CN102643326B - 3,6-dihydroxyl-22(27)imino-4-furan sterene and preparation method and application thereof - Google Patents
3,6-dihydroxyl-22(27)imino-4-furan sterene and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a compound obtained by shifting 5,6-double bond of solasodine and carrying out functional group conversion, namely 3,6-dihydroxyl-22(27)imino-4-furan sterene. The compound has excellent action of resisting cancer cell growth, is high in activity, and can be used as a raw material for preparing anticancer medicaments for resisting leukaemia, colon cancer, rectum cancer, lung cancer and the like. The invention also provides a preparation method of the compound. The preparation method comprises the step of: based on 3 beta,16 beta-diacetoxy-26-chloro-5-cholestene-22-ketone as a raw material, carrying out 3-acetyl alcoholysis, pyridinium chlorochromate carrier reagent oxidation, reduction, amine cyclization and ring-closing reaction.
Description
Technical field
The present invention relates to a kind of chemical-biological technical field, relate in particular to and a kind of solasodine is carried out structural modification and optimizes the compound obtain, more specifically relate to and a kind of the displacement of 5,6 two keys of Solanum aviculare Forst. amine and functional group thereof are transformed to the compound obtaining.The invention still further relates to a kind of preparation method of above-claimed cpd and the application in preparing cancer therapy drug.
Background technology
Solasodine (following structural formula
1) be the aglycon of the tetrahydroisoquinoline alkaloids such as the main anticancer active constituent solasonine (Solasonine) of black nightshade of one of ten large anticancer herbal drugs and solamargine (Solamargine).The toxicity and the teratogenecity that have due to solasodine and solasonine etc., limited its application clinically, wherein, 5, the existence of 6 two keys is major reasons that teratogenecity produces, a large amount of research is verified, and structural modification is synthetic can reduce its toxicity and teratogenecity, and likely obtains the new derivative with high anti-cancer activity.From published document, can find out, the structural modification of solasodine mainly concentrates on N-alkylation (following structural formula
2, Frederick C. J Org Chem, 1967,32 (3): 792-797), or (following structural formula on 5,6 two keys of reduction
3, Xiaoming Zha, Hongbin Sun, Jia Hao, et al. Chemistry & Biodiversity, 2007,4:25-31), and to the displacement of 5,6 two keys and functional group's conversion, with and the research of the antitumour activity of product not yet relate to so far.
Summary of the invention
For solving the problem of above existence, the object of this invention is to provide a kind ofly to the compound that 5,6 of solasodine two keys are shifted and functional group transforms, this compound has good antitumour activity, especially anti-human colon cancer cell (HT-29).
Another object of the present invention is to provide a kind of preparation method of above-claimed cpd.
A further object of the present invention is to provide the application of a kind of above-claimed cpd in preparing cancer therapy drug.
Provided by the invention to the compound that 5,6 of solasodine two keys are shifted and functional group transforms, i.e. 3,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene, there is following constitutional features:
Wherein, the steric configuration of 3 or 6 hydroxyls can be α configuration, can be also beta comfiguration.
Physico-chemical analysis is measured: the molecular formula of this compound is C
27h
43nO
3, molecular weight is 429.64, and outward appearance is white solid, and fusing point is 212.2-213.8 ℃.
