CN106588945B - Aspirin anticancer drug conjugate, synthetic method and its application - Google Patents
Aspirin anticancer drug conjugate, synthetic method and its application Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
The invention discloses a kind of aspirin anticancer drug, shown in structure such as formula (1): in formula (1): A is from the anticancer drug that can carry out acylation reaction with the carboxyl of aspirin.The invention discloses a kind of preparation methods of aspirin anticancer drug conjugate; include: that aspirin or aspirin precursor compound and anticancer drug are subjected to acylation reaction in organic solvent, the aspirin anticancer drug conjugate is prepared.The present invention discloses a kind of conjugates of aspirin-anticancer drug in the function and effect for inhibiting tumor cell proliferation.The present invention is by aspirin and camptothecine or taxanes drug coupling, combine the synergistic effect of both aspirin and anticancer drug, further increase the inhibiting effect to tumour cell, compared with simple anti-tumor drug, the aspirin drug conjugates that the present invention obtains achieve good synergism performance.
Description
Technical field
The invention belongs to anticancer drug studying technological domain, be specifically related to a kind of aspirin anticancer drug conjugate and
Preparation method and applications.
Background technique
Aspirin, chemical name: 2- (acetoxyl group) benzoic acid was listed in 1898, up to the present, aspirin
A century has been applied, one of three big classical drugs in medical history are become, it is still most widely used antipyretic, analgesia in the world so far
And anti-inflammatory agent, and as the standard preparation for comparing and evaluating other drugs.And aspirin also has antithrombotic in vivo
Effect, clinically for preventing the breaking-out of cardiovascular and cerebrovascular disease.By aspirin and other salicyclic acid derivatives and polyethylene
The hydroxyl polymer-containings such as alcohol, cellulose acetate carry out fusion esterification, make its producing high-molecular, the anti-inflammatory of products therefrom and it is antipyretic only
The aspirin of pain specific ionization is more long-acting.Recent study finds that aspirin has the generation and progress for inhibiting tumour
Effect then causes the great interest of people (Effect of as a kind of novel anticancer drug-aspirin again
daily aspirin on long-term risk of death due to cancer:analysis of individual
patient data from randomised trials,The Lancet,2011,377,31-41；Long-term
effect of aspirin on colorectal cancer incidence and mortality:20-year
follow-up of five randomised trials,The Lancet,2010,376,1741-1750)。
Aspirin has document report can be by chemically synthesized mode with forming conjugate along platinum medicine, and generates
Synergy.For example, the patent document of Publication No. CN102942594A discloses a kind of medicinal aspirin platinum cooperation of anticancer
Amine or heterocyclic amine are coordinated to platinum original by the N atom of ligand and the coordination of platinum by object and preparation method thereof, the patent document
On son, then by coordination introducing halogen or hydroxyl, carboxylate radical or substituted carboxylic acid root, it is then oxidized to tetravalence platinum, in axial direction
Aspirin molecule is connected, being formed axially has an aspirin molecule monosubstituted or two aspirin molecules disubstituted four
Valence platinum complexes.Since the tetravalent state of platinum only has the toxic side effect of very little to body than relatively inert, and change drug
Intake approach, improve the anticancer activity of drug, have with cis-platinum anti-tumor activity even more superior on an equal basis, and to drug resistance
Cell also has good lethal effect.
(the The Prodrug Platin-A:Simultaneous Release of such as Rakesh K.Pathak
Cisplatin andAspirin, Angew.Chem.Int.Ed.2014,53,1963-1967) and (The such as Qinqin Cheng
ligation of aspirin to cisplatin demonstratessignificant synergistic effects
On tumor cells, Chem.Commun., 2014,50,7427-7430) aspirin is also individually disclosed with cis-platinum class medicine
The correlative study of object formation conjugate.
Camptothecine clinical test since 1961 starts to be applied to clinic, can specifically inhibit the seventies
The activity of topoisomerase I is a kind of rising anticarcinogen.Water-soluble very poor, the biological utilisation of camptothecine parent nucleus
Spend it is low, therefore, the correlation in terms of the camptothecin derivative that corresponding good water solubility, toxic side effect are small and anti-tumor activity is high
Research and development is rapid.In recent years, the patent about camptothecine pharmacokinetics, pharmacodynamics, derivative and preparation research etc. is more
Up to a thousands of pieces.
