CN109745568A - The inclusion compound of camptothecine and acid-sensitive open loop Cucurbituril - Google Patents
The inclusion compound of camptothecine and acid-sensitive open loop Cucurbituril Download PDFInfo
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- CN109745568A CN109745568A CN201910155343.8A CN201910155343A CN109745568A CN 109745568 A CN109745568 A CN 109745568A CN 201910155343 A CN201910155343 A CN 201910155343A CN 109745568 A CN109745568 A CN 109745568A
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- camptothecine
- open loop
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- loop cucurbituril
- inclusion compound
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 81
- MSBXTPRURXJCPF-DQWIULQBSA-N cucurbit[6]uril Chemical compound N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN([C@H]1N(C%10=O)CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%10[C@H]1N3C5 MSBXTPRURXJCPF-DQWIULQBSA-N 0.000 title claims abstract description 74
- 239000002253 acid Substances 0.000 title claims abstract description 72
- 150000001875 compounds Chemical class 0.000 title claims abstract description 47
- 239000003814 drug Substances 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 20
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 229940127093 camptothecin Drugs 0.000 abstract description 10
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 9
- 230000008685 targeting Effects 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 210000004027 cell Anatomy 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012982 microporous membrane Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940009456 adriamycin Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 231100000956 nontoxicity Toxicity 0.000 description 3
- 229940063179 platinol Drugs 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 201000000053 blastoma Diseases 0.000 description 2
- -1 camptothecine lactone Chemical class 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 201000008184 embryoma Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- 241000759905 Camptotheca acuminata Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229930002341 quinoline alkaloid Natural products 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses the inclusion compounds of a kind of camptothecine and acid-sensitive open loop Cucurbituril, and containing camptothecine and acid-sensitive open loop Cucurbituril, wherein the molar ratio of camptothecine and acid-sensitive open loop Cucurbituril is 1:1 ~ 5:1；The present invention has c-type cavity using open loop Cucurbituril, camptothecin drug can be included and form inclusion compound, since open loop Cucurbituril belongs to flexible molecule, the cavity size of itself can be changed according to drug size, it is matched to form good cavity with drug, and then the water solubility of camptothecine is greatly strengthened, to improve the bioavilability of camptothecine；Meanwhile the inclusion compound can be in the intracavitary drug of tumour external environment (i.e. under solutions of weak acidity) quick release, to realize the Targeting delivery of drug；Inclusion compound good water solubility made from this method, stability are high；The present invention has potential value for the exploitation of camptothecine clinical application.
Description
Technical field
The invention belongs to pharmacy and technical field of medicine, particularly relate to camptothecin drug targeting preparation.
Background technique
Camptothecine (CPT) is that have cell by one kind that M.E. Wall et al. is extracted from plant camptotheca acuminata in 1966
Toxicity has the quinoline alkaloid of anticancer activity again simultaneously.Its mechanism of action is by combining with DNA topoisomerase (Topo I)
And DNA chain is destroyed in the S phase of cell cycle and G2/ M interim (i.e. during DNA replication dna) and is worked.Native camptothecins are water-soluble
Difference, toxic side effect is big, and retention time is short in vivo, lower so as to cause its anti-tumor activity.In addition to this, camptothecine lactone is living
Property form ring-opening reaction easily occurs under physiological pH or alkaline condition and is converted into biological inactive form (carboxylate), therefore limit
The clinical application of camptothecine is made.The Chinese patent of Publication No. CN1660851 is performed the derivatization on camptothecin molecule, is increased
Add some water-soluble groups, prepares a series of camptothecin derivatives；The Chinese patent of Publication No. CN101007809 is also
By derivatization, water-soluble camptothecine derivative is prepared；The Chinese patent of Publication No. CN103611166A, is pasted using ring
Essence includes hydroxy-camptothecin, to obtain a kind of liquid preparation of camptothecine.These camptothecin derivatives and inclusion compound
The water solubility of camptothecine is increased to a certain extent, but derivatization process is comparatively laborious, it is cyclodextrin encapsulated there is no targeting.
