CN108299455A - Podophyllotoxin-derivatives of indirubin, its preparation method and its medical usage - Google Patents
Podophyllotoxin-derivatives of indirubin, its preparation method and its medical usage Download PDFInfo
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- CN108299455A CN108299455A CN201810320029.6A CN201810320029A CN108299455A CN 108299455 A CN108299455 A CN 108299455A CN 201810320029 A CN201810320029 A CN 201810320029A CN 108299455 A CN108299455 A CN 108299455A
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- podophyllotoxin
- indirubin
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The present invention relates to medicinal chemistry arts, and in particular to a kind of podophyllotoxin derivatives of indirubin (I), preparation method and its medical usage.Pharmacological evaluation proves that object of the present invention has the function of extracorporeal anti-tumor cell Proliferation, can be used for clinical prevention or treatment tumor disease.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of podophyllotoxin-derivatives of indirubin (I), their system
Preparation Method and the purposes in preventing or treating the drug of tumour.
Background technology
Podophyllotoxin (podophyllotoxin) is a kind of virtue isolated from little Nie sections may apple Chinese common sinopodophyllum rhi-zome
Base naphthalene lactone lignans, such plant is mainly distributed on western China, civil for treating snake bite and carbuncle furuncle poison
Equal diseases.Studies have shown that podophyllotoxin is main with a variety of pharmacological activity, such as antitumor, antiviral, desinsection, mechanism of action
To inhibit tubulin and Free Radical etc..Since podophyllotoxin will produce serious adverse reaction, such as upset,gastro-intestinal and
Liver renal toxicity etc., this restrict the antitumor clinical applications of podophyllotoxin.Since eighties of last century the fifties, scientist is to ghost
The structure of mortar toxin expands large-scale modification and retrofit work, to reduce its toxicity, wherein it is found that Etoposide
With the Antitumor Drugs of Podophyllotoxins such as Teniposide, clinical treatment lung cancer, breast cancer, lymph cancer, testis have been widely used in it
A variety of diseases such as ball cancer and acute non lymphocytic leukemia.
Bisindole alkaloid indigo red (Indirubin) is the active ingredient of Chinese medicine indigo naturalis, with antimycotic, disease-resistant
A variety of pharmacological activity such as malicious, anti-inflammatory and treatment psoriasis.Meanwhile indigo red also has potential antitumor action, main function
Mechanism is to inhibit cell cycle protein dependent kinase.
In order to find antitumor activity more preferably lead compound, we are former using the pharmacophore split of medicinal chemistry art
Reason, by podophyllotoxin and indigo red, both natural molecules with anti-tumor activity are conjugated, and it is unique to have obtained structure
Podophyllotoxin-derivatives of indirubin.
Invention content
The purpose of the invention is to find antitumor activity more preferably lead compound, we utilize medicinal chemistry art
Pharmacophore principle of hybridization, by podophyllotoxin and indigo red, both natural molecules with anti-tumor activity are conjugated, and obtain
Unique podophyllotoxin-the derivatives of indirubin of structure is arrived.
The present invention relates to medicinal chemistry arts, and in particular to a kind of podophyllotoxin-derivatives of indirubin (I).Pharmacological evaluation
It has been shown that, object of the present invention is to sensitive people's chronic myelogenous leukemia cell K562 and drug resistance people's chronic myelogenous leukemia cell K562/VCR
There is stronger inhibitory activity.Therefore, formula of the invention (I) compound can be used for clinical prevention or treatment tumor disease.
It is as follows that the compound of the present invention leads to formula (I)：
Wherein, n represents 1,2,3,4 or 5.
Pharmaceutical composition of the present invention, wherein containing effective dose object of the present invention, dosage form includes suspension, capsule
Conventional dosage form on the galenic pharmacies such as agent, tablet, spray, gelling agent injection, tincture, sustained release agent, suppository, patch, granule
Form.
The preparation method of compound shown in this logical formula (I) is as follows：
Wherein a~b represents reaction condition：
a：Reagent is bromacyl chloride；Solvent is dichloromethane or tetrahydrofuran；Acid binding agent is triethylamine or potassium carbonate；Reaction
Temperature is 20~35 DEG C；
b：Reagent is cesium carbonate；Solvent is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Catalyst is potassium iodide；Reaction
Temperature is 20~30 DEG C.