Taxanes drug keeps tubulin to stablize, cell is inhibited to have by promoting tubulin polymerization to inhibit depolymerization
Silk division, is primarily adapted for use in oophoroma and breast cancer.Currently, stepping into clinical investigation phase there are many formulation for paclitaxel.Such as Japanese yew
Alcohol vitamin E emulsion (TOCOSOL), the medicine were ratified to carry out III clinical trial phase, but the failure of an experiment through FDA in 2005.This
Outside, there are also polyglutamic acid taxol (XyotaxTM), docosahexaenoic acid taxol (Taxoprexin) and taxols
Microballoon (Paclimer) etc..U.S. FDA ratifies Albumin binding taxol (Abraxane) controlling for metastatic breast cancer
It treats, and achieves extraordinary curative effect.Therefore taxanes drug still has very big application prospects and development space.
There is presently no the relevant reports about aspirin and camptothecine or taxanes drug coupling.
Summary of the invention
The present invention provides a kind of with stronger inhibiting tumour cells effect aspirin anticancer drug conjugate.
The present invention also provides a kind of synthetic method of aspirin anticancer drug conjugate, this method simple processes.
The present invention also provides a kind of aspirin anticancer drug conjugates in the application for preparing anti-anticancer drug, compared to
Traditional anti-tumor drug, aspirin anticancer drug conjugate of the invention have better inhibiting tumour cells effect.
A kind of aspirin anticancer drug conjugate, structure are as follows:
Wherein: A is from the anticancer drug that can carry out acylation reaction with the carboxyl of aspirin.The anticancer drug
Preferably camptothecine or taxanes drug.
The acylation reaction, can be esterification, be also possible to amidation process, and different substrates carry out corresponding acyl
Change reaction, to realize its coupling with aspirin.Preferably, the anticancer drug generally contains phenolic hydroxyl group or alkane hydroxyl
The anti-tumor drug of base, as further preferred, the anticancer drug is selected from 10-hydroxycamptothecine and its derivative, taxol
(PTX), Docetaxel (DTX), one of Cabazitaxel (CTX) etc..
As still more preferably, the anticancer drug is selected from 7-Ethyl-10-hydroxycamptothecin, taxol (PTX) or card
Ba Tasai (CTX), i.e., the structure of the described aspirin anticancer drug conjugate is respectively as shown in following formula (1-1)~(1-3):
The present invention also provides a kind of synthetic methods of above-mentioned aspirin anticancer drug conjugate, comprising: by Ah Si
Woods or aspirin precursor compound and anticancer drug carry out acylation reaction in organic solvent, be prepared described Ah
Take charge of a woods anticancer drug conjugate.
Preferably, the acylation reaction can be esterification.
Preferably, in the esterification system, condensing agent can be added, than as mentioned in above-mentioned preparation method
Condensing agent is preferably 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide or its hydrochloride form.As reaction system uses
When the hydrochloride of condensing agent, need to add triethylamine, n,N-diisopropylethylamine.
Preferably, in the esterification system, acylation catalyst can be added, preferably in above-mentioned preparation method
Acylation catalyst be 4-dimethylaminopyridine etc..
Above-mentioned condensing agent and catalyst etc. can be added simultaneously, are perhaps added one or several kinds of or are added without, are both needed to
It is different according to the difference of substrate.For example, can not add other acid binding agent condensing agent when selecting basic solvent and urge
Agent etc..
It is medium one or more that the organic solvent can be DMF, DMSO, acetone, pyridine, methylene chloride.
The aspirin precursor compound can be aspirin chloride compounds, aspirin anhydride compound etc..
It when selecting aspirin as reaction substrate, generally requires in the reaction system, condensing agent and catalyst etc. is added, to guarantee
The rapid progress of reaction.When reaction substrate is aspirin acyl chlorides or acid anhydrides, catalyst etc. can be added without.
