 0.857 (s, 3H, 19-CH
3), 1.045 (d, 3H, J=6.9,21-CH
3), 3.318 ~ 3.379 (dd, 1H, J=9.3,4.5,2-C
αH), 3.808 (s, 3-OCH
3) 3.846 (s, 3H, 22-OCH
3), 6.434 (d.J=8.1,1H, 22-CH), 7.190 (d.J=8.4,1H, 22-CH), 9.426 (s ,-NOH);
13C NMR (75MHz, CDCl
3) δ: 11.9,12.4,17.8,21.3,24.1,27.6,28.2,29.3,29.7,35.2,36.6,37.1,39.4,43.0,43.1,50.9,53.9,56.4,60.9,61.2,61.5,155.3,157.9,160.6.
Embodiment 3
The present embodiment is to adopt 22-of the present invention to fall-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, and the two methyloxime ether steroidal compounds of 22-O-carry out cell toxicity test to some tumour cell.
Adopt 22-of the present invention to fall-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, and the two methyloxime ethers of 22-O-carry out cell toxicity test to human hepatoma cell strain Bel7404, stomach cancer cell line SGC7901.Adopt the MTT method, carry out vitro cytotoxicity and measure.The 22-that adds different concns in the logarithmic phase cell of cultivating in 96 orifice plates falls-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the two methyloxime ethers of 22-O-, carry out simultaneously 3 parallel tests, compare with control group, cultivate after 72 hours, add MTT, measure its absorbancy, the concentration of compound when calculating respectively inhibition tumor cell and growing into 50% is with IC
50Value representation, the result is as shown in table 1:
Table 122-falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3,22-O-two methyloxime ether anti-tumor activity test result (MTT method, IC
50, μ mol/mL)
Compound 8,9 is carried out the experiment of cell growth inhibition type, and the dead mode that proves cell is to be undertaken by apoptotic mode.Simultaneously, the anti-tumor activity experiment shows in the animal body, and compound 8,9 pairs of ovarian cancers have obvious restraining effect.
Claims (5)
1. a 22-falls-6-hydroxyl beans steroid-3, and the two methyloxime ether steroidal compounds 8 of 22-O-is characterized in that, this structural formula of compound is:
2. a 22-falls-6-oximido beans steroid-3, and the two methyloxime ether steroidal compounds 9 of 22-O-is characterized in that, this structural formula of compound is:
3. 22-as claimed in claim 1 or 2 falls-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the preparation method of the two methyloxime ether steroidal compounds of 22-O-, it is characterized in that, described method is from Stigmasterol, through peroxidation, reduction, ozonize, first oxime etherificate, further is converted into 22-by reduction or the chemical process of oximate and falls-6-hydroxyl beans steroid-3, the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the two methyloxime ethers of 22-O-.
4. 22-as claimed in claim 1 or 2 falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the application of the two methyloxime ether steroidal compounds of 22-O-in the preparation antitumor drug.
5. 22-as claimed in claim 1 or 2 falls-6-hydroxyl beans steroid-3, and the two methyloxime ethers of 22-O-and 22-fall-6-oximido beans steroid-3, the application of medicinal compositions in the preparation antitumor drug that the two methyloxime ether steroidal compounds of 22-O-are activeconstituents.
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| CN103254269A (en) * | 2013-05-19 | 2013-08-21 | 广西师范学院 | A,B-cyclobilactam steroid compound and synthetic method thereof and application A,B-cyclobilactam steroid compound of in preparing antitumor drugs |
| CN111333696A (en) * | 2020-04-07 | 2020-06-26 | 深圳市松懋生物健康有限公司 | Compound for treating gout and preparation method and application thereof |
| CN111333696B (en) * | 2020-04-07 | 2021-09-24 | 华中药业股份有限公司 | Compound for treating gout and preparation method and application thereof |
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