Of the present invention 3,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene is that to take the chloro-5-cholestene-22-of 3 β, 16 β-diacetoxy-26-ketone be raw material; by the alcoholysis of 3-ethanoyl, the oxidation of pyridinium chlorochromate support agent, reduction, amine cyclisation and ring closure reaction are synthetic, obtain, specifically comprise the steps:
(1) with 3 β, the chloro-5-cholestene-22-of 16 β-diacetoxy-26-ketone
ifor raw material, utilize weak base, in the mixed solution of tetrahydrofuran (THF) and methyl alcohol, carry out the hydrolysis of selectivity ester, the chloro-5-cholestene-22-of synthetic compound 3 beta-hydroxy-16 β-acetoxyl group-26-ketone
iI;
(2) by above-claimed cpd
iIbe dissolved in anhydrous CH
2cl
2in, under stirring, adding pyridinium chlorochromate support agent in batches, stirring at room reaction 24-25 hour, has reacted rear decompression desolventizing, through column chromatography purification, obtains the chloro-4-of compound 16 β-acetoxyl group-26-cholestene-3,6,22-triketone
iII, wherein, compound
iIwith the mol ratio of pyridinium chlorochromate support agent be 1:6;
(3) by above-claimed cpd
iIIbe dissolved in the mixed solution of isopyknic tetrahydrofuran (THF) and the formation of methanol, under stirring, slowly add NaBH
4, stirring at room reaction 4-5 hour, adds frozen water after having reacted, and after the desolventizing that extracts, is dried, reduces pressure, obtains compound 3, the chloro-4-cholestene-22-of 6-dihydroxyl-16 β-acetoxyl group-26-ketone
iVcrude product;
(4) by above-claimed cpd
iVcrude product and potassium phthalimide are dissolved in the anhydrous N of new system, in dinethylformamide, under 105 ℃ of oil baths, stir, question response thing is become and is stopped heating after faint yellow from oyster white, after cooling, add saturated aqueous common salt, suction filtration is also used cold water washing, and gained solid is dried and by column chromatography purification, obtained compound 3,6-dihydroxyl-16 β-acetoxyl group-26-Phthalimide base-4-cholestene-22-ketone
v, wherein, compound
iVwith the mol ratio of potassium phthalimide be 1:4;
(5) by above-claimed cpd
vbe dissolved in the mixed solution of formation of isopyknic methylene dichloride and methyl alcohol, stir the lower hydrazine hydrate that slowly drips, react after 15-16 hour and add suitable quantity of water, use CHCl
3extraction, organic phase obtains compound 3 by column chromatography, β-acetoxyl group-22,6-dihydroxyl-16, α-4,27-epimino base-25,22 (N)-cholestadienes through the desolventizing that washs, is dried, reduces pressure
vI, wherein, compound
vwith the mol ratio of hydrazine hydrate be 1:10;
(6) by above-claimed cpd
vIbe dissolved in dehydrated alcohol, add KOH solid, return stirring 24-25 hour, reacted rear cooling and add suitable quantity of water, through extraction, dry, decompression desolventizing, gained residual solid obtains compound 3 through column chromatography, 6-dihydroxyl-22 (27) imido grpup-4-furans steroid alkene
vII, wherein, compound
vIwith the mol ratio of KOH be 1:8.
The present invention 3,6-dihydroxyl-22(27) the concrete synthetic route of imido grpup-4-furans steroid alkene is as follows:
The preferred K of weak base of above-mentioned steps (1)
2cO
3.
The extraction of above-mentioned steps (3) adopts CH
2cl
2extraction, the extraction of step (6) adopts CHCl
3extraction.
Above-mentioned steps (3), step (5), the dry of step (6) are to adopt anhydrous Na
2sO4 or anhydrous MgSO4 are dried.
The washing of above-mentioned steps (3) organic phase is to adopt weak ammonia, saturated aqueous common salt to wash.
The present invention 3,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene is as the application of preparing cancer therapy drug.
Of the present invention 3,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene can be used for the medicine that preparation comprises the kinds cancer diseases such as leukemia, colorectal carcinoma, cancer of the stomach, the rectum cancer, lung cancer, mammary cancer.
Of the present invention 3,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene, there is good antitumour activity, can be used as preparing the raw material of the multiple cancer therapy drugs such as leukemia, colon and rectum carcinoma, lung cancer; In addition, because compound of the present invention is that 5,6 of solasodine two keys are shifted and the conversion of functional group, thereby there is low toxicity and teratogenecity, can be widely used in clinical.
Embodiment
The present invention will be further described to utilize embodiment below, but the present invention is not limited to described embodiment, only otherwise depart from aim of the present invention, all should be included in protection scope of the present invention.