Summary of the invention
The camptothecine and acid-sensitive open loop Cucurbituril that the purpose of the present invention is to provide a kind of dissolubilities is good, binding constant is high
Inclusion compound, the inclusion compound contain guest molecule camptothecine, and structure is as follows:
Camptothecine (Camptothecin)
Wherein the molar ratio of camptothecine and acid-sensitive open loop Cucurbituril is 1:1 ~ 5:1, using solvent inclusion method at 25 DEG C~50 DEG C
Under while stirring to organic solvent (methanol, ethyl alcohol, acetone, acetonitrile or N, the N- dimethyl methyl dissolved with acid-sensitive open loop Cucurbituril
Amide) in camptothecine is added, continue after being protected from light 24~84h of stirring, 4.5 μm of filtering with microporous membrane used to remove insoluble matters, decompression
Solvent evaporated to get camptothecin drug and acid-sensitive open loop Cucurbituril pulverulent solids inclusion compound.
Acid-sensitive open loop Cucurbituril of the present invention, good water solubility can be used for increasing the dissolution of the drug molecule of slightly solubility
Property, and the targeting of drug is increased, so that anti-tumor activity is improved；Since these types of molecular structure is non-annularity
Structure, and have good flexibility, the size of adjustable cavity adapt to the size of drug molecule, structural formula are as follows:
Formula I (a)；
Formula II (b)；
Formula III (c)
Wherein R1Selected from H, CH3, R2Selected from H, CH3, R1And R2It is not simultaneously CH3。
Wherein in the synthetic method reference literature of acid-sensitive open loop Cucurbituril (formula I) method synthesized (Mao D,
Liang Y, Liu Y, et al. Acid‐Labile Acyclic Cucurbit [n] uril Molecular
Containers for Controlled Release[J]. AngewandteChemie, 2017, 129(41): 12788-
12792.), acid-sensitive open loop Cucurbituril (formula II), acid-sensitive open loop Cucurbituril (formula III) are then in acid-sensitive open loop Cucurbituril
It is derivative on the basis of (formula I)；It is broadly divided into three-step reaction, it is poly- from dimer to four first from monomer dimer synthon
Again to six aggressiveness after body, then modified on six aggressiveness.
The present invention uses fluorescent dyes rhodamine (RhB) as the drug of simulation, and analyzes with high intension, in HePG2
Acid labile open loop Cucurbituril (a, R in cell1=CH3, R2=H；R1=H, R2=H) with rhodamine inclusion compound in RhB fluorescence into
As a result row detection is shown in Fig. 5, as can be seen from the figure Luo Dan to compare the ability of the inclusion compound release drug under condition of different pH
Bright intake is different under different pH value in cancer cell from the inclusion compound of acid-sensitive open loop Cucurbituril: pH5.5 > pH6.4 > pH7.4,
It is thus determined that the release conditions of inclusion compound of the present invention are pH less than 5.5.
The method of the present invention compared with the existing technology the advantages of and technical effect:
1) present invention is for the water-soluble low status of camptothecine, in addition to utilizing acid-sensitive open loop Cucurbituril c-type cavity and camptothecine
Outside the clathration of molecule, due under mildly acidic conditions (pH < 5.5, such as tumour cell external environment), acid-sensitive open loop Cucurbituril
The open loop Cucurbituril of four amido salt of band can be formed, so that it declines with the camptothecin drug Binding ability in cavity, to release
Release camptothecine；The Targeting delivery camptothecine process of the inclusion compound is as follows:
；
Wherein
；
2) inclusion compound stability produced by the present invention is good, dissolubility is good, highly-safe, can effectively overcome camptothecin drug water itself
Dissolubility difference and the low disadvantage of bioavilability；Meanwhile the inclusion compound can be quick in tumour external environment (i.e. under solutions of weak acidity)
Intracavitary drug is discharged, to realize the Targeting delivery of drug；The inclusion compound preparation method is simple, mild condition and is easy to grasp
Make, for the exploitation of camptothecine clinical application, there is potential value；
3) inclusion compound of the present invention does not have toxicity to human normal cell line, has certain toxicity to cancer cell.
Detailed description of the invention
Fig. 1 is acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H) nuclear magnetic resonance spectroscopy (1H NMR) figure；
Fig. 2 is acid-sensitive open loop Cucurbituril (a, R1=H, R2=H) nuclear magnetic resonance spectroscopy (1H NMR) figure；
Fig. 3 is camptothecine and acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H) inclusion compound nuclear magnetic resonance spectroscopy (1H NMR)
Figure；
Fig. 4 is camptothecine and acid-sensitive open loop Cucurbituril (a, R1=H, R2=H) inclusion compound nuclear magnetic resonance spectroscopy (1H NMR)
Figure；
Fig. 5 is camptothecine and acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H；R1=H, R2=H) inclusion compound in condition of different pH
The capability result schematic diagram of lower release drug.
