CN102718818B - Nitrogenous troxerutin derivative, preparation method thereof and application - Google Patents
Nitrogenous troxerutin derivative, preparation method thereof and application Download PDFInfo
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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 derivative and preparation method thereof, belong to pharmaceutical chemistry field.
Background technology
Flavonoid compound is the important natural organic matter of a class, extensively be present in the root, stem, leaf, flower, fruit of higher plant, not only kind quantity is various, and structure type complexity is various, is the class secondary metabolite that plant produces in long-term natural selection process.Flavonoid compound has the chemical reactivity of height, can remove the free radical in organism, has antioxygenation.On the other hand, flavonoid compound has again a lot of important pharmacological actions, and mankind's numerous disease is had to therapeutic value, as: anti-mutation, anti-ageing, antitumor, antibacterial etc.In addition flavonoid compound or the root of large-flowered skullcap, the activeconstituents of numerous herbal medicine such as ginkgo.Though 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.Take flavonoid compound as lead compound, it is carried out to structure of modification and composition optimizes mainly concentrates on its C2, C3, C7, C8, C3'(or C5'), chemical modification is carried out in C4' position.Introduce nitrogenous group and be a kind of common method of improving its solvability and physiologically active, as " the amino isoflavone compounds of 2-synthetic " (Acta Pharmaceutica Sinica,
1987, 22,655-661), report that a series of 2-amino-3'-amine methyl-4'-hydroxyls-6-replaces the synthetic of isoflavone derivative; " the Mannich reaction of noroxylin " (organic chemistry,
2003, 23,81-85), report and utilized natural product noroxylin (baicalein) for research object, on its A ring 8-position carbon, carry out Mannich reaction, synthesize the Mannich alkali derivant that methylamino replaces; " Nitrogen-containing avonoid analogues as CDK1/cyclin B inhibitors:Synthesis, SAR analysis, and biological activity " (
bioorg. Med. Chem.,
2008, 16,7127-7132) react natural flavone compounds is carried out to structural modification by Mannich, synthesize the nitogen-contained heterocycle derivant of scutellarin, Quercetin; " effect of the synthetic and external short osteoblast of rabbit growth of onocol amino ethers derivative " (Chinese Journal of Pharmaceuticals,
2001, 32 (1), 9-12.) design and synthesized onocol nitrogen containing derivative.In above nitrogenous flavone derivative synthetic, it is all the synthetic nitrogenous derivative of flavonoid compound of method that adopts chemical catalysis, multistep.For flavonoid compound, in its structure, generally contain multiple groups that react, adopt the method for chemical catalysis, because controllability is not high, easily generate isomeric by product, the aftertreatments such as purifying are not easy.With respect to chemical catalysis, enzyme catalysis have ready conditions gentleness, selectivity advantages of higher, utilize enzyme catalysis, and nitrogenous active group is introduced to flavonoid compound parent, is the good approach of one of this natural product of modification.At present, with enzyme catalysis modification troxerutin, prepare nitrogenous troxerutin derivative and have no report.Meanwhile, because 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 nitrogenous troxerutin derivative that series is new; Another object is to provide does catalyzer, this type of the nitrogenous troxerutin derivative preparation method that simple, by product is few with enzyme.Another object is to provide this compounds in the application of preparing in medicine.
Nitrogenous troxerutin derivative of the present invention has following structure:
Containing the troxerutin derivative (I) of triazine ring
Containing the troxerutin derivative (II) of piperazine
In general formula I, II, n has represented the number of methylene radical, is respectively 2,3,4,5,6,7,8,9,10,11.In general formula I I, R is-H ,-CH
3,-C
2h
5,-CH (CH
3)
2,-CH
2cH
2cH
3, phenyl, tolyl, p-methoxy-phenyl, halogenophenyl.Described halogenophenyl refers to difluorophenyl, chlorophenyl, bromo phenyl.
