CN105924364A - Aloe-emodin quaternary ammonium salt alkyl iodoacetates with multiple-related anti-cancer mechanism - Google Patents
Aloe-emodin quaternary ammonium salt alkyl iodoacetates with multiple-related anti-cancer mechanism Download PDFInfo
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- aloe
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- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/24—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings
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Abstract
The invention discloses aloe-emodin quaternary ammonium salt alkyl iodoacetates with the multiple-related anti-cancer mechanism and a preparation method thereof. The preparation method comprises the steps that firstly, aloe-emodin reacts with phosphorus tribromide to obtain brominated aloe-emodin; secondly, brominated aloe-emodin reacts with N-methyldi-n-octylamine to generate aloe-emodin quaternary ammonium salt; lastly, the aloe-emodin quaternary ammonium salt reacts with chloroacetyl chloride to generate iodine acetylation in the presence of sodium iodide to obtain aloe-emodin quaternary ammonium salt alkyl iodoacetates shown as a structural formula (please see the structural formula in the description). In-vitro cancer cell inhibition tests of aloe-emodin quaternary ammonium salt alkyl iodoacetates show that aloe-emodin quaternary ammonium salt alkyl iodoacetates has the good inhibitory activity on hematopoietic cells, is expected to be developed into anti-leukemia drugs and has the great application prospect.
Description
Technical field
The invention belongs to the preparation field of cancer therapy drug, be specifically related to a kind of Aloe with many re-associations instrument for cancers big
Flavin quaternary ammonium salt Alkyl Iodoacetates.
Background technology
Cancerous cell and Normocellular difference feature have a lot, and that designs only for the single feature of cancerous cell is anticancer
Generally there is the problem that active anticancer is not enough in medicine.Such as, the lipophilic cation such as rhodamine is that a class is for cancerous cell line grain
The cancer therapy drug that body transmembrane potential designs higher than normal cell, although targeting is high, but the most do not possess the anti-of independent patent medicine
Cancer activity.But simply cancerous cell is not possessed multiple features of relatedness as drug design target, it is also difficult to reach
Anticancer effect because a drug molecule is difficult to act on multiple target.So finding the cancerous cell feature ten of relevant property
Divide important.
Cancerous cell not only mitochondrial membrane potential (about 180mV) is significantly higher than normal cell (about 110mV), and unlike normally
The oxidative pressure of cell such tolerated activity oxygen (ROS).Owing to the generation place of ROS is mitochondrion, thus cancerous cell this two
Individual feature is two features that relatedness is the strongest.The rheum emodin quaternary ammonium salt of this seminar synthesis in early days and aloe-emodin quaternary ammonium salt
Just as make use of the two feature of cancerous cell and show good active anticancer simultaneously.Additionally, according to famous
" Warburg effect " (Warburg effect), cancerous cell tends to utilize glycolysis energy supply.Only the line grain of cancerous cell is destroyed
Body energy supply approach, may also be not enough to serious anticancer activity.
The application imagination introduces Alkyl Iodoacetates group on aloe-emodin quaternary ammonium salt, releasably goes out after Alkyl Iodoacetates hydrolysis
Iodoacetic acid, the latter is typical glycolytic inhibitor, can suppress the activity of glyceraldehyde-3-phosphate dehydrogenase in glycolytic cycle,
Thus anticancer glycolysis, destroy cancerous cell glycolysis energy supply approach.And hydrolyze the aloe-emodin quaternary ammonium salt of releasing, then
Because having lipophilic cation structure, cancerous cell mitochondrion energy supply approach can be destroyed.So the aloe-emodin quaternary ammonium of the present invention
Salt Alkyl Iodoacetates, can destroy two kinds of energy supply approach of cancerous cell simultaneously, therefore can cancer cell specific induction of apoptosis well, thus aobvious
Show the highest active anticancer.