Specific embodiment
Further heretofore described method is described below by embodiment, but the scope of the present invention is not by reality
Apply example limitation, reagent used in the present embodiment is conventional commercial reagent or the examination prepared according to a conventional method unless otherwise specified
Agent, the method used are conventional method unless otherwise specified.
Embodiment 1: this camptothecine and acid-sensitive open loop Cucurbituril inclusion compound contain camptothecine and acid-sensitive open loop Cucurbituril
(a), acid-sensitive open loop Cucurbituril structural formula is as follows:
, R1=CH3, R2=H or R1=H, R2=H；
Camptothecine and acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H；R1=H, R2=H) inclusion compound preparation
(1) while stirring to dissolved with 0.1 mmol acid-sensitive open loop Cucurbituril (a, R at 25 DEG C1=CH3, R2=H) ethyl alcohol it is molten
0.1mmol camptothecine is added in liquid, continues after being protected from light stirring for 24 hours, removes insoluble matter, decompression using 4.5 μm of filtering with microporous membrane
Solvent evaporated is to get camptothecine and acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H) pulverulent solids inclusion compound；From Fig. 1,
Fig. 3 can be seen that camptothecine and acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H) inclusion compound is successfully prepared.
(2) while stirring to dissolved with 0.1 mmol acid-sensitive open loop Cucurbituril (a, R at 30 DEG C1=H, R2=H) ethyl alcohol
0.2mmol camptothecine is added in solution, continues after being protected from light stirring 36h, removes insoluble matter using 4.5 μm of filtering with microporous membrane, subtract
Press solvent evaporated to get camptothecine and acid-sensitive open loop Cucurbituril (a, R1=H, R2=H) pulverulent solids inclusion compound；From Fig. 2,
Fig. 4 can be seen that camptothecine and acid-sensitive open loop Cucurbituril (a,；R1=H, R2=H) inclusion compound is successfully prepared.
Take human normal cell (HEK-293), human liver cancer tissue cell (HePG2), human colon cancer cell (HCT-116) and
(concentration is 5 × 10 to human neuroblastoma cells (SH-SY5Y) suspension4A/mL) 96 orifice plates of each 100 μ L addition, in 5% dioxy
It is cultivated under change carbon, 37 DEG C and saturated humidity, then uses camptothecine (CPT), acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H；R1
=H, R2=H) and its inclusion compound cell is handled, with adriamycin and Platinol cisplatin be control, measure OD value respectively with mtt assay, ask
Growth inhibition ratio out compares inclusion compound and the camptothecine not included to the inhibiting effect of tumor cell proliferation, and calculates IC50
Value, above-mentioned experiment are taken its average value afterwards three times in parallel.
1 camptothecine of table, acid-sensitive open loop Cucurbituril, the inclusion compound IC in different cells respectively50It is worth (μM)
In table: 1 represents acid-sensitive open loop Cucurbituril (a, R1=CH3, R2=H), 2 represent acid-sensitive open loop Cucurbituril (a, R1=H, R2
=H)
Acid-sensitive open loop Cucurbituril (a, R as can be seen from the table1=CH3, R2=H；R1=H, R2=H) either to normal cell
Or cancer cell is non-toxic, and camptothecine itself is big to the toxicity of normal cell；Acid-sensitive open loop Cucurbituril (a, R1=CH3,
R2=H；R1=H, R2=H) with the inclusion compound of camptothecine there is no toxicity to normal cell, have certain toxicity to cancer cell, and with Ah mould
Element compares with cis-platinum, is no less than to the function and effect of tumour cell both rear.