Wherein, the preparation method of intermediate (IV) can refer to document (Bioorg.Med.Chem.Lett.2011,21,
2692) the method synthesis reported.
Pharmacological activity it is demonstrated experimentally that object of the present invention can effectively inhibit sensitive people's chronic myelogenous leukemia cell K562 and
The malignant proliferation of drug resistance people's chronic myelogenous leukemia cell K562/VCR.
It is the pharmacological activity test method and result of part of compounds of the present invention below：
CCK-8 methods test anti tumor activity in vitro
Positive drug：Etoposide (VP-16)
Experimental method：
Cell K562 and the K562/VCR cell of exponential phase is separately added into 96 orifice plates, in 5%CO2, 37 DEG C of items
After being cultivated for 24 hours under part, the compound of various concentration is added, sets up negative positive controls.Common hatching 72 hours, is added CCK-
8 reagents (10 μ L) continue hatching 3 hours.Finally the OD values per hole, calculation of half inhibitory concentration (IC are read with microplate reader50) value.
Part of compounds anti tumor activity in vitro result is as follows：
External antiproliferative activity of 1 part of compounds of the present invention of table to K562 and K562/VCR
The result shows that object of the present invention has different degrees of inhibitory activity to two kinds of cell strains of K562 and K562/VCR.Its
In, the activity of compound I-1 is most strong, to the IC of K562 and K562/VCR50Value is respectively 0.034 ± 0.002 μM and 0.076 ±
0.008 μM, it is significantly stronger than positive drug Etoposide.
Specific implementation mode
Instrument and reagent
Fusing point is SGWX-4 melting point apparatus, and mass spectrograph is 6520 types of Agilent Accurate-Mass-Q-TOF-MS, nuclear-magnetism
Resonance instrument is Agilent-NMR-400 types, and thin layer chromatography board and silica gel are purchased from Haiyang Chemical Plant, Qingdao, and other agents useful for same are point
It analyses pure.
The following examples are used to illustrate the preparation of object of the present invention, but the invention is not limited in the following example.
Embodiment 1：Indigo red-N1The preparation of acetic acid esters -4- podophyllotoxins (I-1)
Podophyllotoxin (0.12g, 0.28mmol) is added in anhydrous methylene chloride (5mL), add triethylamine (0.2mL,
1.4mmol), above-mentioned reaction solution is cooled to 0 DEG C, and bromoacetyl chlorine (2.5eq) is slowly added dropwise under stirring.Drop finishes, and reaction solution rises to
30 DEG C are reacted 1-2 hours.Reaction is quenched in ammonium chloride solution, and dichloromethane extracts three times, merges organic layer, and saturated common salt is washed,
Anhydrous magnesium sulfate is dried overnight, and filtering is concentrated to give intermediate III -1.Above-mentioned crude product, indigo red (1eg), cesium carbonate
The potassium iodide of (2.5eq) and catalytic amount is added in anhydrous DMF, is stirred 0.5-1 hours under the conditions of 25 DEG C.Reaction is quenched in saline solution,
Dichloromethane extracts three times, merges organic layer, saturated common salt washing, and anhydrous magnesium sulfate is dried overnight, filters, obtain crude product, column
Chromatographic purifying [eluant, eluent is DCM/MeOH (100/1-20/1)], obtains violet solid indigo red-N1Acetic acid esters -4- podophyllotoxins
Plain (I-1), yield 67%.
1H NMR (400MHz, DMSO-d6) δ 11.07 (s, 1H), 8.81 (d, J=7.2Hz, 1H), 7.67 (d, J=
7.2Hz, 1H), 7.58 (t, J=7.2Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.33 (t, J=7.2Hz, 1H), 7.21 (d,
J=7.6Hz, 1H), 7.10 (t, J=7.2Hz, 1H), 7.02 (t, J=7.2Hz, 1H), 6.92 (s, 1H), 6.56 (s, 1H),
6.25 (s, 2H), 5.97 (d, J=12.0Hz, 3H), 4.96 (d, J=18.0Hz, 1H), 4.79 (d, J=18.0Hz, 1H),
4.54 (s, 1H), 4.26 (t, J=6.8Hz, 1H), 4.15 (t, J=9.6Hz, 1H), 3.57 (s, 3H), 3.54 (s, 6H), 2.87
(s,1H),2.66-2.76(m,1H)；13C NMR(100MHz,DMSO-d6)δ188.96,174.18,169.66,169.25,
162.74,152.93,152.44,147.87,147.37,141.26,139.40,137.72,136.73,135.95,132.74,
129.46,128.46,124.92,122.59,122.02,121.13,119.47,114.03,109.74,109.20,108.28,
107.34,105.15,101.86,74.33,70.94,60.33,56.04,44.34,43.17,41.88,38.71,36.22；
HRMS-ESI(m/z):calcd for C40H32N2O11[M+Na]+739.1898,found 739.1905.
