CN102718818A - Nitrogenous troxerutin derivative, preparation method thereof and application - Google Patents
Nitrogenous troxerutin derivative, preparation method thereof and application Download PDFInfo
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- CN102718818A CN102718818A CN2012101861244A CN201210186124A CN102718818A CN 102718818 A CN102718818 A CN 102718818A CN 2012101861244 A CN2012101861244 A CN 2012101861244A CN 201210186124 A CN201210186124 A CN 201210186124A CN 102718818 A CN102718818 A CN 102718818A
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Abstract
The invention discloses a nitrogenous troxerutin derivative and a preparation method thereof, and belongs to the field of medicinal chemistry. In the method, troxerutin and divinyl ester are used as raw materials, organic solvents serve as reaction media under catalysis of hydrolytic enzyme, the reaction temperature ranges from 40 DEG C to 60 DEG C, troxerutin vinyl ester is obtained and serves as a substrate respectively reacting with dimethyldiguanide or piperazine compounds under enzyme catalysis, troxerutin derivatives containing triazine rings and piperazine rings are respectively obtained, and the compounds have antitumor activity. The preparation method is moderate in reaction condition and simple in operation, the enzyme can be recycled, and a good way is provided for nitrogenous derivatization of natural products.
Description
Technical field
The present invention relates to flavonoid compound, relate in particular to nitrogenous troxerutin verivate and preparation method thereof, belong to the pharmaceutical chemistry field.
Background technology
Flavonoid compound is one type of important natural organic matter; Extensively be present in the root, stem, leaf, flower, fruit of higher plant; Not only kind quantity is various, and the structure type complicacy is various, is one type of secondary metabolite that plant produces in long-term natural selection process.Flavonoid compound has the chemical reactivity of height, can remove biological intravital radical, has antioxygenation.On the other hand, flavonoid compound has a lot of important pharmacological actions again, and human numerous disease is had therapeutic value, like: mutation, anti-ageing, antitumor, antibiotic etc.The flavonoid compound or the root of large-flowered skullcap in addition, the activeconstituents of numerous herbal medicine such as ginkgo.Though the natural flavone compounds is present in occurring in nature in a large number, its complex structure, action site are many, poorly soluble, and the utilization ratio of its physiologically active is not high, has limited their widespread use.With the flavonoid compound is lead compound, and it is carried out structure of modification and composition optimizes mainly concentrates on its C2, C3, and C7, C8, C3' (or C5'), chemical modification is carried out in the C4' position.Introduce nitrogenous group and be a kind of domestic method of improving its solvability and physiologically active, as " synthesizing of the amino isoflavone compounds of 2-" (Acta Pharmaceutica Sinica,
1987, 22,655-661), reported that a series of 2-amino-3'-amine methyl-4'-hydroxyl-6-replaces the synthetic of isoflavone derivative; " the Mannich reaction of noroxylin " (organic chemistry,
2003, 23,81-85), reported and utilized natural product noroxylin (baicalein) to be research object, on the carbon of its A ring 8-position, carry out the Mannich reaction, synthesized the substituted Mannich alkali derivant of methylamino; " Nitrogen-containing avonoid analogues as CDK1/cyclin B inhibitors:Synthesis, SAR analysis, and biological activity " (
Bioorg. Med. Chem.,
2008, 16,7127-7132) carry out structural modification through Mannich reaction pair natural flavone compounds, synthesized the nitogen-contained heterocycle derivant of scutellarin, Quercetin; " effect of the synthetic and external short rabbit Oesteoblast growth of onocol amino ethers verivate " (Chinese Journal of Pharmaceuticals,
2001, 32 (1), 9-12.) the onocol nitrogen containing derivative has been synthesized in design.In above nitrogenous flavone derivative synthetic, all be the synthetic nitrogenous verivate of flavonoid compound of method that adopts chemical catalysis, multistep.For flavonoid compound, generally contain a plurality of groups that react in its structure, adopt the method for chemical catalysis, because of controllability is not high, generate isomeric by product easily, aftertreatments such as purifying are not easy.With respect to chemical catalysis, enzyme catalysis have ready conditions gentleness, selectivity advantages of higher are utilized enzyme catalysis, and nitrogenous reactive group is introduced the flavonoid compound parent, are a kind of good approach of this natural product of modification.At present, do not appear in the newspapers with enzyme catalysis modification troxerutin, the nitrogenous troxerutin verivate of preparation.Simultaneously, because of enzyme selectivity is high, can improve combined coefficient, can simplify post-processing operation, therefore, the reaction system of making catalyzer of enzyme becomes the researchdevelopment direction that flavonoid compound mechanism modifies.
Summary of the invention
The object of the present invention is to provide the new nitrogenous troxerutin verivate of series; Another purpose is to provide with enzyme does catalyzer, simple, this type of nitrogenous troxerutin derivative preparation method that by product is few.Another purpose is to provide the application of this compounds in the preparation medicine.