Embodiment 2: this camptothecine and acid-sensitive open loop Cucurbituril inclusion compound contain camptothecine and acid-sensitive open loop Cucurbituril
(b), wherein acid-sensitive open loop Cucurbituril structural formula is as follows:
；
Camptothecine and acid-sensitive open loop Cucurbituril (b, R1=CH3, R2=H；R1=H, R2=H) inclusion compound preparation
(1) while stirring to dissolved with 0.1 mmol acid-sensitive open loop Cucurbituril (b, R at 35 DEG C1=CH3, R2=H) ethyl alcohol it is molten
0.3mmol camptothecine is added in liquid, continues after being protected from light stirring 48h, removes insoluble matter, decompression using 4.5 μm of filtering with microporous membrane
Solvent evaporated is to get camptothecine and acid-sensitive open loop Cucurbituril (b, R1=CH3, R2=H) pulverulent solids inclusion compound；
(2) while stirring to dissolved with 0.1 mmol acid-sensitive open loop Cucurbituril (b, R at 40 DEG C1=H, R2=H) ethyl alcohol it is molten
0.4mmol camptothecine is added in liquid, continues after being protected from light stirring 60h, removes insoluble matter, decompression using 4.5 μm of filtering with microporous membrane
Solvent evaporated is to get camptothecin drug and acid-sensitive open loop Cucurbituril (b, R1=H, R2=H) pulverulent solids inclusion compound；
Take human normal cell (HEK-293), human liver cancer tissue cell (HePG2), human colon cancer cell (HCT-116) and people's mind
Through blastoma cell (SH-SY5Y) suspension, (concentration is 5 × 104A/mL) 96 orifice plates are added in each 100 μ L, 5% carbon dioxide,
It is cultivated under 37 DEG C and saturated humidity, then uses camptothecine (CPT), acid-sensitive open loop Cucurbituril (b, R1=CH3, R2=H；R1=H, R2
=H) and its inclusion compound cell is handled, with adriamycin and Platinol cisplatin be control, measure OD value respectively with mtt assay, find out growth
Inhibiting rate compares inclusion compound and the camptothecine not included to the inhibiting effect of tumor cell proliferation, and calculates IC50Value, it is above-mentioned
Experiment is taken its average value afterwards three times in parallel.
2 camptothecine of table, acid-sensitive open loop Cucurbituril, the inclusion compound IC in different cells respectively50It is worth (μM)
In table: 1 represents acid-sensitive open loop Cucurbituril (b, R1=CH3, R2=H), 2 represent acid-sensitive open loop Cucurbituril (b, R1=H, R2
=H)
Acid-sensitive open loop Cucurbituril (b, R as can be seen from the table1=CH3, R2=H；R1=H, R2=H) either to normal cell
Or cancer cell is non-toxic, and camptothecine itself is big to the toxicity of normal cell；Acid-sensitive open loop Cucurbituril (b, R1=CH3,
R2=H；R1=H, R2=H) with the inclusion compound of camptothecine there is no toxicity to normal cell, have certain toxicity to cancer cell, and with Ah mould
Element compares with cis-platinum, is no less than to the function and effect of tumour cell both rear.
Embodiment 3: this camptothecine and acid-sensitive open loop Cucurbituril inclusion compound contain camptothecine and acid-sensitive open loop Cucurbituril
(c), wherein acid-sensitive open loop Cucurbituril structural formula is as follows:
；
Camptothecine and acid-sensitive open loop Cucurbituril (c, R1=H, R2=CH3；R1=H, R2=H) inclusion compound preparation
(1) while stirring to dissolved with 0.1 mmol acid-sensitive open loop Cucurbituril (R at 45 DEG C1=H, R2=CH3) ethanol solution
Middle addition 0.5mmol camptothecine, continues after being protected from light stirring 72h, removes insoluble matter using 4.5 μm of filtering with microporous membrane, decompression is steamed
Dry solvent is to get camptothecin drug and acid-sensitive open loop Cucurbituril (c, R1=CH3, R2=H) pulverulent solids inclusion compound；
(2) while stirring to dissolved with 0.1 mmol acid-sensitive open loop Cucurbituril (c, R at 50 DEG C1=H, R2=H) ethyl alcohol it is molten
0.3mmol camptothecine is added in liquid, continues after being protected from light stirring 84h, removes insoluble matter, decompression using 4.5 μm of filtering with microporous membrane
Solvent evaporated is to get camptothecin drug and acid-sensitive open loop Cucurbituril (c, R1=H, R2=H) pulverulent solids inclusion compound；