Embodiment 2：Indigo red-N1The preparation of propionic ester -4- podophyllotoxins (I-2)
Bromo propionyl chloride is replaced into bromoacetyl chlorine, by method described in embodiment 1, remaining required raw material, reagent are the same as real
Example 1 is applied, violet solid indigo red-N is obtained1Propionic ester -4- podophyllotoxins (I-2), yield 70%.
1H NMR (400MHz, DMSO-d6) δ 11.03 (s, 1H), 8.79 (d, J=7.2Hz, 1H), 7.65 (d, J=
7.2Hz, 1H), 7.58 (t, J=6.4Hz, 1H), 7.40 (d, J=7.6Hz, 1H), 7.30 (t, J=6.8Hz, 1H), 7.07 (s,
2H), 7.01 (t, J=6.8Hz, 1H), 6.75 (s, 1H), 6.50 (s, 2H), 5.89 (s, 2H), 5.74 (s, 1H), 5.66 (s,
1H), 4.36 (t, J=7.2Hz, 1H), 4.25 (s, 2H), 4.03 (d, J=5.6Hz, 2H), 3.66 (s, 6H), 3.61 (d, J=
7.2Hz,2H),3.54(s,3H),2.64-2.73(m,2H)；13C NMR(100MHz,DMSO-d6)δ188.98,177.69,
171.17,169.40,153.10,152.87,147.80,146.64,141.07,139.22,138.76,137.65,136.45,
132.70,129.47,127.05,124.88,122.32,121.91,121.18,119.50,113.92,109.31,109.05,
108.22,106.04,105.58,101.60,72.83,70.81,60.27,56.28,55.36,44.07,43.76,35.76,
32.63；HRMS-ESI(m/z):calcd for C41H34N2O11[M+Na]+753.2055,found 753.2059.
Embodiment 3：Indigo red-N1The preparation of butyrate -4- podophyllotoxins (I-3)
Bromo butyl chloride is replaced into bromoacetyl chlorine, by method described in embodiment 1, remaining required raw material, reagent are the same as real
Example 1 is applied, violet solid indigo red-N is obtained1Butyrate -4- podophyllotoxins (I-3), yield 60%.
1H NMR (400MHz, DMSO-d6) δ 11.03 (s, 1H), 8.80 (d, J=8.0Hz, 1H), 7.65 (d, J=
6.8Hz, 1H), 7.57 (t, J=6.8Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.29 (t, J=6.8Hz, 1H), 7.08 (s,
2H), 7.01 (t, J=7.2Hz, 1H), 6.85 (s, 1H), 6.50 (s, 3H), 5.95 (s, 2H), 5.67 (s, 1H), 4.39 (t, J
=7.6Hz, 1H), 4.29 (d, J=14.0Hz, 2H), 3.81 (s, 2H), 3.65 (s, 6H), 3.58 (s, 3H), 3.55 (d, J=
9.2Hz,1H),2.93(s,1H),2.26-2.40(m,2H),1.86(s,2H)；13C NMR(100MHz,DMSO-d6)δ
188.98,177.72,172.67,169.56,153.11,152.86,147.82,146.72,141.55,139.12,138.81,
137.67,136.47,132.63,129.59,127.28,124.91,122.25,121.89,121.20,119.48,113.88,
109.27,108.87,108.26,106.11,105.80,101.64,72.53,70.99,60.34,56.26,44.24,
43.77,38.82,31.12,22.87；HRMS-ESI(m/z):calcd for C42H36N2O11[M+Na]+767.2211,found
767.2217.
Embodiment 4：Indigo red-N1The preparation of capronate -4- podophyllotoxins (I-4)
Bromohexanoyl chloride is replaced into bromoacetyl chlorine, by method described in embodiment 1, remaining required raw material, reagent are the same as real
Example 1 is applied, violet solid indigo red-N is obtained1Capronate -4- podophyllotoxins (I-4), yield 58%.