Nitrogenous troxerutin verivate of the present invention has following structure:
The troxerutin verivate (I) that contains triazine ring
The troxerutin verivate (II) that contains piperazine
N has represented the number of methylene radical among general formula I, the II, is respectively 2,3,4,5,6,7,8,9,10,11.R is-H among the general formula I I ,-CH
3,-C
2H
5,-CH (CH
3)
2,-CH
2CH
2CH
3, phenyl, tolyl, p-methoxy-phenyl, halogenophenyl.Described halogenophenyl refers to fluoro phenyl, chlorophenyl, bromo phenyl.
The above-claimed cpd synthetic route is following:
Its compound method of troxerutin verivate (I) that contains triazine ring realizes through following mode:
The first step: troxerutin and lipid acid divinyl ester are reaction medium with the organic solvent under the catalysis of enzyme, and 40 ℃ ~ 60 ℃ reactions after reaction finishes, are crossed the post separation and obtained the troxerutin vinyl acetate.
Second step: under enzyme catalysis, is reaction medium with the organic solvent with the troxerutin vinyl acetate that obtains, with N1,N1-Dimethylbiguanide reaction, 40 ~ 65 ℃ of temperature of reaction.After reaction finishes, after the removal of solvent under reduced pressure, cross the post separation and obtain containing triazine ring troxerutin verivate (I).
Its compound method of troxerutin verivate (II) that contains piperazine ring realizes through following mode:
The first step: the same;
Second step: under enzyme catalysis, is reaction medium with the organic solvent with the troxerutin vinyl acetate that obtains, with piperazine compounds reaction, 50 ℃ of temperature of reaction.After reaction finishes, after the removal of solvent under reduced pressure, cross post and separate the troxerutin verivate (II) that obtains containing piperazine ring.
Described enzyme comprises Novozym 435, bacillus licheniformis alkali protease, subtilisin, Lipase G Amano 50, Lipase AY Amano 30 G, Lipase LS-10, Lipase porcine pancreas, Lipozyme TL IM, Lipase from
CandidaOr Lipase from
Candida CylindraceaThe add-on of enzyme and the mass volume ratio of reaction solvent are 10mg/mL ~ 250 mg/mL.
Described organic solvent be pyridine,
N, N-N (DMF), the trimethyl carbinol, sec-butyl alcohol, methyl-sulphoxide (DMSO) one of them or two kinds of mixtures; Preferred mixed solvent DMF:DMSO (volume ratio 1:1), DMSO: the trimethyl carbinol (volume ratio 1:1), pyridine: DMF (volume ratio 1:1), the trimethyl carbinol: pyridine (volume ratio 1:1), DMF: the trimethyl carbinol (volume ratio 1:1), DMF:DMSO (volume ratio 1:1).
Advantage of the present invention is that reaction process is simple, and enzymatic regioselectivity is high, obtains single substitution product, and aftertreatment is easy.Owing in non-aqueous media, react, the enzyme that therefore uses can use repeatedly repeatedly, reduces cost; Simultaneously, the new nitrogenous troxerutin verivate of generation has anti-tumor activity, has actual application value preferably, for the screening of medicine provides possibility.
Embodiment
Below in conjunction with practical implementation is that the present invention is described further, but protection scope of the present invention is not limited in this.
Embodiment 1-1
In 100 mL Erlenmeyer flasks, take by weighing troxerutin 560 mg (0.75 mmol); Hexanodioic acid divinyl ester 582mg (3 mmol), 20 mL pyridines are solvent, behind adding bacillus licheniformis alkali protease 600 mg; Put into 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1After reaction 72h finishes, remove by filter enzyme, decompression steams pyridine.With the sherwood oil of volume ratio 3:1 and the remaining pyridine of mixed solvent flush away of chloroform; After obtaining brown xanchromatic sticky solid; Column chromatography separating purification; Eluent is ethyl acetate/methanol/water (15:3.6:0.5 V/V), obtains yellow solid troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol), productive rate 60%.
