CN107936021A - Three（R）Tetrahydrochysene Angustine derivatives and preparation and use - Google Patents
Three（R）Tetrahydrochysene Angustine derivatives and preparation and use Download PDFInfo
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- CN107936021A CN107936021A CN201710944276.9A CN201710944276A CN107936021A CN 107936021 A CN107936021 A CN 107936021A CN 201710944276 A CN201710944276 A CN 201710944276A CN 107936021 A CN107936021 A CN 107936021A
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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Abstract
The present invention provides three (R) tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt, using tryptamines and driffractive ring strychnia starting material, is obtained by series of chemical.The present invention is by simply chemically reacting and purification process, the polycyclic parent nucleus compound of a kind of single chiral is synthesized, such compound has prominent external topoisomerase I inhibitory activity and external anti-HepG2 tumor promotions, can be applied in topoisomerase I inhibitor series antineoplastic medicament is prepared.Three compounds have following structural formula：
Description
Technical field
The invention belongs to pharmaceutical chemistry and area of pharmacology, is related to (R)-tetrahydrochysene Angustine derivatives and preparation, and should
Purposes of the class compound as topoisomerase I inhibitor in antitumor drug is prepared.
Background technology
Topoisomerase I (Topo I) is a very important enzyme during DNA uncoiling, is widely present in lactation life
In thing.It is phosphate-based in the OH group nucleophilic attack DNA chain of tyrosine in the avtive spot of TopoI in DNA uncoiling
Group, makes a DNA chain fracture, and the DNA chain being then broken is rotated around unbroken DNA chain, finally makes DNA uncoiling.Anticancer
The research and development of medicine are one of heat subjects of current drug research, and Topo I are the important target spots of oncotherapy.From being distributed in
The camptothecine extracted in Central-South, the southwestern camplotheca acuminata of China, as classical topoisomerase I inhibitor, has outstanding
Antitumor activity, and derive a series of camptothecin cancer therapy drugs, such as topotecan, Irinotecan.
Tetrahydrochysene Angustine alkaloids are found to be distributed widely in Nauclea sections plant, their indoles simultaneously [2':
3',3:4] pyrido [1,2-b] naphthyridines mother nucleus structure has attracted chemists' note that several fully synthetic methods are also carried
Go out, but there are the problems such as reaction scheme is tediously long, severe reaction conditions, low yield.(R)-tetrahydrochysene Angustine alkaloids are once reported
Road is crossed to be obtained by the isolated Vincosamide of plant through structural modification, but Adams, dense is used in the reaction scheme
This kind of reagent to consersion unit harshness of ammonium hydroxide, and N- derivatizations are not carried out to (R)-tetrahydrochysene Angustine alkaloids.In addition,
Its raceme tetrahydrochysene Angustine alkaloids are only reported with anti-T-24, MK proliferative activity o f tumor and anti-inflammatory activity, its
Pharmacological activity and action target spot still need to be explored.
The content of the invention
The object of the present invention is to provide three (R)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt, has following
Structural formula：
It is a further object to provide the preparation side of (R)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt
Method, is realized by following scheme：Under chemical acid catalysis Pictet- occurs for tryptamines (II) and driffractive ring strychnia (III)
Spengler (PS) reactions obtain raceme product, but dissolubility is poor in the reaction system for R anomeric products, with precipitation form
Separate out, be separated by filtration to obtain single R configuration of compound Vincosamide (IV), with hydrogen (H2) 10%Pd reduction IV be made
Compound V, compound V slough glucose and compound VI, chemical combination are made under the action of glucuroide (Glucosldase)
Thing VI and ammonium acetate (NH4OAc obtained compound VII) is reacted, compound VII makes under the catalysis of p-methyl benzenesulfonic acid (p-TsOH)
Compound VIII is obtained, compound VIII occurs substitution reaction under the action of inorganic base, with R-X (acyl chlorides reagent) and compound is made
I.Wherein, selected as the chemistry acid used in tryptamines (II) and driffractive ring strychnia (III) prepare IV in acetic acid, hydrochloric acid, sulfuric acid
Any one, inorganic base used is selected any in sodium hydride, potassium tert-butoxide, sodium hydroxide when preparing I by compound VIII
It is a kind of.Synthetic reaction formula is：
It is different as topology it is yet another object of the invention to provide (R)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt
Application of the structure enzyme I inhibitor in antitumor drug is prepared.Topoisermerase I Inhibition test shows in vitro, (R)-tetrahydrochysene
Angustine derivatives have topoisermerase I good inhibitory action；Pharmacological evaluation shows in vitro, (R)-tetrahydrochysene
Angustine derivatives have HepG2 cell lines preferably suppresses value-added effect in vitro.
