CN102643326A - 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 a kind of displacement and functional group thereof and transform the compound that obtains 5,6 two keys of Solanum aviculare Forst. amine.The invention still further relates to a kind of preparation method and the application in the preparation cancer therapy drug of above-claimed cpd.
Background technology
Solasodine (following structural formula
1) be main anticancer active constituent solasonine (Solasonine) and the aglycon of solamargine tetrahydroisoquinoline alkaloids such as (Solamargine) of the black nightshade of one of ten big anticancer herbal drugs.Because toxicity and teratogenecity that solasodine and solasonine etc. have; 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 to reduce its toxicity and teratogenecity, and might obtain the new good anticancer active verivate that has.Can find out that from disclosed document 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 reduce (following structural formula on 5,6 two keys
3, Xiaoming Zha, Hongbin Sun, Jia Hao, et al. Chemistry&Biodiversity, 2007,4:25-31), and to the displacement and functional group's conversion of 5,6 two keys, with and the research of the antitumour activity of product do not relate to as yet so far.
Summary of the invention
For solving the problem of above existence, the purpose of this invention is to provide a kind of compound that 5,6 two keys are shifted and functional group transforms to solasodine, this compound has the good anticancer activity, especially anti-human colon cancer cell (HT-29).
Another object of the present invention provides a kind of preparation method of above-claimed cpd.
A further object of the present invention provides the application of a kind of above-claimed cpd in the preparation 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 grpups-4-furans steroid alkene has following constitutional features:
Wherein, the steric configuration of 3 or 6 hydroxyls can be the α configuration, also can be 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 a white solid, and fusing point is 212.2-213.8 ℃.
Of the present invention 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene is to be raw material with 3 β, 16 β-diacetoxy-26-chloro-5-cholestene-22-ketone; Obtain through the alcoholysis of 3-ethanoyl, the oxidation of PCC support agent, reduction, amine cyclisation and ring closure reaction are synthetic, specifically comprise the steps:
(1) with 3 β, 16 β-diacetoxy-26-chloro-5-cholestene-22-ketone
IBe raw material, utilize weak base, in the mixed solution of THF and methyl alcohol, carry out the hydrolysis of selectivity ester, synthetic compound 3 beta-hydroxies-16 β-acetoxyl group-26-chloro-5-cholestene-22-ketone
II;
(2) with above-claimed cpd
IIBe dissolved in anhydrous CH
2Cl
2In, add the PCC support agent under stirring in batches, stirring at room reaction 24-25 hour, the decompression desolventizing got compound 16 β-acetoxyl group-26-chloro-4-cholestene-3,6 through column chromatography purification, the 22-triketone after reaction was accomplished
III, wherein, compound
IIWith the mol ratio of PCC support agent be 1:6;
(3) with above-claimed cpd
IIIBe dissolved in the mixed solution that forms by isopyknic THF and methyl alcohol, stir down slowly adding NaBH
4, stirring at room was reacted 4-5 hour, added frozen water after the reaction completion, behind extraction, drying, decompression desolventizing, got compound 3,6-dihydroxyl-16 β-acetoxyl group-26-chloro-4-cholestene-22-ketone
IVBullion;
(4) with above-claimed cpd
IVBullion and potassium phthalimide are dissolved in the anhydrous N of new system; In the dinethylformamide, under 105 ℃ of oil baths, stir, the question response thing is become by oyster white and stops heating after faint yellow; The cooling back adds saturated aqueous common salt; Suction filtration also uses cold water washing, gained solid to dry after column chromatography purification gets compound 3 6-dihydroxyl-16 β-acetoxyl group-26-NSC 308847 base-4-cholestene-22-ketone
V, wherein, compound
IVWith the mol ratio of potassium phthalimide be 1:4;
(5) with above-claimed cpd
VBe dissolved in the mixed solution of formation of isopyknic methylene dichloride and methyl alcohol, stir and slowly drip Hydrazine Hydrate 80 down, react and add suitable quantity of water after 15-16 hour, use CHCl
3Extraction, organic phase through washing, dry, decompression desolventizing after column chromatography gets compound 3,6-dihydroxyl-16 β-acetoxyl group-22,27-epimino base-25 α-4,22 (N)-cholestadiene
VI, wherein, compound
VWith the mol ratio of Hydrazine Hydrate 80 be 1:10;
(6) with above-claimed cpd
VIBe dissolved in the absolute ethyl alcohol, add the KOH solid, refluxing and stirring 24-25 hour; Reaction is accomplished postcooling and is added suitable quantity of water; Through extraction, dry, decompression desolventizing, the gained residual solid gets compound 3 through column chromatography, 6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene
VII, wherein, compound
VIWith the mol ratio of KOH be 1:8.