1H-NMR?(DMSO
-d 6),?δ?(ppm):?12.49?(s,?1?H,?OH
5),?7.84?(s,?1?H,?H
2’),?7.73?(d,?1H,?J=7.2?Hz,?H
6’),?7.20?(dd,?1?H,?J=6.24?Hz,?J=14.0?Hz,?-OCH=),?7.14?(d,?1?H,?J=7.6?Hz,?H
5’),?6.73?(s,?1?H,?H
8),?6.38?(s,?1?H,?H
6),?5.34?(d,?1?H,?J=7.3?Hz,?H
1’’),?4.89?(m,?1?H,?OCH=CH
2),?4.64?(m,?1?H,?OCH=CH
2),?4.40?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.31?(m,?1?H,?H
1’’’),?4.26?(m,?1?H,?H?of?B?acylated),?4.12-4.06?(m,?4?H,?H?of?A),?3.74?(m,?4?H,?H?of?B),?3.7-3.1?(10?H,?H?of?rhamnoglucosyl),?2.44?(m,?2?H,?-CH
2-COOCH=CH
2),?2.38?(m,?2?H,?-CH
2-CO-troxerutin),?1.58?(m,?4?H,?other?CH
2?of?hexanedioyl?part),?0.99?(d,?3?H,?J=6.2?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3412?(OH),?1726?(C=O),?1648?(C=C);?ESI-MS?(m/z):?919.1?(M?+?Na)
+.?。
In 50 mL Erlenmeyer flasks, add troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol) respectively; According to mol ratio is that 1:10 adds piperazine 387mg; 15 mL pyridines are solvent; After adding Lipase LS-10 lypase 500 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 72h.Filter, enzyme reclaims, and decompression steams pyridine.Residual solids is used dissolve with methanol, utilizes column chromatography to separate, and eluent is ethyl acetate/methanol/water (15:5:1 V/V), and the troxerutin verivate 232mg (0.247mmol) that obtains final product and be containing piperazine is a yellow solid, productive rate 55%.
1H-NMR?(DMSO
-d 6 +?D
2O),?δ?(ppm):?7.82?(s,?1?H,?H
2’),?7.64?(d,?1?H,?J=4.9?Hz,?H
6’),?7.06?(d,?1?H,?J=6.8?Hz,?H
5’),?6.55?(s,?1?H,?H
8),?6.27?(s,?1?H,?H
6),?5.26?(d,?1?H,?J=7.2?Hz,?H
1’’),?4.34?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.26?(m,?1?H,?H
1’’’),?4.22?(m,?1?H,?H?of?B?acylated),?4.05-4.02?(m,?4?H,?H?of?A),?3.74?(m,?4?H,?H?of?B),?3.47-3.30?(10?H,?H?of?rhamnoglucosyl),?2.62,?2.58?(m,?8?H,?H?of?piperazine),?2.25?(m,?2?H,?-CH
2-CO-piperazine)?1.93?(t,?2?H,?7.6?Hz,?6.7?Hz,?-CH
2-CO-troxerutin),?1.47?(m,?4?H,?other?CH
2?of?hexanedioyl?part),?0.88?(d,?3?H,?J=5.8?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3412?(OH),?1726?(C=O),?1400?(C-N);?ESI-MS?(m/z):?961.3?(M?+?Na)
+,?939.4?(M?+?H)
+.?。
Embodiment 1-2
In 100 mL Erlenmeyer flasks, take by weighing troxerutin 560 mg (0.75 mmol); Sebacic acid divinyl ester 756mg (3 mmol), 20 mL pyridines are made solvent, behind adding bacillus licheniformis alkali protease 600 mg; Put into 60 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1After reaction 120h finishes, remove by filter enzyme, decompression steams pyridine.Purifying is the same.Obtain yellow solid troxerutin sebacoyl vinyl acetate 400mg (0.42mmol), productive rate 56%.
1H-NMR?(DMSO
-d 6),?δ?(ppm):?12.49?(s,?1?H,?OH
5),?7.84?(s,?1?H,?H
2’),?7.72?(d,?1H,?J=7.0?Hz,?H
6’),?7.20?(dd,?1?H,?J=6.21?Hz,?J=14.0?Hz,?-OCH=),?7.14?(d,?1?H,?J=7.4?Hz,?H
5’),?6.73?(s,?1?H,?H
8),?6.38?(s,?1?H,?H
6),?5.34?(d,?1?H,?J=7.3?Hz,?H
1’’),?4.89?(m,?1?H,?OCH=CH
2),?4.63?(m,?1?H,?OCH=CH
2),?4.39?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.31?(m,?1?H,?H
1’’’),?4.26?(m,?1?H,?H?of?B?acylated),?4.12-4.06?(m,?4?H,?H?of?A),?3.74?(m,?4?H,?H?of?B),?3.7-3.1?(10?H,?H?of?rhamnoglucosyl),?2.40?(t,?2?H,?J=7.2?Hz,?-CH
2-COOCH=CH
2),?2.33?(t,?2?H,?J=6.9?Hz,?-CH
2-CO-troxerutin),?1.58,?1.22?(m,?12?H,?other?CH
2?of?decanedioyl?part),?0.99?(d,?3?H,?J=6.2?Hz,?CH
3?of?rhamnosyl);IR?(KBr,?cm
-1):?3410?(OH),?1728?(C=O),?1649?(C=C);?ESI-MS?(m/z):?975.2?(M?+?Na)
+.?。
In 50 mL Erlenmeyer flasks, add troxerutin sebacoyl vinyl acetate 400mg (0.42mmol) respectively; According to mol ratio is that 1:10 adds piperazine 361mg; 25 mL pyridines are solvent; After adding Lipase LS-10 lypase 600 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 120h.Filter, enzyme reclaims, and decompression steams pyridine.Aftertreatment is the same.Obtaining the troxerutin verivate 208mg (0.21mmol) that final product contains piperazine is yellow solid, productive rate 50%.