Using tryptamines and driffractive ring strychnia the R anomeric products that PS reacts occur under chemical acid catalysis for the present invention
Dissolubility is poor in the reaction system by Vincosamide, the characteristic separated out with precipitation form, by filter type, from raceme
Isolated single R anomeric products Vincosamide in product, then obtain (R)-tetrahydrochysene Angustine through structural modification and derive
Thing, and find that wherein there is prominent TopoI inhibitory activity and the compound of external anti-HepG2 tumor promotions.The present invention passes through
Simple chemical mode, has synthesized the polycyclic parent nucleus compound of a kind of single chiral, and explores the topology of this kind of compound
Isomerase I inhibitory activity, shows good anti-HepG2 proliferative activity o f tumors.
Brief description of the drawings
Fig. 1 is synthesis (R)-tetrahydrochysene Angustine derivatives (500 μM) to the external inhibitory activity results of TopoI.
Embodiment
The present invention is further illustrated below by specific embodiment.Following embodiments give the conjunction of representative compound
Into and dependency structure appraising datum.Mandatory declaration, following embodiments are to be used to illustrate rather than limitation of the present invention.
The simple modifications that essence carries out the present invention according to the present invention belong to the scope of protection of present invention.
Embodiment 1：It is prepared by the chemical acid catalyzed process of 3 β (R)-Vincosamide (IV)
Under nitrogen protection, it is tryptamines II (0.4g, 2.5mmol) and driffractive ring strychnia III (1.1g, 2.5mmol) is molten
Solution adds 500 μ l acetic acid, when 100 DEG C of reactions 6 are small in 10ml pure water.After the completion of question response, yellow solid is obtained by filtration,
It is washed with water 3 times, obtains 3 β (R)-Vincosamide (IV) 0.54g, yield 46%.
Embodiment 2：The preparation of 3 β (R)-dihydro Vincosamide (V)
Compound IV (3.00g, 6.00mmol) is dissolved in 50ml methanol, adds 10% palladium carbon (300mg) and in room temperature
Lower reaction overnight, is filtered to remove palladium carbon, and vacuum distillation removes solvent, obtains yellow solid 2.98g, yield 98%.
Embodiment 3:The preparation of 3 β (R)-dihydro Vincosamide aglycons (VI)
Compound V (300mg, 0.6mmol) is dissolved in acetic acid-sodium acetate buffer solution (pH=5.0,100ml), is added
5.0mg glucuroides, are incubated 3 days at 37 DEG C, are then extracted with ethyl acetate (50mL × 3), merge organic phase, are concentrated under reduced pressure
Crude product is obtained, then carries out rapid column chromatography, obtains yellow oily liquid 158mg, yield 75%.
Embodiment 4:(1R, 13bS, 14aS) -1- ethyl -2- hydroxyls -1,2,3,7,8,13b, 14,14a- octahydros indoles is simultaneously
[2',3':3,4] preparation of pyrido [1,2-b] [2,7] naphthyridines -5 (13H) -one (VII)
Compound VI (150mg, 0.44mmol) is dissolved in 1mL ethanol, ammonium acetate (340mg, 4.4mmol) is added, 80
DEG C reaction 6 it is small when.After the completion of reaction, vacuum distillation removes ethanol, and carries out rapid column chromatography, obtains product 125mg, directly throws
Enter the next step.