embodiment 1
1, compound 3,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene is synthetic:
(1) with 3 β, the chloro-5-cholestene-22-of 16 β-diacetoxy-26-ketone
ifor raw material, utilize weak base K
2cO
3, in the mixed solution of tetrahydrofuran (THF) and methyl alcohol, carry out 3-acetoxyl group selective hydrolysis (referring to Cheng Shuilian. master thesis, Yunnan University, Kunming, 2007, the 20 pages), obtain the chloro-5-cholestene-22-of 3 beta-hydroxy-16 β-acetoxyl group-26-ketone
iI, productive rate 82%, fusing point: 167.0-168.0 ℃;
(2) pyridinium chlorochromate of silica gel load (PCC) is prepared (referring to Meng Qingyong by concentrated hydrochloric acid, chromium trioxide and silica gel, I expires river Ai Li, and Zhang Li waits quietly. application chemical industry, 2008,37 (3): 314-316), by 4.0 g (8 mmol) compound
iIbe dissolved in the anhydrous CH of 100 mL
2cl
2in, under stirring, add 26 g (48 mmol) PCC support agent in batches, stirring at room reaction 25 hours, reacted rear decompression desolventizing, first through short and thick silicagel column rough segmentation, by silicagel column purifying, obtain the 2.3 g chloro-4-of (4.6 mmol) faint yellow solid compound 16 β-acetoxyl group-26-cholestene-3,6,22-triketone
iII, productive rate 56.3%, fusing point: 181.6-183.1 ℃;
(3) by 2 g (3.96 mmol) compound
iIIbe dissolved in the mixed solution of 10 mL tetrahydrofuran (THF)s and 10 mL the formation of methanols, under stirring, slowly add 0.6 g (15.84 mmol) NaBH
4, stirring at room is reacted approximately 4 hours, adds appropriate frozen water after having reacted, and uses CH
2cl
2extraction, through anhydrous MgSO
4dry, after decompression desolventizing, obtain 1.8 g 3, the chloro-4-cholestene-22-of 6-dihydroxyl-16 β-acetoxyl group-26-ketone
iVcrude product, crude product can directly be done next step reaction;
(4) by 1.5 g (2.94 mmol) compound
iVcrude product and 2.2 g (11.8 mmol) potassium phthalimide is dissolved in the anhydrous N of 25 mL new system, in dinethylformamide, under 105 ℃ of oil baths, stir, question response thing is become and is stopped heating after faint yellow from oyster white, reaction approximately needs 48 hours, after cooling, add 50 mL saturated aqueous common salts, suction filtration is also considered after cake 3 times to obtain micro-band yellow solid with cold water washing, oven dry obtains 1.35 g (2.2 mmol) white solid compound 3 by purification by silica gel column chromatography, 6-dihydroxyl-16 β-acetoxyl group-26-Phthalimide base-4-cholestene-22-ketone
v, productive rate 75%, fusing point: 109.6-111.8 ℃;
(5) by 1 g (1.1.65 mmol) compound
vbe dissolved in the mixed solution of formation of 10 mL methylene dichloride and 10 mL methyl alcohol, stir lower 1 mL (16.5 mmol) hydrazine hydrate that slowly drips, reaction approximately needs 15 hours, adds suitable quantity of water after having reacted, and uses CHCl
3extraction, organic phase is through weak ammonia, saturated common salt water washing, anhydrous Na
2sO4 is dry, and decompression desolventizing also obtains 0.52 g (1.1 mmol) white solid compound 3, β-acetoxyl group-22,6-dihydroxyl-16, α-4,27-epimino base-25,22 (N)-cholestadienes through silica gel column chromatography
vI, productive rate 68%, fusing point: 252.6-254.2 ℃;
(6) by 0.4 g (0.85 mmol) compound
vIbe dissolved in 15 mL dehydrated alcohols, add 0.3 g (6.8 mmol) KOH solid, return stirring approximately 24 hours, has reacted rear cooling and add suitable quantity of water, CHCl
3extraction, anhydrous Na
2sO
4dry, decompression desolventizing gained residual solid obtains 0.2 g (0.5 mmol) white solid compound 3 through silica gel column chromatography, 6-dihydroxyl-22 (27) – imido grpup-4-furans steroid alkene
vII, productive rate 60.1%, fusing point: 212.2-213.8 ℃.
Gained compound 3,6-dihydroxyl-22 (27) – imido grpup-4-furans steroid alkene, its structure is as follows:
Wherein, the steric configuration of 3 or 6 hydroxyls can be α configuration, can be also beta comfiguration, visible, and this compound is that the two keys on 5,6 are transferred on 4,5 by solasodine, and on the 6th, connects many hydroxyls.
