CN102532218B - A kind of isosidine alkaloid and its preparation method and application - Google Patents
A kind of isosidine alkaloid and its preparation method and application Download PDFInfo
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- 229930013930 alkaloid Natural products 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 claims abstract 4
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- 241001279009 Strychnos toxifera Species 0.000 claims abstract 2
- 229960005453 strychnine Drugs 0.000 claims abstract 2
- 238000010189 synthetic method Methods 0.000 claims description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 1
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- 208000032839 leukemia Diseases 0.000 abstract description 14
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- 238000000338 in vitro Methods 0.000 abstract description 2
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- XBAMJZTXGWPTRM-UHFFFAOYSA-N epi-strictosidinic acid methyl ester Natural products C=CC1C(CC2C3=C(C4=CC=CC=C4N3)CCN2)C(C(=O)OC)=COC1OC1OC(CO)C(O)C(O)C1O XBAMJZTXGWPTRM-UHFFFAOYSA-N 0.000 abstract 1
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a strictosidine-like alkaloid and a pharmaceutically acceptable salt (I) of the strictosidine-like alkaloid. According to the invention, a target compound is prepared from a 2-(1-indol)-ethylamine derivative and diffractive ring strychnine in the presence of immobilized strictosidine synase. The in vitro cytotoxicity experiment of the compound provided by the invention indicates that the compound has inhibition action on K562 tumor cell growth and can be applied to preparation of a medicine for preventing and treating human chronic myelogonium leukemia. The general formula of the compound is shown in the specification.
Description
Technical field
The invention belongs to zymochemistry, pharmaceutical chemistry field, relate to a kind of piperidines diindyl class different lima bean glycosides alkaloid and preparation method and purposes with salt that can medicine.
Background technology
Terpene indole alkaloid is the large class of one in natural product, and it has pharmacologically active very widely, as antitumour activity, hypertension, anti-arrhythmia etc.The initial intermediate of key that different lima bean glycosides is most of terpene indole alkaloids, and in nature there is Pictet-Spengler reaction by tryptamines and driffractive ring vauqueline and obtain in different lima bean glycosides synthetic under strictosidine synthase (STR) catalysis.Therefore, research for strictosidine synthase has many relevant reports in the world, especially there has been to research (Joachim Stockigt more fully the aspects such as structure function of strictosidine synthase, Andrey P. Antonchick, Fangrui Wu, Herbert Waldmann, The Pictet-Spengler Reaction in Nature and in Organic Chemistry.
angewandte Chemie, 2011,50,2-29).
Summary of the invention
The object of this invention is to provide a kind different lima bean glycosides alkaloid and can medicine with salt, there is following general structure:
Wherein:
R
1, R
2, R
3, R
4identical or different, select hydrogen, halogen, containing the saturated hydrocarbyl of 1 ~ 8 carbon.
The compound being specifically related to has:
i-1: (3a, 15a, 16a, 17a)-19, the two different lima bean glycosides-17-of the dehydrogenation-16-vinyl-piperidines diindyl class β-D-Glucose glycosides of 20-;
i-2: (3a, 15a, 16a, 17a)-10-is fluoro-19, the two different lima bean glycosides-17-of the dehydrogenation-16-vinyl-piperidines diindyl class β-D-Glucose glycosides of 20-;
i-3: (3a, 15a, 16a, 17a)-12-methyl isophthalic acid 9, the two different lima bean glycosides-17-of the dehydrogenation-16-vinyl-piperidines diindyl class β-D-Glucose glycosides of 20-.
Another object of the present invention is to provide a kind different lima bean glycosides alkaloid and the preparation method with salt that can medicine thereof, is by 2-(1-indoles)-1-ethanamine derivatives (
iII) preparation formula (
i) method of compound, by following scheme, realize: by 2-(1-indoles)-1-ethanamine derivatives (
iII) and driffractive ring vauqueline (
iV) under the catalysis of (coming from snakewood) of immobilized strictosidine synthase, make piperidines diindyl class different lima bean glycosides alkaloid and can medicine with salt (
i), reaction formula is:
Wherein: R
1, R
2, R
3, R
4identical or different, select hydrogen, halogen, containing the saturated hydrocarbyl of 1 ~ 8 carbon.