1H-NMR?(DMSO
-d 6?+?D
2O),?δ?(ppm):?7.84?(s,?1?H,?H
2’),?7.72?(d,?1?H,?J=7.2?Hz,?H
6’),?7.14?(d,?1?H,?J=7.4?Hz,?H
5’),?6.73?(s,?1?H,?H
8),?6.38?(s,?1?H,?H
6),?5.34?(d,?1?H,?J=7.3?Hz,?H
1’’),?4.39?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.31?(m,?1?H,?H
1’’’),?4.26?(m,?1?H,?H?of?B?acylated),?4.12-4.06?(m,?4?H,?H?of?A),?3.74?(m,?4?H,?H?of?B),?3.70-3.10?(10?H,?H?of?rhamnoglucosyl),?2.59,?2.53?(m,?8?H,?H?of?piperazine),?2.40?(t,?2?H,?J=7.2?Hz,?-CH
2-CO-piperazine),?2.33?(t,?2?H,?J=6.9?Hz,?-CH
2-CO-troxerutin),?1.58,?1.22?(m,?12?H,?other?CH
2?of?decanedioyl?part),?0.87?(d,?3?H,?J=5.7?Hz,?CH
3?of?rhamnosyl);IR?(KBr,?cm
-1):?3410?(OH),?1728?(C=O),?1379?(C-N);?ESI-MS?(m/z):?1017.4?(M?+?Na)
+.?。
Embodiment 1-3
In 50 mL Erlenmeyer flasks, add troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol) respectively; According to mol ratio is that 1:10 adds 1-n-propyl piperazine 576mg; 25 mL pyridines are solvent; After adding Lipase LS-10 lypase 600 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 120h.Aftertreatment is the same.Obtaining the troxerutin verivate 242mg (0.248mmol) that final product contains piperazine is yellow solid, productive rate 55%.
1H-NMR?(DMSO
-d 6?+?D
2O),?δ?(ppm):?7.85?(s,?1?H,?H
2’),?7.73?(d,?1?H,?J=7.1?Hz,?H
6’),?7.16?(d,?1?H,?J=7.6?Hz,?H
5’),?6.71?(s,?1?H,?H
8),?6.36?(s,?1?H,?H
6),?5.35?(d,?1?H,?J=7.2?Hz,?H
1’’),?4.40?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.30?(m,?1?H,?H
1’’’),?4.27?(m,?1?H,?H?of?B?acylated),?4.11-4.07?(m,?4?H,?H?of?A),?3.75?(m,?4?H,?H?of?B),?3.71-3.11?(10?H,?H?of?rhamnoglucosyl),?2.60,?2.54?(m,?8?H,?H?of?piperazine),?2.39?(t,?2?H,?J=7.2?Hz,?-CH
2-CO-piperazine),?2.37?(t,?2?H,?J=6.2?Hz,?-C
H 2CH
2CH
3),?2.31?(t,?2?H,?J=6.7?Hz,?-CH
2-CO-troxerutin),?2.97?(3?H,?piperazine-CH
3),?1.59,?1.24?(m,?14?H,?other?CH
2?of?decanedioyl?part,?-CH
2C
H 2CH
3),?0.99?(t,?3?H,?J=5.1?Hz,?-CH
2CH
2C
H 3),?0.86?(d,?3?H,?J=5.6?Hz,?CH
3?of?rhamnosyl);IR?(KBr,?cm
-1):?3411?(OH),?1729?(C=O),?1378?(C-N);?ESI-MS?(m/z):?1003.2?(M?+?Na)
+.?。
Embodiment 1-4
In 100 mL Erlenmeyer flasks, take by weighing troxerutin 560 mg (0.75 mmol); Hexanodioic acid divinyl ester 582mg (3 mmol), 20 mL pyridines are solvent, behind adding subtilisin proteolytic enzyme 600 mg; Put into 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1After reaction 72h finishes, remove by filter enzyme, decompression steams pyridine.Aftertreatment is the same.Obtain yellow solid troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol), productive rate 60%.Nuclear-magnetism, infrared data are seen embodiment 1-1.