, 3,6-dihydroxyl-22 (27) – imido grpup-4-furans steroid alkene chemical structure analysis
13c nucleus magnetic resonance related data (
13c NMR):
（CDCl
3,?125MHz）δ：15.59(CH
3),?16.87(CH
3),?19.96(CH
3),?20.11(CH
3),?21.24(CH
2),?23.06(CH),?30.07(CH),?30.08(CH
2),?31.75(CH),?32.31(CH),?32.48(CH
2),?34.34(CH
2),?34.47(CH
2),?36.45(CH
2),?38.35(C),?40.28(CH
2),?41.16(C),?41.69(CH),?42.54(CH
2),?48.06(CH
2),?54.68(CH),?56.06(CH),?63.22(CH),?68.18(CH,?C
3),?68.70(CH,?C
6),?79.06(CH,?C
16),?98.64(C),?120.67(CH?,?C
4),?149.13(C
5)。
1h nucleus magnetic resonance related data (
1h NMR)
（CDCl
3,?500MHz）δ：?0.81(s?,?3H,?H-19),?0.81-0.85(d?,?3H),?0.93-.095(d?,?3H,?H-21),?1.05(s,?3H,?H-18),?1.25-1.34(m,?3H),?1.42-1.47?(m,?5H),?1.62(m,?2H),?1.69-1.72(m,?7H),?1.88-1.95(m,?4H),?2.03-2.06(m,?3H),?2.58-2.66(m,?3H),?4.19(m,?1H,?H-C
6),?4.27(m,?1H,?H-C
3),?4.28(m,?1H,?H-C
16),?5.67(d，1H，H-C
4)。
:m/z measured value: 430.3282 (M
++ H), calculated value: C
27h
43nO
3(M
++ H): 430.3321.
embodiment 2
3, the 6-dihydroxyl-22 (restraining effect of 27) – imido grpup-4-furans steroid alkene to growth of tumour cell
Active testing concrete operation method: test knurl strain used purchased from Shanghai cell resource center of Sheng Ke institute of the Chinese Academy of Sciences, the 1640 complete culture solutions cultivations containing 10% foetal calf serum for all knurl strains (37 ℃, 5 % CO
2under condition).During test, the cell of logarithmic phase is adjusted into proper concn (suspension cell 6 * 10
4/ mL, attached cell 5 * 10
4/ mL) after, add 96 well culture plates, 90 mL/ holes.Medicine is established 5 concentration, and each concentration is established 3 parallel holes, and 10 mL/ holes make tested concentration be respectively 0.01,0.1,1,10,100 mg/mL; Blank well is 100 mL nutrient solutions, and negative control hole is the nutrient solution that the cell of 90 mL adds 10 mL; Positive control is anticarcinogen cis-platinum.Adherent growth cell wait cultivate 24 hours adherent after dosing; After the inoculation of suspension growth cell, it is dosing.Dosing is placed on 37 ℃, 5% CO
2incubator, cultivate after 48 hours, add tetramethyl-azo azoles salt (5mg/ml), 10 mL/ holes, continue cultivation and add three liquid after 4 hours, 100 mL/ holes, place after 12 hours, by microplate reader, under 570 nm wavelength, measure optical density(OD) (OD) value in each hole, utilize following formula to calculate the growth inhibition ratio of cell:
Growth inhibition ratio (%)=(OD
negative control-OD
medicine feeding hole)/OD
negative control' 100%
Then by LOGIT method, calculate and be subject to the half-inhibition concentration IC of reagent to each growth of tumour cell
50.
Growth of tumour cell is suppressed to result as shown in table 1:
Table 1: antitumour activity test result (IC
50: μ g/mL)
Note: HL60 in above-mentioned table: people's acute myeloblastic leukemia cell strain; K562: people's chronic myelogenous leukemia cell strain; HT-29: human colon cancer cell strain; A549: Non-small cell lung carcinoma cell strain; Bcap-37: human breast cancer cell strain.
As can be seen from the above table, of the present invention 3,6-dihydroxyl-22 (27) imido grpup-4-furans steroid alkene all has good restraining effect to above-mentioned various human cancer cells, and wherein the activity of even best than the current curative effect cis-platinum of anti-human colon cancer cell activity is taller.
Claims (2)
1. 3, a 6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene, has following constitutional features:
Wherein, the steric configuration of 3 or 6 hydroxyls is α configuration or beta comfiguration.