Described immobilized strictosidine synthase is that the strictosidine synthase of purifying is pumped on nickel-nitrilo acetic acid pillar by constant flow pump.
A further object of the present invention is to provide a described kind different lima bean glycosides alkaloid and the application in the chronic myelogone leukemia medicament of preparation control people with salt that can medicine thereof.
The present invention is by having searched out a brand-new synthetic substrate to the analysis of the aspects such as structure activity relationship of enzyme, this substrate (comes from snakewood at strictosidine synthase, Hampp N., Zenk MH., Homogeneous strictosidine synthase from cell suspension cultures of
rauvolfia serpentine.
phytochemistry1988,27, under catalysis 3811-3815), prepare the different lima bean glycosides of brand-new piperidines diindyl class alkaloid parent nucleus, the part chemical structure of this new compound is similar to different lima bean glycosides but has its specificity, increased the diversity in terpene indole alkaloid storehouse, also for the later stage finds that new active alkaloid provides material base.Meanwhile, alkaloid involved in the present invention adopts strictosidine synthase to catalyze and synthesize gained, has avoided the shortcomings such as the low and stereoselectivity of traditional chemical synthetic method efficiency is poor.According to the whole world especially susceptibility of often swell knurl spectrum of disease and the tumour cell of China, the present invention selects the chronic myelogone leukemia cell line of people (K562) as the index of in vitro cytotoxic effect Pharmacological Evaluation, result shows that the chronic myelogone leukaemia cancer cell of people K562 cell is had to cytotoxicity, can be prepared as the new medicine with anti-chronic myelogone leukemia effect.
Embodiment
Below by specific embodiment, further illustrate the present invention.Following embodiment has provided the synthetic and dependency structure appraising datum of representative compound.Mandatory declaration, following embodiment is for the present invention rather than limitation of the present invention are described.The simple modifications that essence according to the present invention is carried out the present invention all belongs to the scope of protection of present invention.
embodiment 1: (3a, 15a, 16a, 17a)-19, the two different lima bean glycosides-17-of the dehydrogenation-16-vinyl-piperidines diindyl class β-D-Glucose glycosides of 20-(
i-1) preparation
The present invention relates to a class suc as formula (
i) shown in piperidines diindyl class different lima bean glycosides alkaloid and the synthetic method with salt that can medicine.Be specifically related to alkaloid
i-1preparation: under room temperature, 10 mg strictosidine synthases are dissolved in phosphoric acid buffer (50 mM, pH=7.0), and are fixed on nickel-nitrilo acetic acid (Ni-NTA) pillar; Get 1.60g 2-(1-indoles)-ethamine (10 mmol), be dissolved in 100 mL phosphate buffered saline buffers (50 mM, pH=7.0); Again 3.88 g driffractive ring vauquelines (10 mmol) are dissolved in the phosphate buffered saline buffer (50 mM, pH=7.0) of 100 mL; After both are mixed, by Ni-NTA post, overall flow rate is controlled as 1 milliliter of per minute, and gained effluent liquid cooled with liquid nitrogen postlyophilization, after methanol wash desalination, prepares liquid column chromatography separation and obtain corresponding product
i-1.
By unified mode, explain physics and the chemical data of the synthetic compound obtaining below.Proton nmr spectra (
1h NMR, data obtain in 500MHz nuclear magnetic resonance analyser), electrospray ionization mass spectrum (ESI – MS);
1the reagent that H NMR is used is generally deuterochloroform (CDCl
3); NMR spectrogram peak shape is expressed as: unimodal (s), bimodal (d), wide unimodal (brs), double doublet (dd), triplet (t), quartet (q); Coupling constant (
j) unit with hertz (Hz), represent; Chemical displacement value (δ) unit represents with ppm.