Embodiment 5:(S) -1- ethyls -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2-b] [2,7]
The preparation of naphthyridines -5 (13H) -one (VIII)
Compound VII (125mg) is dissolved in 5mL toluene, the p-methyl benzenesulfonic acid of catalytic amount is added, when 80 DEG C of reactions 5 are small.Treat
After the completion of reaction, vacuum distillation removes toluene and obtains crude product, and yellow solid 40mg, yield 40% are obtained through column chromatography.
Embodiment 6：(R) -1- benzoyls -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2-b]
[2,7] preparation of naphthyridines -5 (13H) -one (I-a)
Compound VIII (10mg, 0.03mmol) is dissolved in 1mL tetrahydrofurans, under nitrogen protection, is added dropwise to ice
In THF (0.5mL) suspension of t-BuOK (8mg, 0.06mmol), stir 20 minutes, then chlorobenzoyl chloride (0.05mmol) is added
Enter in reaction system, reaction 3-4 it is small when.After the completion of question response, add saturated ammonium chloride solution and be quenched, ethyl acetate extraction (3
× 3mL), merge organic phase, vacuum distillation removes organic solvent, obtains crude product, obtained through column chromatography, white solid 8mg, yield
61%.1H NMR(500MHz,CDCl3):δ=9.15 (1H, s), 8.49 (1H, s), 7.80 (2H, d, J=7.0Hz), 7.72
(1H, t, J=7.5Hz), 7.58 (2H, t, J=7.0Hz), 7.54 (1H, d, J=7.5Hz), 7.23 (1H, t, J=7.0Hz),
7.06 (1H, t, J=7.5Hz), 6.62 (1H, d, J=7.5Hz), 5.46 (1H, d, J=13.0Hz), 5.31 (1H, ddd, J=
), 13.0,5.0,1.5Hz 3.46 (1H, dd, J=16.0,3.5Hz), 3.09 (1H, td, J=12.0,3.5Hz), 3.00 (1H,
M), 2.93 (1H, m), 2.74 (1H, dd, J=16.0,13.0Hz), 2.53 (2H, q, J=7.5Hz), 1.10 (3H, t, J=
7.5Hz)；13C NMR(125MHz,CHCl3):δ=169.4,163.7,152.0,148.1,143.1,140.3,137.2,
135.0,134.8,133.4,133.2,132.0,129.3,128.5,124.3,123.2,119.3,118.9,114.4,52.0,
38.2,30.9,23.0,21.5,14.3.HRESI-MS[M+H]+422.1869。
Embodiment 7：(R) -1- (4- chlorobenzoyls chloro) -7,8,13b, 14- tetrahydro indoles simultaneously [2', 3':3,4] pyrido
The preparation of [1,2-b] [2,7] naphthyridines -5 (13H) -one (I-b)
Operating process simply replaces chlorobenzoyl chloride with 4- chlorobenzoyl chlorides, obtains white-yellowish solid, receive referring to embodiment 6
Rate 58%.1H NMR(500MHz,CDCl3):δ=9.18 (1H, s), 8.54 (1H, s), 7.80 (2H, d, J=8.0Hz), 7.59
(2H, d, J=8.0Hz), 7.57 (1H, d, J=7.5Hz), 7.28 (1H, t, J=7.0Hz), 7.11 (1H, t, J=7.5Hz),
6.65 (1H, d, J=7.5Hz), 5.51 (1H, d, J=13Hz), 5.31 (1H, dd, J=13.0,5.0Hz), 3.46 (1H, dd, J
=16.0,3.5Hz), 3.11 (1H, td, J=12.0,3.5Hz), 3.01 (1H, m), 2.91 (1H, m), 2.75 (1H, dd, J=
), 16.0,13.0Hz 2.55 (2H, q, J=7.5Hz), 1.13 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=
168.3,163.6,151.9,147.9,143.2,140.1,137.0,134.8,133.0,128.7,128.6,124.5,
123.4,119.7,119.0,114.3,52.0,38.2,30.9,23.0,21.4,14.3.HRESI-MS[M+H]+456.1479。
Embodiment 8：(R) -1- acetyl group -7,8,13b, 14- tetrahydro indole simultaneously [2', 3':3,4] pyrido [1,2-b] [2,
7] preparation of naphthyridines -5 (13H) -one (I-c)
Operating process simply replaces chlorobenzoyl chloride with chloroacetic chloride, obtains white solid, yield 38% referring to embodiment 6.1H
NMR(500MHz,CDCl3):δ=9.17 (1H, s), 8.51 (1H, s), 7.75 (1H, t, J=8.0Hz), 7.56 (1H, d, J=