Summary of the invention
It is an object of the invention to provide a kind of aloe-emodin quaternary ammonium salt iodoacetic acid with many re-associations instrument for cancers
Ester and preparation method thereof.By introducing long carbon chain quaternary ammonium salt as lipophilic cation targeting mitochondrion also on aloe-emodin
Produce active oxygen, be re-introduced into an Alkyl Iodoacetates, in order to after hydrolysis, generation iodoacetic acid is as glycolytic inhibitor, thus significantly carries
The active anticancer of high aloe-emodin.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers, its structural formula is as follows:
。
The described aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers, its synthetic route such as Fig. 1 institute
Show:
It specifically includes following steps:
1) synthesis of bromo aloe-emodin: 5.1 mmol aloe-emodins are dissolved in 150 mLCCl4In, add 5 under room temperature
mL PBr3, it being warming up to 65 DEG C, stirred at reflux reacts 48 h；Then rotation is evaporated off solvent, and residue is pure through silica gel column chromatography
Change to obtain bromo aloe-emodin；
2) synthesis of aloe-emodin quaternary ammonium salt: 0.30 mmol bromo aloe-emodin is dissolved in 25 mL CHCl3In, heating
Adding 0.1 mL dioctyl methyl tertiary amine after backflow, lower back flow reaction 6 h of stirring, solvent is spin-dried for after terminating by reaction, residue
Aloe-emodin quaternary ammonium salt is obtained through silica gel column chromatography gradient elution；
3) synthesis of aloe-emodin quaternary ammonium salt Alkyl Iodoacetates: by 0.34 mmol aloe-emodin quaternary ammonium salt, 12.05 mmol
Potassium iodide and 3.62 mmol potassium carbonate are dissolved in there-necked flask with 30 mL acetone, add 1.38 mmol chloracetyl chlorides, stirring reaction
30min；Removing solvent with Rotary Evaporators after stopped reaction, gradient elution carries out column chromatography purification, obtains aloe-emodin season
Ammonium salt Alkyl Iodoacetates.
In step 1), the eluant used by silica gel column chromatography purification is: CH2Cl2Mix with petroleum ether 2:1 by volume
Solvent.
Step 2) in gradient elution particularly as follows:V(CH2Cl2):V(C2H5OH)=50:1→40:1→35:1→30:1→25:
1。
Gradient elution in step 3) particularly as follows:V(CH2Cl2):V(C2H5OH)=50:1→ 40:1→ 30:1→25:1→
20:1。
A kind of aloe-emodin quaternary ammonium salt Alkyl Iodoacetates as above with many re-associations instrument for cancers is controlled in preparation
Treat the application in cancer drug；Described cancer includes leukemia.
The remarkable advantage of the present invention is:
The aloe-emodin quaternary ammonium salt Alkyl Iodoacetates of present invention synthesis has long carbon chain quaternary ammonium salt, it is possible to use cancerous cell mitochondrion
Transmembrane potential is high and is enriched in cancerous cell mitochondrion；It has anthraquinone ring the most simultaneously, has electron transmission ability, thus the most online
Electron transfer be captured to forming active oxygen after oxygen on mitochondrial respiratory chain；It is re-introduced into an Alkyl Iodoacetates on this basis, hydrolysis
After can produce famous glycolytic inhibitor iodoacetic acid (glyceraldehyde-3-phosphate dehydrogenase in suppression glycolysis), cancer can be suppressed
The glycolysis of cell；Therefore, this compound of present invention synthesis has multiple anticancer mechanism, can destroy cancer largely thin
The energy supply of born of the same parents；And the degree of association is the highest between these anticancer mechanism, easily plays anticancer cooperative effect and show high anticancer
Activity.
Accompanying drawing explanation
The synthetic route of Fig. 1 aloe-emodin quaternary ammonium salt Alkyl Iodoacetates.
Detailed description of the invention
In order to make content of the present invention easily facilitate understanding, below in conjunction with detailed description of the invention to of the present invention
Technical scheme is described further, but the present invention is not limited only to this.