Above-claimed cpd synthetic route is as follows:
Its synthetic method of troxerutin derivative (I) containing triazine ring realizes in the following way:
The first step: troxerutin and lipid acid divinyl ester are under the catalysis of enzyme, and take organic solvent as reaction medium, 40 ℃ ~ 60 ℃ reactions, after reaction finishes, cross post separation and obtain troxerutin vinyl acetate.
Second step: the troxerutin vinyl acetate obtaining, under enzyme catalysis, take organic solvent as reaction medium, is reacted to 40 ~ 65 ℃ of temperature of reaction with N1,N1-Dimethylbiguanide.After reaction finishes, after removal of solvent under reduced pressure, cross post separation and obtain containing triazine ring troxerutin derivative (I).
Its synthetic method of troxerutin derivative (II) containing piperazine ring realizes in the following way:
The first step: the same;
Second step: the troxerutin vinyl acetate obtaining, under enzyme catalysis, take organic solvent as reaction medium, is reacted to 50 ℃ of temperature of reaction with piperazine compounds.After reaction finishes, after removal of solvent under reduced pressure, cross post and separate the troxerutin derivative (II) obtaining 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 Cylindracea; The 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-dimethyl formamide (DMF), the trimethyl carbinol, sec-butyl alcohol, methyl-sulphoxide (DMSO) one of them or two kinds of mixtures; Preferably 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 to reacting in non-aqueous media, the enzyme therefore using can Reusability repeatedly, reduce costs; Meanwhile, the new nitrogenous troxerutin derivative of generation has anti-tumor activity, has good actual application value, for the screening of medicine provides possibility.
Embodiment
Be that the present invention is described further below in conjunction with concrete enforcement, but protection scope of the present invention is not limited in this.
Embodiment 1-1
In 100 mL Erlenmeyer flasks, take troxerutin 560 mg(0.75 mmol), vinyl hexanediacetate 582mg(3 mmol), 20 mL pyridines are solvent, add after bacillus licheniformis alkali protease 600 mg, put into 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 72h finishes, remove by filter enzyme, decompression steams pyridine.Wash away remaining pyridine with the sherwood oil of volume ratio 3:1 and the mixed solvent of chloroform, obtain after the sticky solid of brown color, column chromatography separating purification, eluent is ethyl acetate/methanol/water (15:3.6:0.5 V/V), obtain 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 respectively troxerutin hexanedioyl vinyl acetate 403mg(0.45mmol), be that 1:10 adds piperazine 387mg according to mol ratio, 15 mL pyridines are solvent, add after Lipase LS-10 lipase 500 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 72h, finish reaction.Filter, enzyme reclaims, and decompression steams pyridine.Residual solids dissolve with methanol, utilizes column chromatography to separate, and eluent is ethyl acetate/methanol/water (15:5:1 V/V), and obtaining final product is the troxerutin derivative 232mg(0.247mmol containing piperazine) be 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 troxerutin 560 mg(0.75 mmol), sebacic acid divinyl ester 756mg(3 mmol), 20 mL pyridine solvents, add after bacillus licheniformis alkali protease 600 mg, put into 60 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After 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 respectively troxerutin sebacoyl vinyl acetate 400mg(0.42mmol), be that 1:10 adds piperazine 361mg according to mol ratio, 25 mL pyridines are solvent, add after Lipase LS-10 lipase 600 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 120h, finish reaction.Filter, enzyme reclaims, and decompression steams pyridine.Aftertreatment is the same.Obtain the troxerutin derivative 208mg(0.21mmol of final product containing piperazine) be 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 respectively troxerutin hexanedioyl vinyl acetate 403mg(0.45mmol), be that 1:10 adds 1-n-propyl piperazine 576mg according to mol ratio, 25 mL pyridines are solvent, add after Lipase LS-10 lipase 600 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 120h, finish reaction.Aftertreatment is the same.Obtain the troxerutin derivative 242mg(0.248mmol of final product containing piperazine) be 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 troxerutin 560 mg(0.75 mmol), vinyl hexanediacetate 582mg(3 mmol), 20 mL pyridines are solvent, add after subtilisin proteolytic enzyme 600 mg, put into 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After 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 shown in embodiment 1-1.