8.0Hz), 7.08 (1H, t, J=8.0Hz), 6.64 (1H, d, J=8.0Hz), 5.59 (1H, d, J=13.0Hz), 5.31 (1H,
Dd, J=13.0,5.0Hz), 3.48 (1H, dd, J=16.0,3.5Hz), 3.11 (1H, td, J=12.0,3.5Hz), 3.02
(1H, m), 2.96 (3H, s), 2.86 (1H, m), 2.75 (1H, dd, J=16.0,13.0Hz), 2.55 (2H, q, J=7.5Hz),
1.12 (3H, t, J=7.5Hz)；13C NMR(125MHz,CHCl3):δ=169.4,163.7,152.0,148.0,141.8,
136.0,135.3,131.9,129.6,125.0,123.6,122.1,119.5,119.3,114.5,53.8,38.2,31.6,
27.6,21.4,14.7.HRESI-MS[M+H]+360.1712。
To better understand the essence of the present invention, further illustrate the present invention below by Pharmacological Examples.Pharmacology is real
Apply the amount of activated data that example gives representative compound.Mandatory declaration, following Pharmacological Examples are to be used to illustrate the present invention
Rather than limitation of the present invention, the simple modifications that essence carries out the present invention according to the present invention belong to application claims and protect
The scope of shield.
Embodiment 9:Anti-tumor biological test method：
Tumour cell cultured in vitro：Tumour cell HepG2 is chosen in 37 DEG C, 5%CO2It is incubated in cell incubator, band is thin
After born of the same parents' density grows to 70-90%, passed on after being digested with Puck ' s EDTA, for test later needed for.
Mtt assay measures external antiproliferative effect of (R)-tetrahydrochysene Angustine derivatives to HepG2 tumour cells：
HepG2 tumour cells in exponential phase are diluted to 4 × 104A cell/ml, in 96 porocyte culture plates
In per hole add 0.1ml, then add concentration be 20.0 μM, 10.0 μM, 5.0 μM, 1.0 μM of testing compound, jointly in 37
DEG C, 5%CO2It is control with DMSO (1%) when incubation 72 is small in cell incubator.72 it is small when after, add it is final concentration of
The MTT of 0.25mg/ml, in 7 DEG C, 5%CO2When incubation 4 is small in cell incubator, solvent is blotted afterwards, and 100 μ L are added per hole
DMSO, absorbance (OD values) is measured with enzyme linked immunological instrument at 570nm, and the data obtained is used to calculate IC50.Acquired results are shown in Table 1.
IC of (the R)-tetrahydrochysene Angustine derivatives that table 1 synthesizes to HepG2 tumour cells50(μM) value
It can be seen that compound I series shows human liver cancer HepG2 tumor cell lines in good suppression work from upper table 1
With, it is possible to develop into the new medicine with antihepatocarcinoma effect.
Embodiment 10:(R)-tetrahydrochysene Angustine derivatives are to the external inhibitory activity test method of topoisermerase I：
Each 1 μ l of sample are taken, is mixed with 10 × Topo I reaction buffer, 1 μ l, adds 1 μ l of 0.1%BSA,
1 μ l and Topo I (0.2U/ μ l) of pBR322 DNA (50ng/ μ l), 1 μ l, are finally settled to 10 μ l with DEPC water, put 37 DEG C.Water-bath
Reacting 30min, [every group of experiment is all provided with blank control and negative control.Topo I and drug sample are not added with blank control, that is, system
(200 μM), volume is supplied with DEPC water；Drug sample is not added with negative control, that is, system, equally supplies volume with DEPC water].
