CN106243071A - New derivatives of tanshinone IIA and its preparation method and application - Google Patents
New derivatives of tanshinone IIA and its preparation method and application Download PDFInfo
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- CN106243071A CN106243071A CN201610559712.6A CN201610559712A CN106243071A CN 106243071 A CN106243071 A CN 106243071A CN 201610559712 A CN201610559712 A CN 201610559712A CN 106243071 A CN106243071 A CN 106243071A
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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Abstract
New derivatives that the invention discloses tanshinone IIA and its preparation method and application, wherein, this new derivatives molecular formula: C18H20O4, Mass:300.14, structural formula:It can be applied in the medicine of the tumors such as preparation suppression gastric cancer, colon cancer, breast carcinoma, hepatocarcinoma, pulmonary carcinoma.The invention have benefit that: the new derivatives that (1) present invention prepares can be directly targeted HMGB1, effectively suppression kinds of tumor cells propagation, and normal cell is had not significant impact；(2) preparation method is stable, simple and direct, easy, and the compound property prepared is stable, and purity is high.
Description
Technical field
New derivatives that the present invention relates to tanshinone IIA and its preparation method and application, belongs to biochemical field.
Background technology
Chemotherapy is key one ring in Multimodality Therapy of Malignant Tumors strategy, and it is pre-that its Drug therapy reactivity clearly affects patient
After.Research and development new type antineoplastic medicine, just becomes the important directions of oncotherapy research.High-arsenic lead (HMGB1) exists
Each core link of tumor development all plays a significant role.There is HMGB1 gene overexpression in Several Kinds of Malignancy, and with
The prognosis of malignant tumor is correlated with.In addition, there will be research and find that HMGB1 is inflammatory factor important in sepsis.HMGB1 is as one
Plant important inflammatory mediator and proinflammatory cytokine, be the central element starting and maintaining the reaction of inflammation waterfall type, with multiple inflammation
The pathogenesis of disease property disease and autoimmune disease is in close relations.Therefore, novel HMGB1 function inhibitor is researched and developed, not only
For inflammation associated treatment, there is important function, especially as antitumor drug, will for improve malignant tumor medicine chemotherapy with
And combined therapy effect provides new selection.
Summary of the invention
New derivatives that it is an object of the invention to provide tanshinone IIA and its preparation method and application, wherein, this is new
Type derivant can not only effectively suppress tumor cell proliferation, and all have inhibitory action to kinds of tumor cells, and aligns
Often cell has not significant impact effect, and the method preparing this new derivatives is easy, quick, obtained compound purity is high,
Without other impurity, and through repeatedly verifying, available high-purity, the compound of stable in properties.
In order to realize above-mentioned target, the present invention adopts the following technical scheme that:
The new derivatives of tanshinone IIA, it is characterised in that molecular formula: C18H20O4, Mass:300.14, structural formula:
The method preparing the new derivatives of aforesaid tanshinone IIA, it is characterised in that comprise the following steps:
Step one, synthesis
(1) by precursor Angene 024-021-75 and BBr3At CH2Cl2Middle reaction 4h, reaction temperature be-78 DEG C to often
Temperature, generation product TSA518, wherein,
The molecular formula of precursor Angene 024-021-75: C13H18O, Mass:190.14, structural formula:
The molecular formula of product TSA518: C12H16O, Mass:176.12, structural formula:
(2) at malonic acid and 85%P2O5In the presence of, product TSA518 is mixed with polyphosphoric acids, at 75 DEG C of bars
Reaction 3h under part, generation product TSA519, wherein,
The molecular formula of product TSA519: C15H16O3, Mass:244.11, structural formula:
(3) in the presence of toluene/ethanol, product TSA519 is mixed with chlroacetone, acetic acid/ammonium acetate, backflow
24h, by series connected alkylation/intramolecular aldol reaction, generates product TSA520, wherein,
The molecular formula of product TSA520: C18H18O3, Mass:282.13, structural formula:
(4) adding the ethanol solution containing 5%KOH in product TSA520, backflow 3h, product TSA520 are hydrolyzed by KOH,
The complex TSA521 of generation open loop, wherein,
The molecular formula of product TSA521: C18H20O4, Mass:300.14, structural formula:
Step 2, purification
Use rp-hplc method, the product of generation is crossed C18 post, cross column purification, with the water containing 0.05% trifluoroacetic acid
For flowing phase, the water by containing 0.05% trifluoroacetic acid: containing the methanol of 0.05% trifluoroacetic acid, proportioning is from 70:30 to 30:
70 linear elutions at least 30min, flow velocity 1.0mL/min, being eluted to about 28min can isolated product TSA521.
The invention have benefit that:
(1) new derivatives
High-arsenic lead (HMGB1) all plays a significant role at each core link of tumor development.Many
Plant malignant tumor and there is HMGB1 gene overexpression, and relevant to the prognosis of malignant tumor, it is novel derivative that the present invention prepares
Thing can be directly targeted HMGB1, effectively suppression kinds of tumor cells propagation, and has not significant impact for normal cell, this
For research and development new type antineoplastic medicine, provide new selection for improving malignant tumor medicine chemotherapy and combined therapy effect.