1H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 8.80 (d, J=6.0Hz, 1H), 7.65 (d, J=
6.0Hz, 1H), 7.57 (s, 1H), 7.40 (d, J=6.8Hz, 1H), 7.31 (s, 1H), 7.07 (s, 2H), 7.01 (s, 1H),
6.81(s,1H),6.58(s,1H),6.50(s,2H),5.97(s,2H),5.63(s,1H),4.39(s,1H),4.27(s,1H),
4.21 (d, J=8.0Hz, 1H), 3.78 (s, 2H), 3.68 (s, 6H), 3.59 (s, 3H), 2.94 (s, 1H), 2.87 (s, 1H),
2.14(s,2H),1.59(s,2H),1.45(s,2H),1.23(s,2H)；13C NMR(100MHz,DMSO-d6)δ189.02,
177.84,172.96,169.43,153.06,152.92,147.86,146.68,141.63,139.08,138.79,137.66,
132.76,129.61,127.21,124.96,122.17,121.85,121.15,119.47,113.92,109.01,108.50,
106.07,101.67,72.39,70.81,60.35,56.29,43.98,43.89,33.73,27.34,26.17,24.36；
HRMS-ESI(m/z):calcd for C44H40N2O11[M+Na]+795.2524,found 795.2519.
Claims (4)
1. podophyllotoxin-derivatives of indirubin and its medical usage, it is characterized in that：
The compound of logical formula (I)：
Wherein, n is represented：1,2,3,4 or 5.
2. podophyllotoxin-derivatives of indirubin leads to the preparation method of formula (I) compound, it is characterized in that including：
The wherein definition of n is the same as claim 1；
Wherein a~b represents reaction condition：
a：Reagent is bromacyl chloride；Solvent is dichloromethane or tetrahydrofuran；Acid binding agent is triethylamine or potassium carbonate；Reaction temperature
It is 20~35 DEG C；
b：Reagent is cesium carbonate；Solvent is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Catalyst is potassium iodide；Reaction temperature
It is 20~30 DEG C.
3. podophyllotoxin-derivatives of indirubin as described in claim 1 and its medical usage, it is characterized in that：Contain effective agent
The pharmaceutical composition of the logical formula (I) compound of any one of the claim 1~2 of amount, dosage form includes suspension, capsule, piece
Agent, spray, gelling agent injection, tincture, sustained release agent, suppository, patch, granule.
4. by podophyllotoxin-derivatives of indirubin and its medical usage described in claims 1 to 3, it is characterized in that：Described 1~3
Any one of logical formula (I) compound prepare prevent or treatment tumour drug in application.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794501A (en) * | 2018-07-26 | 2018-11-13 | 遵义医学院 | Podophyllotoxin-formoononetin conjugate, its preparation method and its medical usage |
| CN114085230A (en) * | 2021-09-24 | 2022-02-25 | 遵义医药高等专科学校 | N-succinic acid mono-substituted indole (oxazole) spliced podophyllotoxin compound and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632405A (en) * | 2015-11-04 | 2017-05-10 | 兰州大学 | Podophyllotoxin and norcantharidin combined compound as well as preparation and application thereof |
-
2018
- 2018-04-11 CN CN201810320029.6A patent/CN108299455A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632405A (en) * | 2015-11-04 | 2017-05-10 | 兰州大学 | Podophyllotoxin and norcantharidin combined compound as well as preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| LEI ZHANG，等: "Novel isatin derivatives of podophyllotoxin: synthesis and cytotoxic evaluation against human leukaemia cancer cells as potent anti-MDR agents", 《RSC ADV》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794501A (en) * | 2018-07-26 | 2018-11-13 | 遵义医学院 | Podophyllotoxin-formoononetin conjugate, its preparation method and its medical usage |
| CN114085230A (en) * | 2021-09-24 | 2022-02-25 | 遵义医药高等专科学校 | N-succinic acid mono-substituted indole (oxazole) spliced podophyllotoxin compound and preparation method and application thereof |
| CN114085230B (en) * | 2021-09-24 | 2024-02-06 | 遵义医药高等专科学校 | N-succinic acid monosubstituted indole (azole) spliced podophyllotoxin compound and preparation method and application thereof |
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