In 50 mL Erlenmeyer flasks, add troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol) respectively; According to mol ratio is that 1:10 adds piperazine 387mg; 15 mL pyridines are solvent; After adding Lipase G Amano 50 enzymes 500 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 72h.Aftertreatment is the same.Obtaining the troxerutin verivate 190mg (0.202mmol) that final product contains piperazine is yellow solid, productive rate 44.8%.Nuclear-magnetism, infrared data are seen embodiment 1-1.
Embodiment 1-5
In 50 mL Erlenmeyer flasks, add hexanedioyl troxerutin vinyl acetate 403mg (0.45mmol) respectively; According to mol ratio is that 1:10 adds piperazine 387mg; 25 mL DMSO and trimethyl carbinol mixed solvent (volume ratio 1:1); After adding Lipase LS-10 lypase 500 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 96h.Aftertreatment is the same.Obtaining the troxerutin verivate 190mg (0.203mmol) that final product contains piperazine is yellow solid, productive rate 45%.Nuclear-magnetism, infrared data are seen embodiment 1-1.
Embodiment 1-6
In 100 mL Erlenmeyer flasks, take by weighing troxerutin 560 mg (0.75 mmol); Pentanedioic acid divinyl ester 552mg (3 mmol), 20 mL pyridines are solvent, behind adding bacillus licheniformis alkali protease 600 mg; Put into 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1After reaction 72h finishes, remove by filter enzyme, decompression steams pyridine.Aftertreatment is the same, obtains yellow solid troxerutin glutaryl vinyl acetate 430mg (0.48mmol), productive rate 65%.
1H-NMR?(DMSO
-d 6),?δ?(ppm)：12.49?(s,?1?H,?OH
5),?7.85?(s,?1?H,?H
2’),?7.74?(d,?1?H,?J=7.2?Hz,?H
6’),?7.22?(dd,?1?H,?J=6.4?Hz,?J=14.1?Hz,?-OCH=),?7.17?(d,?1?H,?J=6.6?Hz,?H
5’),?6.75?(s,?1?H,?H
8),?6.38?(s,?1?H,?H
6),?5.35?(d,?1?H,?J=7.6?Hz,?H
1’’),?4.89?(m,?1?H,?OCH=CH
2),?4.65?(m,?1?H,?OCH=CH
2),?4.47?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.32?(m,?1?H,?H
1’’’),?4.26?(m,?1?H,?H?of?B?acylated),?4.12-4.05?(m,?4?H,?H?of?A),?3.75?(m,?4?H,?H?of?B),?3.71-3.04?(10?H,?H?of?rhamnoglucosyl),?2.47?(m,?2?H,?-CH
2-COOCH=CH
2),?2.26?(m,?2?H,?-CH
2-CO-troxerutin),?1.80?(m,?2?H,?other?CH
2?of?glutaridioyl?part),?0.97?(d,?3?H,?J=6.2?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3385?(OH),?1732?(C=O),?1645?(C=C);?ESI-MS?(m/z):?905.1?(M?+?Na)
+.?。
In 50 mL Erlenmeyer flasks, add troxerutin glutaryl vinyl acetate 396mg (0.45mmol) respectively; According to mol ratio is that 1:10 adds 1-(p-methoxyphenyl) piperazine 864mg; 15 mL pyridines are solvent; After adding Lipase LS-10 lypase 500 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 72h.Filter, enzyme reclaims, and decompression steams pyridine.Aftertreatment is the same.The troxerutin verivate 245mg (0.238mmol) that obtains final product and be containing piperazine is a yellow solid, productive rate 52.8%.
1H-NMR?(DMSO
-d 6 +?D
2O),?δ?(ppm):?7.83?(s,?1?H,?H
2’),?7.63?(d,?1?H,?J=4.8?Hz,?H
6’),?7.05?(d,?1?H,?J=6.6?Hz,?H
5’),?6.53?(s,?1?H,?H
8),?6.42-6.54?(4?H,?Ph),?6.29?(s,?1?H,?H
6),?5.25?(d,?1?H,?J=7.1?Hz,?H
1’’),?4.33?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.27?(m,?1?H,?H
1’’’),?4.23?(m,?1?H,?H?of?B?acylated),?4.04-4.01?(m,?4?H,?H?of?A),?3.75?(m,?4?H,?H?of?B),?3.48-3.31?(13?H,?H?of?rhamnoglucosyl,?-OC
H 3),?2.61,?2.57?(m,?8?H,?H?of?piperazine),?2.26?(m,?2?H,?-CH
2-CO-piperazine)?1.94?(t,?2?H,?7.5?Hz,?6.6?Hz,?-CH
2-CO-troxerutin),?1.48?(m,?4?H,?other?CH
2?of?hexanedioyl?part),?0.89?(d,?3?H,?J=5.6?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3413?(OH),?1727?(C=O),?1601,?1498?(Ph),?1400?(C-N),?1248?(C-O);?ESI-MS?(m/z):1053.1?(M?+?Na)
+.?。
Embodiment 1-7
In 50 mL Erlenmeyer flasks, add troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol) respectively; According to mol ratio is that 1:10 adds 1-(2-fluorophenyl) piperazine 810mg; 15 mL pyridines are solvent; After adding Lipase LS-10 lypase 500 mg, place 50 ℃ of constant temperature oscillators to react, rotating speed 250 revmin
-1Finish reaction behind the reaction 72h.Filter, enzyme reclaims, and decompression steams pyridine.Aftertreatment is the same.The troxerutin verivate 215mg (0.211mmol) that obtains final product and be containing piperazine is a yellow solid, productive rate 47%.