The concrete synthetic route of the present invention 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene is as follows:
The preferred K of weak base of above-mentioned steps (1)
2CO
3
CH is adopted in the extraction of above-mentioned steps (3)
2Cl
2Extraction, CHCl is adopted in the extraction of step (6)
3Extraction.
The drying of above-mentioned steps (3), step (5), step (6) is to adopt anhydrous Na
2SO4 or anhydrous MgSO4 carry out drying.
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 grpups-4-furans steroid alkene are as the application for preparing cancer therapy drug.
Of the present invention 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene can be used for preparing the medicine that comprises multiple Cancerous 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 grpups-4-furans steroid alkene have the good anticancer activity, can be used as the raw material of multiple cancer therapy drugs such as preparation leukemia, colorectal carcinoma, the rectum cancer, 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 has low toxicity and teratogenecity, can be widely used in clinical.
Embodiment
Utilize embodiment that the present invention is further specified below, but the present invention is not limited to said embodiment, only otherwise break away 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 grpups-4-furans steroid alkene is synthetic:
(1) with 3 β, 16 β-diacetoxy-26-chloro-5-cholestene-22-ketone
IBe raw material, utilize weak base K
2CO
3, in the mixed solution of THF and methyl alcohol, carry out the 3-acetoxyl group selective hydrolysis (referring to Cheng Shuilian. master thesis, Yunnan University, Kunming, 2007, the 20 pages), 3 beta-hydroxies-16 β-acetoxyl group-26-chloro-5-cholestene-22-ketone
II, productive rate 82%, fusing point: 167.0-168.0 ℃;
(2) PCC of silica gel load (PCC) by concentrated hydrochloric acid, chromium trioxide and preparation of silica gel (referring to Meng Qingyong, I expires river Ai Li, and Zhang Li waits quietly. use chemical industry, 2008,37 (3): 314-316), with 4.0 g (8 mmol) compound
IIBe dissolved in the anhydrous CH of 100 mL
2Cl
2In; Stir and add 26 g (48 mmol) PCC support agent down in batches; Back decompression desolventizing is accomplished in stirring at room reaction 25 hours, reaction, elder generation through short and thick silicagel column rough segmentation after the silicagel column purifying gets 2.3 g (4.6 mmol) faint yellow solid compound, 16 β-acetoxyl group-26-chloro-4-cholestene-3; 6, the 22-triketone
III, productive rate 56.3%, fusing point: 181.6-183.1 ℃;
(3) with 2 g (3.96 mmol) compound
IIIBe dissolved in the mixed solution of 10 mL THFs and 10 mL methyl alcohol formation, stir down slowly adding 0.6 g (15.84 mmol) NaBH
4, stirring at room was reacted about 4 hours, added an amount of frozen water after reaction is accomplished, and used CH
2Cl
2Extraction is through anhydrous MgSO
4Drying gets 1.8 g 3,6-dihydroxyl-16 β-acetoxyl group-26-chloro-4-cholestene-22-ketone behind the decompression desolventizing
IVBullion, bullion can directly be done next step reaction;
(4) with 1.5 g (2.94 mmol) compound
IVBullion and 2.2 g (11.8 mmol) potassium phthalimide is dissolved in the anhydrous N of 25 mL new systems; In the dinethylformamide; 105 ℃ of oil baths are stirred down, and the question response thing is become by oyster white and stops heating after faint yellow, and reaction needs 48 hours approximately; The cooling back adds 50 mL saturated aqueous common salts; Suction filtration and with cold water washing consider after the cake 3 times little band yellow solid, oven dry is after purification by silica gel column chromatography gets 1.35 g (2.2 mmol) white solid compound 3,6-dihydroxyl-16 β-acetoxyl group-26-NSC 308847 base-4-cholestene-22-ketone
V, productive rate 75%, fusing point: 109.6-111.8 ℃;