Embodiment 1
There is the preparation method of the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates of many re-associations instrument for cancers, concretely comprise the following steps:
1) synthesis of bromo aloe-emodin
5.1 mmol aloe-emodins are dissolved in 150 mL CCl4, under room temperature, add 5 mL PBr3(excessive), is warming up to 65
DEG C, stirred at reflux reacts 48 h；After rotation is evaporated off solvent, residue is through silica gel column chromatography purification (eluantV(CH2Cl2):V
(petroleum ether)=2:1) obtain orange solids bromo aloe-emodin；Characterization of The Products data are as follows:
Productivity 72.1%；Fusing point: 72-73 DEG C；1 H NMR (400 MHz, CDCl3) δ: 12.09 (s, 1H, ArOH),
12.06 (s, 1H, ArOH), 7.89 (d, J=5.2 Hz, 1H, ArH), 7.88 (s, 1H, ArH), 7.73 (t,J=7.6 Hz, 1H, ArH), 7.36 (s, 1H, ArH), 7.35 (d, J=6.4 Hz, 1H, ArH), 4.51 (s,
2H, ArCH2Br); ESI-MS m/z 331.1 (M-H)-;HRMS m/z 330.9619, theoretical value (M-H)-
330.9611.
2) synthesis of aloe-emodin quaternary ammonium salt
The 0.3 mmol bromo aloe-emodin that step 1) synthesizes is dissolved in 25 mL CCl4, add 0.1mL dioctyl after backflow
Methyl tertiary amine, stirred at reflux reaction 6h；After rotation is evaporated off solvent, it is solid that residue obtains kermesinus through silica gel column chromatography gradient elution
Body, i.e. aloe-emodin quaternary ammonium salt；Eluting order is:V(CH2Cl2) : V(C2H5OH) = 50:1→ 40:1→ 35:1→
30:1→25:1；Characterization of The Products data are as follows:
Productivity 67.3%；m.p. 80-81℃；1 H NMR (400 MHz, CDCl3) δ: 11.94 (s, 1H, ArOH),
11.88 (s, 1H, ArOH), 7.94 (s, 1H, ArH), 7.83 (d, J=7.6 Hz, 1H, ArH), 7.81 (s,
1H, ArH), 7.73 (t, J=7.6 Hz, 1H, ArH), 7.35 (d, J=8.4Hz, 1H, ArH), 5.29 (s,
2H, ArCH2N), 3.58—3.45 (m, 4H, 2×NCH2C7H15), 3.37(s, 3H, NCH3), 1.93—1.76
(m, 4H, 2×NCH2CH2C6H13), 1.48—1.25 [m, 20H, 2×(CH2)5CH3], 0.91 (t, J=7.2 Hz,
6H, 2×CH3)；13 C NMR (400 MHz, CDCl3) δ: 192.1, 180.3, 162.7, 162.3, 137.8,
137.1, 133.5, 132.8, 129.5, 125.1, 123.0, 120.3, 116.4, 115.3, 63.9, 61.2,
48.3, 31.6, 29.12, 29.09, 26.4, 22.6, 14.1; ESI-MS m/z 508.6 (M-Br)+; Calcd
for C32H46BrNO4·0.5H2O: C 64.31, H 7.93, N 2.34; Found: C 64.54, H 7.86, N
2.65.