1H-NMR?(DMSO
-d 6 +?D
2O),?δ?(ppm):?7.85?(s,?1?H,?H
2’),?7.66?(d,?1?H,?J=5.1?Hz,?H
6’),?7.07?(d,?1?H,?J=7.0?Hz,?H
5’),?6.57?(s,?1?H,?H
8),?6.59,?6.87?(4?H,?Ph),?6.28?(s,?1?H,?H
6),?5.28?(d,?1?H,?J=7.4?Hz,?H
1’’),?4.36?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.28?(m,?1?H,?H
1’’’),?4.23?(m,?1?H,?H?of?B?acylated),?4.06-4.03?(m,?4?H,?H?of?A),?3.75?(m,?4?H,?H?of?B),?3.46-3.31?(10?H,?H?of?rhamnoglucosyl),?2.60,?2.56?(m,?8?H,?H?of?piperazine),?2.23?(m,?2?H,?-CH
2-CO-piperazine)?1.91?(t,?2?H,?7.5?Hz,?6.8?Hz,?-CH
2-CO-troxerutin),?1.48?(m,?4?H,?other?CH
2?of?hexanedioyl?part),?0.88?(d,?3?H,?J=5.9?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3411?(OH),?1730?(C=O),?1495,?1596?(Ph),?1404?(C-N);?ESI-MS?(m/z):1041.4?(M?+?Na)
+.?。
Embodiment 2-1
In 100 mL Erlenmeyer flasks, add troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol); According to mol ratio is that 1:4 adds N1,N1-Dimethylbiguanide 232mg; 40 mL pyridines are solvent; After adding Lipase G Amano 50 lypase 2g, place constant temperature oscillator to react, react under 50 ℃ of conditions.Finish reaction behind the reaction 120h.Enzyme is removed in filtration, and decompression steams pyridine.Residual solids is used dissolve with methanol, utilizes column chromatography to separate, and eluent is ethyl acetate/methanol/water (15:3.6:1 V/V), obtains containing the troxerutin verivate of triazine ring, yellow solid, 273mg (0.284mmol), productive rate 63%.
1H-NMR?(DMSO
-d 6 ),?δ?(ppm):?12.49?(s,?1?H,?OH
5),?7.84?(s,?1?H,?H
2’),?7.73?(d,?1?H,?J=7.2?Hz,?H
6’),?7.14?(d,?1?H,?J=7.6?Hz,?H
5’),?6.74?(s,?1?H,?H
8),?6.38?(s,?1?H,?H
6),?5.38?(d,?1?H,?J=7.3?Hz,?H
1’’),?4.40?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.31?(m,?1?H,?H
1’’’),?4.26?(m,?1?H,?H?of?B?acylated),?4.11-4.05?(m,?4?H,?H?of?A),?3.74?(m,?4?H,?H?of?B),?3.23?(m,?6?H,?N(CH
3)
2),?3.02?(10?H,?H?of?rhamnoglucosyl),?2.37?(m,?2?H,?-CH
2-triazine),?2.08?(s,?2?H,?-CH
2-CO-troxerutin),?1.58?(m,?4?H,?other?CH
2?of?hexanedioyl?part),?0.95?(d,?3?H,?J=6.2?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3376?(OH),?3176?(N-H),?1726?(C=O),?1569?(C=N),?1063?(C-N);?ESI-MS?(m/z):?986.5?(M?+?Na)
+,?964.5?(M?+?H)
+.?。
Embodiment 2-2
In 100 mL Erlenmeyer flasks, take by weighing troxerutin 560 mg (0.75 mmol); Nonane diacid divinyl ester 720mg (3 mmol), 20 mL pyridines are solvent, behind adding bacillus licheniformis alkali protease 700 mg; Put into 40 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1After reaction 148h finishes, remove by filter enzyme, decompression steams pyridine.Aftertreatment is the same.Obtain yellow solid troxerutin azelaoyl nonanedioyl vinyl acetate 387mg (0.413mmol), productive rate 55%.