(5) with 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 and slowly drip 1 mL (16.5 mmol) Hydrazine Hydrate 80 down, reaction needs 15 hours approximately, and back adding suitable quantity of water is accomplished in reaction, uses CHCl
3Extraction, organic phase is through weak ammonia, saturated common salt water washing, anhydrous Na
2SO4 is dry, and the decompression desolventizing also gets 0.52 g (1.1 mmol) white solid compound 3,6-dihydroxyl-16 β-acetoxyl group-22,27-epimino base-25 α-4,22 (N)-cholestadiene through silica gel column chromatography
VI, productive rate 68%, fusing point: 252.6-254.2 ℃;
(6) with 0.4 g (0.85 mmol) compound
VIBe dissolved in the 15 mL absolute ethyl alcohols, add 0.3 g (6.8 mmol) KOH solid, about 24 hours of refluxing and stirring, reaction is accomplished postcooling and is added suitable quantity of water, CHCl
3Extraction, anhydrous Na
2SO
4Drying, decompression desolventizing gained residual solid gets 0.2 g (0.5 mmol) white solid compound 3 through silica gel column chromatography, 6-dihydroxyl-22 (27) – imido grpups-4-furans steroid alkene
VII, productive rate 60.1%, fusing point: 212.2-213.8 ℃.
Gained compound 3,6-dihydroxyl-22 (27) – imido grpups-4-furans steroid alkene, its structure is following:
Wherein, the steric configuration of 3 or 6 hydroxyls can be the α configuration, also can be beta comfiguration, and visible, this compound is that solasodine is transferred on 4,5 at the two keys on 5,6, and on the 6th, connects many hydroxyls.
, 3, (27) – imido grpups-4-furans steroid alkylene are learned structural analysis to 6-dihydroxyl-22
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, (27) – imido grpups-4-furans steroid alkene is to the restraining effect of growth of tumour cell for 6-dihydroxyl-22
The active testing concrete operation method: test used knurl strain available from cell resource center of Shanghai Sheng Ke institute of the Chinese Academy of Sciences, all knurl strains with 1640 complete culture solutions that contain 10% foetal calf serum cultivate (37 ℃, 5 % CO
2Under the condition).Cell with logarithmic phase during test is adjusted into proper concn (suspension cell 6 * 10
4/ mL, attached cell 5 * 10
4/ mL) back adds 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 and tried concentration and 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 the anticarcinogen cis-platinum.The adherent growth cell waits to cultivate adherent back dosing in 24 hours; Be dosing behind the suspension growth cell inoculation.Dosing is placed on 37 ℃, 5% CO
2Incubator was cultivated after 48 hours, added tetramethyl-azo azoles salt (5mg/ml); 10 mL/ holes; Continue to cultivate adding three liquid after 4 hours, 100 mL/ holes are placed after 12 hours; The optical density(OD) (OD) of under 570 nm wavelength, measuring each hole with ELIASA is worth, and utilizes formula to calculate the growth inhibition ratio of cell:
Growth inhibition ratio (%)=(OD
Negative control-OD
The dosing hole)/OD
Negative control' 100%
Calculate with the LOGIT method then and receive the half-inhibition concentration IC of reagent each growth of tumour cell
50
It is as shown in table 1 that growth of tumour cell is suppressed the result:
Table 1: antitumour activity test result (IC
50: μ g/mL)
Annotate: HL60 in the 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: people's non-small cell lung cancer cell strain; Bcap-37: human breast cancer cell strain.
Can find out that by last table of the present invention 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene all has good inhibitory effect to above-mentioned various human cancer cells, the cis-platinum that wherein anti-human colon cancer cell is active even more best than present curative effect active taller.
Claims (8)
1. 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene has following constitutional features:
Wherein, the steric configuration of 3 or 6 hydroxyls is α configuration or beta comfiguration.
2. compound according to claim 1 is characterized in that: said compound is a white solid, and fusing point is 212.2-213.8 ℃.