In above-mentioned reaction, preferably, the molar ratio of the anticancer drug and aspirin is 1:1.
Above-mentioned acylation reaction can carry out at room temperature, not need harsh reaction condition, the work of production easy to accomplish
Industry.
The present invention also provides a kind of above-mentioned aspirin anticancer drug conjugates in the application for preparing anti-anticancer drug.
Anticancer drug and aspirin coupling latter aspect can improve the endocytosis of drug, and can reduce tumor cell membrane
The affinity of upper resistance to Teat pipette increases so as to cause intracellular savings concentration.Such as Qinqin Cheng (The ligation of
aspirin to cisplatin demonstratessignificant synergistic effects on tumor
Cells, Chem.Commun., 2014,50,7427-7430) aspirin is reported with after cisplatin medicine coupling, effectively increase
The savings concentration of the cis-platinum in various tumour cells is added, to play better Inhibit proliferaton effect.In addition, aspirin
It is the inhibitor of cyclooxygenase COX-1and COX-2 as a kind of non-steroidal anti-inflammatory drugs；And COX-2 withers in the resistance to of tumour cell
Die and mechanism of drug resistance in play a significantly greater role；Therefore aspirin molecule is expected to increase induced by chemotherapeutic agents tumour cell and withers
The ability died.
Compared with prior art, the beneficial effects of the present invention are embodied in:
Aspirin and camptothecine or taxanes drug coupling are combined the anti-of aspirin by the present invention
Scorching and antitumor action, further increases the inhibiting effect to tumour cell, compared with simple anti-tumor drug, the present invention
The inhibition synergistic effect of obtained Aspirin Conjugate is substantially all in 2 times or more.In addition, aspirin anticarcinogen of the invention
Preparation method is simple for object conjugate, does not need harsh reaction condition, it is easy to accomplish large production, reduce drug at
This.
Specific embodiment
Embodiment 1
SN38 (200mg, 0.5mmol) and aspirin (92mg, 0.5mmol), dissolution are added in 100mL round-bottomed flask
In 10mL anhydrous DMF (N, N '-dimethyl formamide), EDC.HCl (1- (3- dimethylamino-propyl) -3- ethyl carbon is added
Diimmonium salt hydrochlorate, 107.4mg, 0.56mmol), DMAP (4-dimethylaminopyridine) (69mg, 0.56mmol) and DIEA (N, N-
Diisopropylethylamine) (73mg, 0.56mmol).It is stirred overnight at room temperature, then uses water, 5% citric acid, unsaturated carbonate hydrogen respectively
Sodium, saturated salt solution cleaning；Organic phase is dried, filtered with anhydrous sodium sulfate, and solvent is removed under reduced pressure after collecting filtrate；Solid column
Thin layer chromatography obtains product 1 (213mg, yield 76.8%) after isolating and purifying (DCM:MeOH=100:1).
Product1H NMR nuclear magnetic data is as follows:
1H NMR (400MHz, CDCl3): δ 1.05-1.06 (m, 3H), 1.42 (s, 3H), 2.34-2.38 (t, 2H),
3.16-3.19(m,3H),4.13-4.20(m,2H),5.27(s,2H),5.33-5.35(t,1H),5.73-5.78(m,2H),
7.24-7.26 (d, 1H, J=8), 7.49-7.59 (m, 2H), 7.66-7.68 (m, 2H), 7.83-7.84 (d, 1H, J=4),
8.24-8.31(m,2H).
Embodiment 2
Be added in 100mL round-bottomed flask taxol (PTX) (200mg, 0.233mmol) and aspirin (47mg,
0.257mmol), be dissolved in 1 0mL anhydrous DMF (N, N '-dimethyl formamide), add EDCHCl (69mg,
0.35mmol), DMAP (4-dimethylaminopyridine) (32mg, 0.257mmol) and DIEA (n,N-diisopropylethylamine) (46mg,
0.35mmol).It is stirred overnight at room temperature, then uses water, 5% citric acid, saturated sodium bicarbonate, saturated salt solution cleaning respectively；Have
Machine is mutually dried, filtered with anhydrous sodium sulfate, and solvent is removed under reduced pressure after collecting filtrate；Solid is isolated and purified with column chromatography chromatogram
(DCM:MeOH=200:1) product 2 (172mg, yield 72.6%) is obtained after.