(2) preparation method
Preparing this new derivatives by chemosynthesis, rp-hplc purification, method is stable, simple and direct, easy.
Through repeatedly verifying, using the compound property obtained by the method stable, purity is high, it is possible to effectively suppress
HMGB1 activity, and possess the potentiality carrying out commercial application.
Accompanying drawing explanation
Fig. 1 is the flow chart of the new derivatives preparing tanshinone IIA；
Fig. 2 is TSA521 Yu HMGB1 affinity analysis chart；
Fig. 3 (a) be TSA521 under 100 μMs of dosage, the proliferative conditions of MCF-7 cell；
Fig. 3 (b) is the proliferative conditions of matched group MCF-7 cell；
Fig. 4 (a) be TSA521 under 50 μMs of dosage, the proliferative conditions of Hela cell；
Fig. 4 (b) is the proliferative conditions of matched group Hela cell；
Fig. 5 (a) be TSA521 under 100 μMs of dosage, the proliferative conditions of HepG2 cell；
Fig. 5 (b) is the proliferative conditions of matched group HepG2 cell；
Fig. 6 (a) be TSA521 under 100 μMs of dosage, the proliferative conditions of normal people HuPBMCs；
Fig. 6 (b) is the proliferative conditions of matched group normal people HuPBMCs.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention made concrete introduction.
One, the structure of the new derivatives of tanshinone IIA
The new derivatives of the tanshinone IIA that the present invention proposes, is designated as TSA521, its molecular formula: C18H20O4, Mass:
300.14, structural formula:
Two, preparation method
Step one, synthesis
(1) by precursor Angene 024-021-75 and BBr3At CH2Cl2Middle reaction 4h, reaction temperature be-78 DEG C to often
Temperature, generates product TSA518.Wherein,
The molecular formula of precursor Angene 024-021-75: C13H18O, Mass:190.14, structural formula:
The molecular formula of product TSA518: C12H16O, Mass:176.12, structural formula:
Being computed, the yield of product TSA518 is 85%.
(2) at malonic acid and 85%P2O5In the presence of, product TSA518 is mixed with polyphosphoric acids (PPA), 75
React 3h under the conditions of DEG C, generate product TSA519.Wherein,
The molecular formula of product TSA519: C15H16O3, Mass:244.11, structural formula:
Being computed, the yield of product TSA519 is 30%.
(3) in the presence of toluene (or ethanol), product TSA519 is mixed with chlroacetone, acetic acid (or ammonium acetate)
Closing, reflux 24h, reacts (or intramolecular aldol reaction) by series connected alkylation, generates product TSA520.Wherein,
The molecular formula of product TSA520: C18H18O3, Mass:282.13, structural formula:
Being computed, the yield of product TSA520 is 80%.
(4) adding the ethanol solution containing 5%KOH in product TSA520, backflow 3h, product TSA520 are hydrolyzed by KOH,
Generate the complex TSA521 of open loop.Wherein,
The molecular formula of product TSA521: C18H20O4, Mass:300.14, structural formula:
Being computed, the yield of product TSA521 is 55%.
2, purification
Use rp-hplc method, the product of generation is crossed C18 post (phenomene × primesphers 5 C18
MC.11DA.250 × 45mm), cross column purification, with the water containing 0.05% trifluoroacetic acid for flowing phase, (contained by water
0.05% trifluoroacetic acid): methanol (containing 0.05% trifluoroacetic acid), proportioning from 70:30 to 30:70 linear elution at least 30min,
Flow velocity 1.0mL/min, being eluted to about 28min can isolated product TSA521.
Identified, the m/z=300.14 of product TSA521, there are maximum light absorption value, corresponding chemistry to divide at 283.8nm
Minor is C18H20O4, structural formula is:
Three, functional analysis
1, TSA521HMGB1 affinity is analyzed:
We utilize surface plasma body resonant vibration analytical technology to be studied the affinity of TSA521 with HMGB1.
Fig. 2 is TSA521 Yu HMGB1 affinity analysis chart.
As shown in Figure 2: surface TSA521 Yu HMGB1 has good affinity.
2, Suppressive effect:
Utilizing kinds of tumor cells, the oncobiology effect of TSA521 is studied by we.
Fig. 3 (a) be TSA521 under 100 μMs of dosage, the proliferative conditions of MCF-7 cell.
Fig. 4 (a) be TSA521 under 50 μMs of dosage, the proliferative conditions of Hela cell.
Fig. 5 (a) be TSA521 under 100 μMs of dosage, the proliferative conditions of HepG2 cell.
Fig. 6 (a) be TSA521 under 100 μMs of dosage, the proliferative conditions of normal people HuPBMCs.
Fig. 3 (b), Fig. 4 (b), Fig. 5 (b) and Fig. 6 (b) are the proliferative conditions of matched group.
From above-mentioned 8 width figures: in the case of giving TSA521 (dosage is respectively 50 μMs, 100 μMs), kinds of tumors is thin
Born of the same parents, including MCF-7, Hela, HepG2 etc., its propagation is significantly suppressed；But for normal human peripheral blood single nucleus cell
(HuPBMCs), the TSA521 of application Isodose, cell proliferation is not significantly affected.