3. the preparation method of claim 1 said 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene is characterized in that said method comprises the steps:
(1) with 3 β, 16 β-diacetoxy-26-chloro-5-cholestene-22-ketone
IBe raw material, utilize weak base, in the mixed solution of THF and methyl alcohol, carry out the hydrolysis of selectivity ester, synthetic compound 3 beta-hydroxies-16 β-acetoxyl group-26-chloro-5-cholestene-22-ketone
II;
(2) with above-claimed cpd
IIBe dissolved in anhydrous CH
2Cl
2In, add the PCC support agent under stirring in batches, stirring at room reaction 24-25 hour, the decompression desolventizing got compound 16 β-acetoxyl group-26-chloro-4-cholestene-3,6 through column chromatography purification, the 22-triketone after reaction was accomplished
III, wherein, compound
IIWith the mol ratio of PCC support agent be 1:6;
(3) with above-claimed cpd
IIIBe dissolved in the mixed solution that forms by isopyknic THF and methyl alcohol, stir down slowly adding NaBH
4, stirring at room was reacted 4-5 hour, added frozen water after the reaction completion, behind extraction, drying, decompression desolventizing, got compound 3,6-dihydroxyl-16 β-acetoxyl group-26-chloro-4-cholestene-22-ketone
IVBullion;
(4) with above-claimed cpd
IVBullion and potassium phthalimide are dissolved in the anhydrous N of new system; In the dinethylformamide, under 105 ℃ of oil baths, stir, the question response thing is become by oyster white and stops heating after faint yellow; The cooling back adds saturated aqueous common salt; Suction filtration also uses cold water washing, gained solid to dry after column chromatography purification gets compound 3 6-dihydroxyl-16 β-acetoxyl group-26-NSC 308847 base-4-cholestene-22-ketone
V, wherein, compound
IVWith the mol ratio of potassium phthalimide be 1:4;
(5) with above-claimed cpd
VBe dissolved in the mixed solution of isopyknic methylene dichloride and methyl alcohol formation, stirring slowly drips Hydrazine Hydrate 80 down, reacts to add suitable quantity of water after 15-16 hour, uses CHCl
3Extraction, organic phase through washing, dry, decompression desolventizing after column chromatography gets compound 3,6-dihydroxyl-16 β-acetoxyl group-22,27-epimino base-25 α-4,22 (N)-cholestadiene
VI, wherein, compound
VWith the mol ratio of Hydrazine Hydrate 80 be 1:10;
(6) with above-claimed cpd
VIBe dissolved in the absolute ethyl alcohol, add the KOH solid, refluxing and stirring 24-25 hour; Reaction is accomplished postcooling and is added suitable quantity of water; Through extraction, dry, decompression desolventizing, the gained residual solid gets compound 3 through column chromatography, 6-dihydroxyl-22 (27) – imido grpups-4-furans steroid alkene
VII, wherein, compound
VIWith the mol ratio of KOH be 1:8.
4. the preparation method of 3,6-dihydroxyl-22 (27) imido grpups according to claim 3-4-furans steroid alkene is characterized in that: the preferred K of weak base of said step (1)
2CO
3
5. according to the preparation method of claim 3 or 4 described 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene, it is characterized in that: CH is adopted in the extraction of said step (3)
2Cl
2Extraction, CHCl is adopted in the extraction of step (6)
3Extraction.
6. the preparation method of 3,6-dihydroxyl-22 (27) imido grpups according to claim 5-4-furans steroid alkene is characterized in that: the drying of said step (3), step (5), step (6) is to adopt anhydrous Na
2SO4 or anhydrous MgSO4 carry out drying.
7. the preparation method of 3,6-dihydroxyl-22 (27) imido grpups according to claim 6-4-furans steroid alkene is characterized in that: the washing of said step (3) organic phase is to adopt weak ammonia, saturated aqueous common salt to wash.
8. said 3,6-dihydroxyl-22 (27) imido grpups-4-furans steroid alkene of a claim 1 is as the application in the preparation cancer therapy drug.
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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 (1)
| Title |
|---|
| WILLIAM GAFFIELD AND RICHARD F. KEELER: "Structure-activity relations of teratogenic natural products", 《PURE &APPL.CHEM.》 * |
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