Compound
i-1: faint yellow solid;
1h NMR (500 MHz, CDCl
3):
δ7.52 (1H, s), 7.50 (1H, d,
j=8.0 Hz), 7.17 (1H, d,
j=8.5 Hz), 7.10 (1H, t,
j=7.5 Hz), 7.05 (1H, t,
j=7.5 Hz), 6.19 (1H, s), 5.68 (1H, m), 5.46 (1H, d,
j=6.5 Hz), 5.25 (1H, d,
j=17.5 Hz), 5.19 (1H, d,
j=10.5 Hz), 4.69 (1H, d,
j=7.0 Hz), 4.16 (1H, m), 3.98 (1H, m); 3.89 (1H, m), 3.77 (2H, m); 3.68 (3H, s), 3.59 (1H, m); 3.50 (1H, m), 3.39 (2H, m); 3.21 (1H, m), 3.06 (2H, m); 2.63 (2H, m), 1.95 (2H, m); HRMS (ESI): m/z (M)
+calculated value is 498.2002, and measured value m/z is 498.1996.
embodiment 2: compound
i-2with
i-3preparation
According to the method for embodiment 1, take corresponding 2-[1-(6-fluoro indole)]-ethamine and 2-[1-(4-skatole)]-ethamine is raw material, under the catalysis of strictosidine synthase, reacts and prepares compound with driffractive ring vauqueline respectively
i-2((3a, 15a, 16a, 17a)-10-is fluoro-19, the two different lima bean glycosides-17-of the dehydrogenation-16-vinyl-piperidines diindyl class β-D-Glucose glycosides of 20-
)and compound
i-3((3a, 15a, 16a, 17a)-12-methyl isophthalic acid 9, the two different lima bean glycosides-17-of the dehydrogenation-16-vinyl-piperidines diindyl class β-D-Glucose glycosides of 20-
).
Compound
i-2: faint yellow solid;
1h NMR (500 MHz, CDCl
3):
δ7.51 (1H, s), 7.20 (1H, m), 7.12 (1H, m), 7.06 (1H, m), 6.21 (1H, s), 5.69 (1H, m), 5.47 (1H, d,
j=6.0 Hz), 5.27 (1H, d,
j=17.5 Hz), 5.22 (1H,
j=11.5 Hz), 4.73 (1H, d,
j=7.5 Hz), 4.19 (1H, m), 4.01 (1H; m), 3.91 (1H, m); 3.82 (2H, s), 3.69 (3H; s), 3.61 – 3.30 (4H, m); 3.11 (2H, m), 2.65 (1H; m), 2.06 (2H, m); HRMS (ESI): m/z (M)
+calculated value is 516.1908, and measured value is 516.1905.
Compound
i-3: faint yellow solid;
1h NMR (500 MHz, CDCl
3):
δ7.51 (1H, s), 7.03 (2H, m), 6.86 (1H, dd,
j=7.5,2.0 Hz), 6.22 (1H, s), 5.69 (1H, m), 5.46 (1H, d,
j=6.0 Hz), 5.26 (1H, d,
j=17.0 Hz), 5.20 (1H, d,
j=11.0 Hz), 4.69 (1H, d,
j=7.5 Hz), 4.26 (1H, m), 3.99 (1H, m); 3.90 (1H, m), 3.78 (2H, m), 3.68 (3H; s), 3.59 (1H, m), 3.50 (1H, m); 3.41 (2H, m), 3.23 (1H, m); 3.10 (2H, m), 2.65 (1H, m); 2.48 (3H, s), 1.97 (2H, m); HRMS (ESI): m/z (M)
+calculated value is 512.2159, and measured value is 512.2153.