3) synthesis of aloe-emodin quaternary ammonium salt Alkyl Iodoacetates
By step 2) aloe-emodin quaternary ammonium salt 0.34 mmol that synthesizes and potassium iodide 12.05 mmol and potassium carbonate 3.62
Mmol, is dissolved in there-necked flask with 30 mL acetone, adds chloracetyl chloride 1.38 mmol, and half an hour is reacted in stirring；After stopped reaction
Removing solvent with Rotary Evaporators, gradient elution carries out column chromatography purification, obtains yellow compound aloe-emodin quaternary ammonium salt iodine
Acetas；Eluting order is:V(CH2Cl2):V(C2H5OH)=50:1→ 40:1→ 30:1→25:1→20:1.Characterization of The Products
Data are as follows:
Productivity 27.3%；m.p. 65-66℃；1 H NMR (400 MHz, CDCl3) δ: 11.72 (s, 1H, ArOH),
7.78 (s, 2H, ArH), 7.64 (s, 2H, ArH), 7.24 (s, 2H, ArH), 5.25 (s, 2H,
ArCH2N), 5.14 (s, 1H, COCH2I), 4.15 (s, 1H, COCH2I), 3.47 (m, 4H, N(CH2C7H15)2),
3.34 (s, 3H, NCH3), 1.86 (m, 4H, N(CH2CH2C6H13)2), 1.28 (m, 20H, N
(C2H4C5H10CH3)2), 0.88 (t, 6H, N(C7H14CH3)2); 13 C NMR (400 MHz, CDCl3) δ: 193.45,
162.86, 162.24, 143.33, 142.11, 136.87, 134.90, 124.42, 119.18, 118.90,
116.56, 115.37, 115.31, 65.95, 61.32, 49.56, 32.72, 31.69, 29.69, 29.16,
29.11, 26.30, 22.85, 22.60, 14.06; ESI-MS, m/z: 676.35 (M-Br-)+; HRMS, m/z:
676.2483 (M-Br-)+, theoretical value: 676.2499 (M-Br-)+.
Application Example 1
Aloe-emodin quaternary ammonium salt Alkyl Iodoacetates is to leukemia cell growth inhibition assay
Using aloe-emodin quaternary ammonium salt Alkyl Iodoacetates as test medicine, by culture medium by drug dilution；By leukaemia
(HL60) density is adjusted to 1 × 105Individual/mL, is inoculated in 96 orifice plates, every hole 100 μ L, puts 37 DEG C, 5% CO2Incubator is cultivated
24 h；Remove old culture medium, add test medicine, every hole 100 μ L, separately set blank group, aloe-emodin group and Aloe
Rheum emodin quaternary ammonium salt group, often group sets 4 multiple holes.After medicine effect 48h, inhale abandon pastille culture medium, in every hole add serum-free,
Without phenol red 1640 culture medium 100 μ L, add MTT solution 10 μ L, continue to hatch 4h, terminate cultivating；Careful suction abandons 96 orifice bores
Interior supernatant, every hole adds 100 μ L DSMO, and vibrate 10min, measures each hole absorbance value in microplate reader at 570nm wavelength
(OD value), calculation of half inhibitory concentration IC50Value.Result is as shown in table 1.
Table 1 aloe-emodin quaternary ammonium salt Alkyl Iodoacetates, aloe-emodin and aloe-emodin quaternary ammonium salt are to leukaemia
Inhibitory activity (the IC of HL6050, μmol/L)
Test result indicate that, aloe-emodin quaternary ammonium salt Alkyl Iodoacetates is because fully utilizing many re-associations instrument for cancers of cancerous cell
System, shows good active anticancer to HL-60 cells, and its active anticancer improves 30 times than primer aloe-emodin
Above, also improve by about one time than the active anticancer of aloe-emodin quaternary ammonium salt.This result shows iodoacetic acid and Aloe Radix Et Rhizoma Rhei
To carry out covalent bond be good Anti-Cancer Drug Design thinking to element quaternary ammonium salt, by glycolytic inhibitor with can suppress mitochondrion energy supply
Compound to combine be the Anti-Cancer Drug Design work that is worth continuously attempting to.
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent with
Modify, all should belong to the covering scope of the present invention.