In 50 mL Erlenmeyer flasks, add respectively troxerutin hexanedioyl vinyl acetate 403mg(0.45mmol), be that 1:10 adds piperazine 387mg according to mol ratio, 15 mL pyridines are solvent, add after Lipase G Amano 50 enzyme 500 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 72h, finish reaction.Aftertreatment is the same.Obtain the troxerutin derivative 190mg(0.202mmol of final product containing piperazine) be yellow solid, productive rate 44.8%.Nuclear-magnetism, infrared data are shown in embodiment 1-1.
Embodiment 1-5
In 50 mL Erlenmeyer flasks, add respectively hexanedioyl troxerutin vinyl acetate 403mg(0.45mmol), be that 1:10 adds piperazine 387mg according to mol ratio, 25 mL DMSO and trimethyl carbinol mixed solvent (volume ratio 1:1), add after Lipase LS-10 lipase 500 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 96h, finish reaction.Aftertreatment is the same.Obtain the troxerutin derivative 190mg(0.203mmol of final product containing piperazine) be yellow solid, productive rate 45%.Nuclear-magnetism, infrared data are shown in embodiment 1-1.
Embodiment 1-6
In 100 mL Erlenmeyer flasks, take troxerutin 560 mg(0.75 mmol), pentanedioic acid divinyl ester 552mg(3 mmol), 20 mL pyridines are solvent, add after bacillus licheniformis alkali protease 600 mg, put into 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After 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 respectively troxerutin glutaryl vinyl acetate 396mg(0.45mmol), be that 1:10 adds 1-(p-methoxyphenyl) piperazine 864mg according to mol ratio, 15 mL pyridines are solvent, add after Lipase LS-10 lipase 500 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 72h, finish reaction.Filter, enzyme reclaims, and decompression steams pyridine.Aftertreatment is the same.Obtaining final product is the troxerutin derivative 245mg(0.238mmol containing piperazine) be 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 respectively troxerutin hexanedioyl vinyl acetate 403mg(0.45mmol), be that 1:10 adds 1-(2-fluorophenyl) piperazine 810mg according to mol ratio, 15 mL pyridines are solvent, add after Lipase LS-10 lipase 500 mg, be placed in 50 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 72h, finish reaction.Filter, enzyme reclaims, and decompression steams pyridine.Aftertreatment is the same.Obtaining final product is the troxerutin derivative 215mg(0.211mmol containing piperazine) be 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), be that 1:4 adds N1,N1-Dimethylbiguanide 232mg according to mol ratio, 40 mL pyridines are solvent, add after Lipase G Amano 50 lipase 2g, be placed in constant temperature oscillator and react, under 50 ℃ of conditions, react.After reaction 120h, finish reaction.Filter enzyme is removed, decompression steams pyridine.Residual solids dissolve with methanol, utilizes column chromatography to separate, and eluent is ethyl acetate/methanol/water (15:3.6:1 V/V), obtains the troxerutin derivative containing 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 troxerutin 560 mg(0.75 mmol), nonane diacid divinyl ester 720mg(3 mmol), 20 mL pyridines are solvent, add after bacillus licheniformis alkali protease 700 mg, put into 40 ℃ of constant temperature oscillators and react, rotating speed 250 revmin
-1.After reaction 148h finishes, remove by filter enzyme, decompression steams pyridine.Aftertreatment is the same.Obtain yellow solid troxerutin azelaoyl 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 vinyl acetate 387mg(0.413mmol), be that 1:4 adds N1,N1-Dimethylbiguanide 213mg according to mol ratio, 20 mL pyridines are solvent, add after Lipase G Amano 50 lipase 2 g, be placed in constant temperature oscillator and react, under 60 ℃ of conditions, react.After reaction 140h, finish reaction.Aftertreatment is the same.Obtain the troxerutin derivative containing 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), be that 1:4 adds N1,N1-Dimethylbiguanide 232mg according to mol ratio, 30 mL pyridines are solvent, add after Lipase AY Amano 30 G lipase 1 g, be placed in constant temperature oscillator and react, under 45 ℃ of conditions, react.After reaction 148h, finish reaction.Aftertreatment is the same.Obtain the troxerutin derivative containing triazine ring, yellow solid, 251mg(0.261mmol), productive rate 58%.Nuclear-magnetism, infrared data are shown in embodiment 2-1.