After water-bath, 6 × Loading Buffer, 2 μ L are added in above-mentioned each reaction solution (10 μ l), are splined on
On 0.8% Ago-Gel, electrophoresis is carried out in tbe buffer liquid, under 100V voltages 60 minutes.After sixty minutes, electrophoresis is finished
Glue is placed in (EB) solution of bromination second shallow lake and dyes, and gel imaging is simultaneously analyzed.Acquired results are shown in Fig. 1.Fig. 1 the result shows that, compound I
Series has Topo I good inhibitory activity, is expected to become new topoisomerase I inhibitor.
Claims (5)
1. three (R)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt, have following structural formula：
2. the preparation method of three (the R)-tetrahydrochysene Angustine derivatives and its pharmaceutically useful salt described in claim 1, it is special
Sign is, is realized by following steps：Under chemical acid catalysis Pictet- occurs for tryptamines (II) and driffractive ring strychnia (III)
Spengler (PS) reactions obtain raceme product, but dissolubility is poor in the reaction system for R anomeric products, with precipitation form
Separate out, be separated by filtration to obtain single R configuration of compound Vincosamide (IV), with hydrogen (H2) 10%Pd reduction IV be made
Compound V, compound V slough glucose and compound VI, chemical combination are made under the action of glucuroide (Glucosldase)
Thing VI and ammonium acetate (NH4OAc obtained compound VII) is reacted, compound VII makes under the catalysis of p-methyl benzenesulfonic acid (p-TsOH)
Compound VIII is obtained, compound VIII occurs substitution reaction under the action of inorganic base, with R-X (acyl chlorides reagent) and compound is made
I.Wherein, selected as the chemistry acid used in tryptamines (II) and driffractive ring strychnia (III) prepare IV in acetic acid, hydrochloric acid, sulfuric acid
Any one, inorganic base used is selected any in sodium hydride, potassium tert-butoxide, sodium hydroxide when preparing I by compound VIII
It is a kind of.Synthetic reaction formula is：
3. the preparation method of (R)-tetrahydrochysene Angustine derivatives according to claim 2 and its pharmaceutically useful salt, it is special
Sign is, is selected as the chemistry acid used in tryptamines (II) and driffractive ring strychnia (III) prepare IV in acetic acid, hydrochloric acid, sulfuric acid
Any one.
4. the preparation method of (R)-tetrahydrochysene Angustine derivatives according to claim 2 and its pharmaceutically useful salt, it is special
Sign is that inorganic base used is selected any one in sodium hydride, potassium tert-butoxide, sodium hydroxide when preparing I by compound VIII
Kind.
5. (R)-tetrahydrochysene Angustine derivatives according to claim 1 and its pharmaceutically useful salt are different as a kind of topology
Application of the structure enzyme I inhibitor in antitumor drug is prepared.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824678A (en) * | 2019-03-20 | 2019-05-31 | 浙江大学 | A kind of azatropylidene indoles alkaloid and preparation and anti-malarial purposes |
-
2017
- 2017-10-12 CN CN201710944276.9A patent/CN107936021A/en active Pending
Non-Patent Citations (3)
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| C.A.J.ERDELMEIER ET AL.: "Indole Alkaloids with in vitro Antiproliferative Activity from the Ammoniacal Extract of Nauclea orientalis", 《PLANTA MED.》 * |
| GUOQIANG DONG ET AL.: "Selection of Evodiamine as a Novel Topoisomerase I Inhibitor by Structure-Based Virtual Screening and Hit Optimization of Evodiamine Derivatives as Antitumor Agents", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 祝华建: "STR1表达体系优化，新底物发现与新吲哚生物碱化学法制备及杂环化合物的构建", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824678A (en) * | 2019-03-20 | 2019-05-31 | 浙江大学 | A kind of azatropylidene indoles alkaloid and preparation and anti-malarial purposes |
| CN109824678B (en) * | 2019-03-20 | 2020-06-19 | 浙江大学 | Azole indole alkaloid, preparation and antimalarial application thereof |
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Application publication date: 20180420 |