1H-NMR?(DMSO
-d 6),?δ?(ppm):?12.50?(s,?1?H,?OH
5),?7.85?(s,?1?H,?H
2’),?7.75?(d,?1?H,?J=8.4?Hz,H
6’),?7.21?(dd,?1?H,?J=6.0?Hz,?J=13.8?Hz,?-OCH=),?7.15?(d,?1?H,?J=8.4?Hz,?H
5’),6.75?(s,?1?H,?H
8),?6.38?(s,?1?H,?H
6),?5.41?(d,?1?H,?J=10.0?Hz,?H
1’’),?4.91?(m,?1?H,?OCH=CH
2),?4.61?(m,?1?H,?OCH=CH
2),?4.41?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.32?(m,?1?H,?H
1’’’),?4.26?(m,?1?H,?H?of?B?acylated),?4.12-4.06?(m,?4?H,?H?of?A),?3.75?(m,?4?H,?H?of?B),?3.71-3.00?(10?H,?H?of?rhamnoglucosyl),?2.39?(t,?2?H,?J=7.2?Hz,?-CH
2-COOCH=CH
2),?2.34?(t,?2?H,?J=7.2Hz,?-CH
2-CO-troxerutin),?1.52?,1.25?(m,?10?H,?other?CH
2?of?nonoanedioyl?part),?0.99?(d,?3?H,?J=6.2?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3377?(OH),?1735?(C=O),?1647?(C=C);?ESI-MS?(m/z):?961.3?(M?+?Na)
+.
In 100 mL Erlenmeyer flasks, add troxerutin azelaoyl nonanedioyl vinyl acetate 387mg (0.413mmol); According to mol ratio is that 1:4 adds N1,N1-Dimethylbiguanide 213mg; 20 mL pyridines are solvent; After adding Lipase G Amano 50 lypase 2 g, place constant temperature oscillator to react, react under 60 ℃ of conditions.Finish reaction behind the reaction 140h.Aftertreatment is the same.Obtain containing the troxerutin verivate of triazine ring, yellow solid, 216mg (0.215mmol), productive rate 52%.
1H-NMR?(DMSO
-d 6 ),?δ?(ppm):?7.80?(s,?1?H,?H
2’),?7.65?(d,?1?H,?J=8.4?Hz,?H
6’),?7.01?(d,?1?H,?J=8.4?Hz,?H
5’),6.55?(s,?1?H,?H
8),?6.26?(s,?1?H,?H
6),?5.23?(d,?1?H,?J=10.0?Hz,?H
1’’),?4.35?(m,?3?H,?2?H?of?A?acylated,?1?H?of?B?acylated),?4.22?(m,?1?H,?H
1’’’),?4.21?(m,?1?H,?H?of?B?acylated),?4.00?(m,?4?H,?H?of?A),?3.74?(m,?4?H,?H?of?B),?3.39-3.15?(10?H,?H?of?rhamnoglucosyl),?3.05?(m,?6?H,?N(CH
3)
2),?2.21?(t,?2?H,?J=7.2?Hz,?-CH
2-triazine),?2.17?(t,?2?H,?J=7.2Hz,?-CH
2-CO-troxerutin),?1.38?,?1.12?(m,?10?H,?other?CH
2?of?nonoanedioyl?part),?0.88?(d,?3?H,?J=6.2?Hz,?CH
3?of?rhamnosyl);?IR?(KBr,?cm
-1):?3377?(OH),?3159?(N-H),?1735?(C=O),?1552?(C=N),?1059?(C-N);?ESI-MS?(m/z):?1029.0?(M?+?Na)
+.?。
Embodiment 2-3
In 100 mL Erlenmeyer flasks, add troxerutin hexanedioyl vinyl acetate 403mg (0.45mmol); According to mol ratio is that 1:4 adds N1,N1-Dimethylbiguanide 232mg; 30 mL pyridines are solvent; After adding Lipase AY Amano 30 G lypase 1 g, place constant temperature oscillator to react, react under 45 ℃ of conditions.Finish reaction behind the reaction 148h.Aftertreatment is the same.Obtain containing the troxerutin verivate of triazine ring, yellow solid, 251mg (0.261mmol), productive rate 58%.Nuclear-magnetism, infrared data are seen embodiment 2-1.
Biological activity test: adopt Cyclex CDK1/cyclin B kinases assay kit institute's calibration method and mtt assay that synthetic is contained the troxerutin verivate (I) of triazine ring and the troxerutin verivate (II) that contains piperazine ring has carried out the active mensuration of inhibition CDK1/cyclin B respectively and tumor cell in vitro suppresses active mensuration.
Partial test result such as following table:
Above data presentation compound (I) and (II) the inhibition activity of CDK1/cyclin B is better than troxerutin greatly, extracorporeal anti-tumor suppress description of test this compounds prostate cancer cell (PC-3) and lung carcinoma cell (A-549) have been shown stronger anti-tumor activity.Can be with it as a kind of potential drug development.