Biological activity test: the mensuration and the tumor cell in vitro that adopt Cyclex CDK1/cyclin B kinases assay kit institute's calibration method and mtt assay that the synthetic troxerutin derivative (I) that contains triazine ring and the troxerutin derivative (II) that contains piperazine ring have been carried out respectively to inhibition CDK1/cyclin B activity suppress active mensuration.
Partial test result is as following table:
Above data presentation compound (I) and (II) the inhibition activity of CDK1/cyclin B is better than to 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 to stronger anti-tumor activity.Can set it as a kind of potential drug development.
Claims (9)
1. nitrogenous troxerutin derivative, is characterized in that, it is the troxerutin derivative containing triazine ring, has following structural formula:
（Ⅰ），
N is 2,3,4,5,6,7,8,9,10,11.
2. nitrogenous troxerutin derivative, is characterized in that, it is the troxerutin derivative containing 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 preparation method of nitrogenous troxerutin derivative as claimed in claim 1, is characterized in that, realizes by following steps:
The first step: troxerutin and lipid acid divinyl ester are under the catalysis of enzyme, and take organic solvent as reaction medium, 40 ℃ ~ 60 ℃ reactions, after reaction finishes, cross post separation and obtain troxerutin vinyl acetate;
Second step: the troxerutin vinyl acetate obtaining, under enzyme catalysis, take organic solvent as reaction medium, is reacted to 50 ℃ of temperature of reaction with N1,N1-Dimethylbiguanide; After reaction finishes, removal of solvent under reduced pressure, crosses post separation and obtains containing triazine ring troxerutin derivative (I);
Enzyme used 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 or Lipase from
candida.
4. the preparation method of nitrogenous troxerutin derivative 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 preparation method of nitrogenous troxerutin derivative as claimed in claim 2, is characterized in that, realizes by following steps:
The first step: troxerutin and lipid acid divinyl ester are under the catalysis of enzyme, and take organic solvent as reaction medium, 40 ℃ ~ 60 ℃ reactions, after reaction finishes, cross post separation and obtain troxerutin vinyl acetate;
Second step: the troxerutin vinyl acetate obtaining, under enzyme catalysis, take organic solvent as reaction medium, is reacted with piperazine compounds, 50 ℃ of temperature of reaction, after reaction finishes, after removal of solvent under reduced pressure, cross post and separate the troxerutin derivative (II) obtaining containing piperazine ring;
Enzyme used 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 or Lipase from
candida.
6. the preparation method of nitrogenous troxerutin derivative 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. the preparation method of the nitrogenous troxerutin derivative as described in claim 3 or 5, is characterized in that, the organic solvent using for pyridine,
n, N-dimethyl formamide (DMF), the trimethyl carbinol, sec-butyl alcohol, methyl-sulphoxide (DMSO) one of them or two kinds of mixtures.
8. the preparation method of the nitrogenous troxerutin derivative as described in claim 3 or 5, is characterized in that, the add-on of enzyme and the mass volume ratio of reaction solvent are 10mg/mL ~ 250 mg/mL.
9. nitrogenous troxerutin derivative as claimed in claim 1 or 2, in the application of preparing in medicine, is characterized in that, sets it as active substance and prepares anti-prostate cancer or lung-cancer medicament.
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Citations (1)
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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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| Publication number | Priority date | Publication date | Assignee | Title |
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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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| Highly regioselective enzymatic synthesis of polymerizable derivatives of methyl shikimate;Chao Li et al.;《Bioorganic & Medicinal Chemistry Letters》;20071022;第17卷;第6687–6690页 * |
| Regioselective enzymatic acylation of troxerutin in nonaqueous medium;Yong Mei Xiao et al.;《Chinese Chemical Letters》;20101231;第21卷;第59–62页 * |
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