Preliminary research confirms, TSA521 has clear and definite inhibitory action, but do not has normal cell kinds of tumor cells
There is significantly impact.
Conclusion: the new derivatives (TSA521) of the tanshinone IIA of the present invention can be applied at preparation suppression gastric cancer, colon
In the medicine of the tumors such as cancer, breast carcinoma, hepatocarcinoma, pulmonary carcinoma.
Become it should be noted that above-described embodiment limits the present invention, all employing equivalents or equivalence the most in any form
The technical scheme that the mode changed is obtained, all falls within protection scope of the present invention.
Claims (4)
1. the new derivatives of tanshinone IIA, it is characterised in that molecular formula: C18H20O4, Mass:300.14, structural formula:
2. the method for the new derivatives of preparation tanshinone IIA described in claim 1, it is characterised in that comprise the following steps:
Step one, synthesis
(1) by precursor Angene 024-021-75 and BBr3At CH2Cl2Middle reaction 4h, reaction temperature be-78 DEG C to room temperature, raw
One-tenth product TSA518, wherein,
The molecular formula of precursor Angene 024-021-75: C13H18O, Mass:190.14, structural formula:
The molecular formula of product TSA518: C12H16O, Mass:176.12, structural formula:
(2) at malonic acid and 85%P2O5In the presence of, product TSA518 is mixed with polyphosphoric acids, under the conditions of 75 DEG C
Reaction 3h, generation product TSA519, wherein,
The molecular formula of product TSA519: C15H16O3, Mass:244.11, structural formula:
(3) in the presence of toluene/ethanol, being mixed with chlroacetone, acetic acid/ammonium acetate by product TSA519, reflux 24h,
By series connected alkylation/intramolecular aldol reaction, generate product TSA520, wherein,
The molecular formula of product TSA520: C18H18O3, Mass:282.13, structural formula:
(4) adding the ethanol solution containing 5%KOH in product TSA520, backflow 3h, product TSA520 are hydrolyzed by KOH, generate
The complex TSA521 of open loop, wherein,
The molecular formula of product TSA521: C18H20O4, Mass:300.14, structural formula:
Step 2, purification
Use rp-hplc method, the product of generation is crossed C18 post, cross column purification, with the water containing 0.05% trifluoroacetic acid for stream
Dynamic phase, the water by containing 0.05% trifluoroacetic acid: containing the methanol of 0.05% trifluoroacetic acid, proportioning is from 70:30 to 30:70 line
Property eluting at least 30min, flow velocity 1.0mL/min, being eluted to about 28min can isolated product TSA521.
3. the new derivatives of the tanshinone IIA described in claim 1 application in the medicine of preparation suppression tumor.
Application the most according to claim 3, it is characterised in that described tumor includes: gastric cancer, colon cancer, breast carcinoma, liver
Cancer, pulmonary carcinoma.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922384A (en) * | 2019-11-14 | 2020-03-27 | 中国科学院昆明植物研究所 | Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with anti-platelet activity and application thereof |
Citations (2)
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| WO2010080414A2 (en) * | 2008-12-19 | 2010-07-15 | The University Of North Carolina At Chapel Hill | Substituted fno (2-[furan-2-yl] naphthalen-1-ol) derivatives as anti-cancer agents |
| CN103193860A (en) * | 2013-03-11 | 2013-07-10 | 常州大学 | Tanshinone compounds, preparation method and use thereof |
-
2016
- 2016-07-15 CN CN201610559712.6A patent/CN106243071A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010080414A2 (en) * | 2008-12-19 | 2010-07-15 | The University Of North Carolina At Chapel Hill | Substituted fno (2-[furan-2-yl] naphthalen-1-ol) derivatives as anti-cancer agents |
| CN103193860A (en) * | 2013-03-11 | 2013-07-10 | 常州大学 | Tanshinone compounds, preparation method and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| RICK L. DANHEISER ET AL.: "Aromatic Annulation Strategy for the Synthesis of Angularly-Fused Diterpenoid Quinones. Total Synthesis of (+)-Neocryptotanshinone, (-)-Cryptotanshinone, Tanshinone IIA, and (f)-Royleanone", 《J. ORG. CHEM.》 * |
| XIHONG WANG ET AL.: "Antitumor Agents. 239. Isolation, Structure Elucidation, Total Synthesis, and Anti-Breast Cancer Activity of Neo-tanshinlactone from Salvia miltiorrhiza", 《J. MED. CHEM.》 * |
| YIZHOU DONG ET AL.: "Antitumor agents 269. Non-aromatic ring-A neotanshinlactone analog, TNO, as a new class of potent antitumor agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 何玲玲: "高效液相色谱法测定丹参中丹参酮IIA的含量", 《中国医药指南》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922384A (en) * | 2019-11-14 | 2020-03-27 | 中国科学院昆明植物研究所 | Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with anti-platelet activity and application thereof |
| CN110922384B (en) * | 2019-11-14 | 2021-09-28 | 中国科学院昆明植物研究所 | Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with anti-platelet activity and application thereof |
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Application publication date: 20161221 |