Take human normal cell (HEK-293), human liver cancer tissue cell (HePG2), human colon cancer cell (HCT-116) and people's mind
Through blastoma cell (SH-SY5Y) suspension, (concentration is 5 × 104A/mL) 96 orifice plates are added in each 100 μ L, 5% carbon dioxide,
It is cultivated under 37 DEG C and saturated humidity, then uses camptothecine (CPT), acid-sensitive open loop Cucurbituril (c, R1=CH3, R2=H；R1=H, R2
=H) and its inclusion compound cell is handled；It is control with adriamycin and Platinol cisplatin；It measures OD value respectively with mtt assay, finds out growth
Inhibiting rate compares inclusion compound and the camptothecine not included to the inhibiting effect of tumor cell proliferation, and calculates IC50Value；It is above-mentioned
Experiment is taken its average value afterwards three times in parallel；
3 camptothecine of table, acid-sensitive open loop Cucurbituril, the inclusion compound IC in different cells respectively50It is worth (μM)
In table: 1 represents acid-sensitive open loop Cucurbituril (c, R1=CH3, R2=H), 2 represent acid-sensitive open loop Cucurbituril (c, R1=H, R2
=H)
Acid-sensitive open loop Cucurbituril (c, R as can be seen from the table1=H, R2=CH3；R1=H, R2=H) either to normal cell
Or cancer cell is non-toxic, and camptothecine itself is big to the toxicity of normal cell；Acid-sensitive open loop Cucurbituril (c, R1=CH3,
R2=H；R1=H, R2=H) with the inclusion compound of camptothecine there is no toxicity to normal cell, have certain toxicity to cancer cell, and with Ah mould
Element compares with cis-platinum, is no less than to the function and effect of tumour cell both rear.
Claims (2)
1. the inclusion compound of a kind of camptothecine and acid-sensitive open loop Cucurbituril, it is characterised in that: contain camptothecine and acid-sensitive open loop
Cucurbituril, wherein the molar ratio of camptothecine and acid-sensitive open loop Cucurbituril is 1:1 ~ 5:1.
2. the inclusion compound of camptothecine according to claim 1 and acid-sensitive open loop Cucurbituril, which is characterized in that acid-sensitive is opened
Ring Cucurbituril is selected from following structural formula:
Formula I；
Formula II；
Formula III
Wherein R1Selected from H, CH3, R2Selected from H, CH3, R1And R2It is not simultaneously CH3。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908116A (en) * | 2019-04-09 | 2019-06-21 | 栾云鹏 | A kind of inclusion compound and preparation method thereof of cannabidiol and open loop Cucurbituril |
| CN111701034A (en) * | 2020-07-22 | 2020-09-25 | 武汉工程大学 | High-water-solubility rifampicin inclusion compound and preparation method thereof |
| CN113603710A (en) * | 2021-07-13 | 2021-11-05 | 昆明理工大学 | Targeting type ring-opening cucurbiturils and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108771675A (en) * | 2018-07-19 | 2018-11-09 | 昆明理工大学 | The inclusion compound and preparation method thereof of artemisinin-based drug and open loop Cucurbituril |
-
2019
- 2019-03-01 CN CN201910155343.8A patent/CN109745568A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108771675A (en) * | 2018-07-19 | 2018-11-09 | 昆明理工大学 | The inclusion compound and preparation method thereof of artemisinin-based drug and open loop Cucurbituril |
Non-Patent Citations (2)
| Title |
|---|
| FANJIE LI ET AL.: ""Acid-controlled release complexes of podophyllotoxin and etoposide with acyclic cucurbit[n]urils for low cytotoxicity"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| NAN DONG ET AL.: ""Cucurbit[n]urils (n 5 7, 8) binding of camptothecin and the effects on solubility and reactivity of the anticancer drug"", 《SUPRAMOLECULAR CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908116A (en) * | 2019-04-09 | 2019-06-21 | 栾云鹏 | A kind of inclusion compound and preparation method thereof of cannabidiol and open loop Cucurbituril |
| CN111701034A (en) * | 2020-07-22 | 2020-09-25 | 武汉工程大学 | High-water-solubility rifampicin inclusion compound and preparation method thereof |
| CN111701034B (en) * | 2020-07-22 | 2023-04-11 | 武汉工程大学 | High-water-solubility rifampicin inclusion compound and preparation method thereof |
| CN113603710A (en) * | 2021-07-13 | 2021-11-05 | 昆明理工大学 | Targeting type ring-opening cucurbiturils and preparation method thereof |
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