In order to understand better essence of the present invention, below by pharmacology, embodiment further illustrates the present invention.Pharmacology embodiment has provided the part activity data of representative compound.Mandatory declaration, following pharmacology embodiment is that the simple modifications that essence according to the present invention is carried out the present invention all belongs to the scope of protection of present invention for the present invention rather than limitation of the present invention are described.
embodiment 3:compound
i-1cytotoxic activity to the chronic myelogone leukemia cell of people (K562)
The chronic myelogone leukemia cell of people (K562), by RPMI 1640 culture medium culturing, contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate in substratum.Cell is with every hole 1 * 10
4individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2in the incubator of damp atmosphere, cultivate 24 hours.
Improvement mtt assay for the measuring method of cell survival rate.Cell is after 24 hours hatch, respectively by the compound of newly joining
i-1the dimethyl sulfoxide solution ultimate density that joins compound in Zhong，Shi hole, each hole with concentration gradient be respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), then continue at 37 ℃ 5%CO
2in the incubator of damp atmosphere, cultivate 3 hours, in every hole, add 150 milliliters of methyl-sulphoxides, the MTT crystal formazan (formazan) generating is dissolved in vibration, microplate reader colorimetric under 570 nm wavelength for formed formazan, and cell survival rate is the ratio calculation for contrast OD value by sample OD value.Compound wherein
i-1half-inhibition concentration (IC to K562 cell
50) by dose effect curve, obtained.Compound
i-1iC
50for: 61.3 μ M.
This test is usingd an antitumor line medication camptothecine (CPT) as positive control, the 503nhibiting concentration IC of CPT to the chronic myelogone leukemia cell of people
50be 0.6 μ M.
This experiment shows that the different lima bean glycosides of this type of piperidines diindyl class alkaloid has cytotoxicity to the chronic myelogone leukaemia cancer cell of people K562 cell, can be prepared as the new medicine with anti-chronic myelogone leukemia effect.
embodiment 4:compound
i-2, I-3cytotoxic activity to the chronic myelogone leukemia cell of people (K562)
According to the method for embodiment 3, compound
i-2 and I-3with with embodiment 4 in
i-1identical method and concentration gradient join in 96 orifice plates of hatching K562 cell, according to the mtt assay identical with embodiment 4 and dose effect curve, obtain compound respectively to the chronic myelogone leukemia K 562 of people cell 503nhibiting concentration IC
50, result is referring to table 1.
Table 1 compound
i-2and
i-3to K562 cell 503nhibiting concentration IC
50(μ M)
| Compound number | I-2 | I-3 |
| IC 50 | 35.2 | 42.7 |
This experiment shows that the different lima bean glycosides of this type of piperidines diindyl class alkaloid has cytotoxicity to the chronic myelogone leukaemia cancer cell of people K562 cell, can be prepared as the new medicine with anti-chronic myelogone leukemia effect.
Claims (4)
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0156267A2 (en) * | 1984-03-21 | 1985-10-02 | Gyogynöveny Kutato Intezet | Method for the preparation of strictozidin |
| WO2001030753A2 (en) * | 1999-10-25 | 2001-05-03 | Stephen F. Austin State University | Enhancement of production of camptothecins from plants |
| CN101805383A (en) * | 2010-04-09 | 2010-08-18 | 浙江大学 | Strictosidine lactam derivatives and preparation method and use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0156267A2 (en) * | 1984-03-21 | 1985-10-02 | Gyogynöveny Kutato Intezet | Method for the preparation of strictozidin |
| WO2001030753A2 (en) * | 1999-10-25 | 2001-05-03 | Stephen F. Austin State University | Enhancement of production of camptothecins from plants |
| CN101805383A (en) * | 2010-04-09 | 2010-08-18 | 浙江大学 | Strictosidine lactam derivatives and preparation method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| Peter Bernhardt，et al..Rapid Identification of Enzyme Variants for Reengineered Alkaloid Biosynthesis in Periwinkle.《Chemistry & Biology》.2007,888-897. * |
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