2. 3,6-dihydroxyl-22(27 described in a claim 1) preparation method of imido grpup-4-furans steroid alkene, is characterized in that, described method comprises the steps:
(1) with 3 β, the chloro-5-cholestene-22-of 16 β-diacetoxy-26-ketone
ifor raw material, utilize weak base, in the mixed solution of tetrahydrofuran (THF) and methyl alcohol, carry out the chloro-5-cholestene-22-of selectivity ester hydrolysis compound 3 beta-hydroxy-16 β-acetoxyl group-26-ketone
iI;
(2) by above-claimed cpd
iIbe dissolved in anhydrous CH
2cl
2in, under stirring, adding pyridinium chlorochromate support agent in batches, stirring at room reaction 24-25 hour, has reacted rear decompression desolventizing, through column chromatography purification, obtains the chloro-4-of compound 16 β-acetoxyl group-26-cholestene-3,6,22-triketone
iII, wherein, compound
iIwith the mol ratio of pyridinium chlorochromate support agent be 1:6;
(3) by above-claimed cpd
iIIbe dissolved in the mixed solution of isopyknic tetrahydrofuran (THF) and the formation of methanol, under stirring, slowly add NaBH
4, stirring at room reaction 4-5 hour, adds frozen water after having reacted, and after the desolventizing that extracts, is dried, reduces pressure, obtains compound 3, the chloro-4-cholestene-22-of 6-dihydroxyl-16 β-acetoxyl group-26-ketone
iVcrude product;
(4) by above-claimed cpd
iVcrude product and potassium phthalimide are dissolved in the anhydrous N of new system, in dinethylformamide, under 105 ℃ of oil baths, stir, question response thing is become and is stopped heating after faint yellow from oyster white, after cooling, add saturated aqueous common salt, suction filtration is also used cold water washing, and gained solid is dried and by column chromatography purification, obtained compound 3,6-dihydroxyl-16 β-acetoxyl group-26-Phthalimide base-4-cholestene-22-ketone
v, wherein, compound
iVwith the mol ratio of potassium phthalimide be 1:4;
(5) by above-claimed cpd
vbe dissolved in the mixed solution of isopyknic methylene dichloride and the formation of methanol, stir the lower hydrazine hydrate that slowly drips, react after 15-16 hour and add suitable quantity of water, use CHCl
3extraction, organic phase obtains compound 3 by column chromatography, β-acetoxyl group-22,6-dihydroxyl-16, α-4,27-epimino base-25,22 (N)-cholestadienes through the desolventizing that washs, is dried, reduces pressure
vI, wherein, compound
vwith the mol ratio of hydrazine hydrate be 1:10;
(6) by above-claimed cpd
vIbe dissolved in dehydrated alcohol, add KOH solid, return stirring 24-25 hour, reacted rear cooling and add suitable quantity of water, through extraction, dry, decompression desolventizing, gained residual solid obtains compound 3 through column chromatography, 6-dihydroxyl-22 (27) – imido grpup-4-furans steroid alkene
vII, wherein, compound
vIwith the mol ratio of KOH be 1:8.
3. 3,6-dihydroxyl-22(27 according to claim 2) preparation method of imido grpup-4-furans steroid alkene, is characterized in that: the weak base of described step (1) is K
2cO
3.
4. according to 3, the 6-dihydroxyl-22(27 described in claim 2 or 3) preparation method of imido grpup-4-furans steroid alkene, it is characterized in that: the extraction of described step (3) adopts CH
2cl
2extraction, the extraction of step (6) adopts CHCl
3extraction.
5. 3, the 6-dihydroxyl-22(27 according to claim 4) preparation method of imido grpup-4-furans steroid alkene, is characterized in that: described step (3), step (5), the dry of step (6) are to adopt anhydrous Na
2sO4 or anhydrous MgSO4 are dried.
6. 3, the 6-dihydroxyl-22(27 according to claim 5) preparation method of imido grpup-4-furans steroid alkene, is characterized in that: the washing of described step (5) organic phase is to adopt weak ammonia, saturated aqueous common salt to wash.
7. described in a claim 13,6-dihydroxyl-22(27) imido grpup-4-furans steroid alkene is as preparing the application in leukemia, colorectal carcinoma, lung cancer and breast cancer medicines.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1345728A (en) * | 2000-09-29 | 2002-04-24 | 刘良 | Solasodine hydrochlorate and productive method and application in medicine |
| CN1887900A (en) * | 2006-07-21 | 2007-01-03 | 中国科学院上海有机化学研究所 | Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds |
-
2012
- 2012-04-25 CN CN201210123473.1A patent/CN102643326B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1345728A (en) * | 2000-09-29 | 2002-04-24 | 刘良 | Solasodine hydrochlorate and productive method and application in medicine |
| CN1887900A (en) * | 2006-07-21 | 2007-01-03 | 中国科学院上海有机化学研究所 | Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds |
Non-Patent Citations (3)
| Title |
|---|
| Appl.Chem.》.1994,第66卷(第10/11期),2407-2410. * |
| William Gaffield and Richard F. Keeler.Structure-activity relations of teratogenic natural products.《Pure & * |
| William Gaffield and Richard F. Keeler.Structure-activity relations of teratogenic natural products.《Pure &Appl.Chem.》.1994,第66卷(第10/11期),2407-2410. |
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