Claims (10)
1. nitrogenous troxerutin verivate is characterized in that, it is the troxerutin verivate that contains triazine ring, has following structural formula:
（Ⅰ），
N is 2,3,4,5,6,7,8,9,10,11.
2. nitrogenous troxerutin verivate is characterized in that, it is the troxerutin verivate that contains piperazine ring, has following structural formula:
（Ⅱ）
N is 2,3,4,5,6,7,8,9,10,11;
R is-H-CH
3,-C
2H
5,-CH (CH
3)
2,-CH
2CH
2CH
3, phenyl, tolyl, p-methoxy-phenyl, fluorine, chlorine or bromine are for phenyl.
3. the method for the nitrogenous troxerutin verivate of preparation as claimed in claim 1 is characterized in that, realizes through following steps:
The first step: troxerutin and lipid acid divinyl ester are reaction medium with the organic solvent under the catalysis of enzyme, and 40 ℃ ~ 60 ℃ reactions after reaction finishes, are crossed the post separation and obtained the troxerutin vinyl acetate;
Second step: under enzyme catalysis, is reaction medium with the organic solvent with the troxerutin vinyl acetate that obtains, with N1,N1-Dimethylbiguanide reaction, 50 ℃ of temperature of reaction; After reaction finished, removal of solvent under reduced pressure was crossed the post separation and is obtained containing triazine ring troxerutin verivate (I).
4. the preparation method of nitrogenous troxerutin verivate as claimed in claim 3 is characterized in that, the mol ratio of reactant troxerutin vinyl acetate and N1,N1-Dimethylbiguanide is 1:2 ~ 1:20.
5. the method for the nitrogenous troxerutin verivate of preparation as claimed in claim 2 is characterized in that, realizes through following steps:
The first step: troxerutin and lipid acid divinyl ester are reaction medium with the organic solvent under the catalysis of enzyme, and 40 ℃ ~ 60 ℃ reactions after reaction finishes, are crossed the post separation and obtained the troxerutin vinyl acetate;
Second step: under enzyme catalysis, is reaction medium with the organic solvent with the troxerutin vinyl acetate that obtains, and reacts with piperazine compounds; 50 ℃ of temperature of reaction; After reaction finishes, after the removal of solvent under reduced pressure, cross post and separate the troxerutin verivate (II) that obtains containing piperazine ring.
6. the preparation method of nitrogenous troxerutin verivate as claimed in claim 5 is characterized in that, the mol ratio of reactant troxerutin vinyl acetate and bridged piperazine derivatives is 1:2 ~ 1:20.
7. like the preparation method of claim 3 or 5 described nitrogenous troxerutin verivates; It is characterized in that used enzyme is Novozym 435, bacillus licheniformis alkali protease, subtilisin, Lipase G Amano 50, Lipase AY Amano 30 G, Lipase LS-10, Lipase porcine pancreas, Lipozyme TL IM, Lipase from
CandidaOr Lipase from
Candida Cylindracea
8. like the preparation method of claim 3 or 5 described nitrogenous troxerutin verivates, it is characterized in that, employed organic solvent be pyridine,
N, N-N (DMF), the trimethyl carbinol, sec-butyl alcohol, methyl-sulphoxide (DMSO) one of them or two kinds of mixtures.
9. like the preparation method of claim 3 or 5 described nitrogenous troxerutin verivates, it is characterized in that the add-on of enzyme and the mass volume ratio of reaction solvent are 10mg/mL ~ 250 mg/mL.
10. the application of 1 of claim or 2 described nitrogenous troxerutin verivates in the preparation medicine is characterized in that, it is prepared anti-prostate cancer or lung-cancer medicament as active substance.
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| CN107163096A (en) * | 2017-05-26 | 2017-09-15 | 河南工业大学 | Troxerutin amide derivatives and its preparation method and use |
| WO2018218903A1 (en) * | 2017-05-27 | 2018-12-06 | 华南理工大学 | Method for preparing troxerutin ester using whole cell catalysis |
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| RO104721B1 (en) * | 1989-07-10 | 1994-12-12 | Inst Medicina Farmacie | Hydroxi-alkyl-homo-piperazidine of ruthozide derivatives and preparation method therefore |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107163096A (en) * | 2017-05-26 | 2017-09-15 | 河南工业大学 | Troxerutin amide derivatives and its preparation method and use |
| CN107163096B (en) * | 2017-05-26 | 2020-01-14 | 河南工业大学 | Troxerutin amide derivative and synthesis method and application thereof |
| WO2018218903A1 (en) * | 2017-05-27 | 2018-12-06 | 华南理工大学 | Method for preparing troxerutin ester using whole cell catalysis |
| US11286511B2 (en) | 2017-05-27 | 2022-03-29 | South China University Of Technology | Method for preparing troxerutin ester using whole-cell catalysis |
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