Claims (8)
1. an aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers, it is characterised in that: its structural formula
As follows:
。
2. prepare the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates as claimed in claim 1 with many re-associations instrument for cancers for one kind
Method, it is characterised in that: by aloe-emodin with excess phosphorus tribromide react, obtain bromo aloe-emodin；Bromo Aloe
Rheum emodin carries out nucleophilic substitution with dioctyl methyl tertiary amine again and obtains aloe-emodin quaternary ammonium salt；Aloe-emodin quaternary ammonium salt
Esterification and iodide reaction is occurred to obtain aloe-emodin quaternary ammonium salt Alkyl Iodoacetates in the presence of sodium iodide with chloracetyl chloride.
The preparation of the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers the most according to claim 2
Method, it is characterised in that: specifically include following steps:
1) synthesis of bromo aloe-emodin: 5.1 mmol aloe-emodins are dissolved in 150 mLCCl4In, add 5 mL under room temperature
PBr3, it being warming up to 65 DEG C, stirred at reflux reacts 48 h；Then rotation is evaporated off solvent, and residue obtains through silica gel column chromatography purification
Bromo aloe-emodin；
2) synthesis of aloe-emodin quaternary ammonium salt: 0.30 mmol bromo aloe-emodin is dissolved in 25 mL CHCl3In, heat back
Adding 0.1 mL dioctyl methyl tertiary amine after stream, lower back flow reaction 6 h of stirring, solvent is spin-dried for after terminating by reaction, residue warp
Silica gel column chromatography gradient elution obtains aloe-emodin quaternary ammonium salt；
3) synthesis of aloe-emodin quaternary ammonium salt Alkyl Iodoacetates: by 0.34 mmol aloe-emodin quaternary ammonium salt, 12.05 mmol
Potassium iodide and 3.62 mmol potassium carbonate are dissolved in there-necked flask with 30 mL acetone, add 1.38 mmol chloracetyl chlorides, stirring reaction
30min；Removing solvent with Rotary Evaporators after stopped reaction, gradient elution carries out column chromatography purification, obtains aloe-emodin season
Ammonium salt Alkyl Iodoacetates.
The preparation of the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers the most according to claim 3
Method, it is characterised in that: in step 1), the eluant used by silica gel column chromatography purification is: CH2Cl2With petroleum ether 2:1 by volume
The solvent mixed.
The preparation of the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers the most according to claim 3
Method, it is characterised in that: step 2) in gradient elution particularly as follows:V(CH2Cl2):V(C2H5OH)=50:1→40:1→35:1→
30:1→25:1。
The preparation of the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates with many re-associations instrument for cancers the most according to claim 3
Method, it is characterised in that: gradient elution in step 3) particularly as follows:V(CH2Cl2):V(C2H5OH)=50:1→ 40:1→ 30:1
→25:1→20:1。
7. an aloe-emodin quaternary ammonium salt Alkyl Iodoacetates as claimed in claim 1 with many re-associations instrument for cancers is in system
Application in standby treatment cancer drug.
The most according to claim 7 have the aloe-emodin quaternary ammonium salt Alkyl Iodoacetates of many re-associations instrument for cancers in preparation
Application in treatment cancer drug, it is characterised in that: described cancer includes leukemia.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110003021A (en) * | 2019-03-16 | 2019-07-12 | 福建医科大学附属协和医院 | The preparation method of quaternary ammonium salt dichloroacetic acid ester with anti-leukocythemia liveness |
| CN110981909A (en) * | 2019-12-27 | 2020-04-10 | 福州大学 | Copper-containing aloe-emodin quaternary phosphonium salt and synthetic method and application thereof |
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| CN110003021A (en) * | 2019-03-16 | 2019-07-12 | 福建医科大学附属协和医院 | The preparation method of quaternary ammonium salt dichloroacetic acid ester with anti-leukocythemia liveness |
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| CN110981909B (en) * | 2019-12-27 | 2021-06-29 | 福州大学 | Copper-containing aloe-emodin quaternary phosphonium salt and synthetic method and application thereof |
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