Product1H NMR nuclear magnetic data is as follows:
1H NMR (400MHz, CDCl3): δ 0.84-0.89 (m, 1H), 1.14 (s, 3H), 1.23-1.26 (d, 6H, J=
12),1.68(s,3H),1.86-1.88(m,2H),1.91-1.93(t,3H),1.96-2.03(m,1H),2.16(s,3H),
2.18-2.20 (t, 1H), 2.23 (s, 3H), 2.42-2.47 (t, 3H), 2.53-2.59 (m, 2H), 3.81-3.82 (d, 1H, J=
4), 4.20-4.21 (d, 1H, J=4), 4.31-4.32 (d, 1H, J=4), 4.96-4.98 (d, 1H, J=8), 5.51-5.52
(d, 1H, J=4), 5.68-5.69 (d, 1H, J=4), 5.95-5.97 (m, 1H), 6.24-6.27 (t, 1H), 6.30 (s, 1H),
6.90-6.92 (d, 1H, J=8), 7.26 (s, 1H), 7.34-7.38 (m, 3H), 7.40-7.42 (m, 4H), 7.50-7.53 (m,
3H), 7.59-7.62 (t, 1H), 7.73-7.74 (d, 2H, J=4), 8.13-8.14 (d, 2H, J=4)
Embodiment 3
Cabazitaxel (CTX) (300mg, 0.36mmol) and aspirin acid anhydrides are added in 100mL round-bottomed flask
(138mg, 0.395mmol) is dissolved in 10mL anhydrous pyridine.Be stirred overnight at room temperature, then oil pump pumps pyridine, after use respectively
Water, 0.1mol/L hydrochloric acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried, filtered with anhydrous sodium sulfate, is collected
Solvent is removed under reduced pressure after filtrate；Solid obtains product 3 after isolating and purifying (DCM:MeOH=100:1) with column chromatography chromatogram
(286mg, yield 79%).
Product1H NMR nuclear magnetic data is as follows:
1H NMR (400MHz, CDCl3): δ 1.21-1.25 (m, 9H), 1.39 (s, 9H), 1.73 (s, 2H), 2.03 (s,
3H), 2.15 (s, 2H), 2.31-2.32 (d, 1H, J=4), 2.35-2.36 (d, 3H, J=4), 2.45-2.46 (d, 3H, J=
4), 2.71-2.77 (m, 1H), 3.33-3.34 (d, 3H, J=4), 3.47 (s, 3H), 3.51-3.52 (t, 1H), 3.88-3.89
(d, 1H, J=4), 3.92-3.95 (m, 1H), 4.20-4.21 (d, 1H, J=4), 4.33-4.35 (d, 1H, J=8), 4.85-
4.86 (d, 1H, J=4), 5.02-5.04 (d, 1H, J=8), 5.67-5.69 (d, 1H, J=8), 6.29 (s, 1H), 7.12-
7.17(m,1H),7.22-7.27(m,1H),7.33-7.38(m,4H),7.41-7.48(m,3H),7.52-7.56(m,3H),
7.62-7.65 (m, 1H), 8.13-8.15 (d, 2H, J=8)
Active testing example 1: vitro cytotoxicity test
For the compound 1~3 that embodiment 1-3 is prepared, vitro cytotoxicity test is carried out using mtt assay:
Make respectively for compound 1~3, SN38, taxol, Cabazitaxel, aspirin that embodiment 1-3 is prepared
It is tested as follows for sample to be tested:
According to listed by table 1~3, logarithmic growth phase cell is inoculated in 96 well culture plates (5000 cells/wells).It is put into
In 37 DEG C of cell incubators constant temperature incubation for 24 hours after, be added sample to be tested, 7 concentration gradients are taken, with SN38, taxol, kappa
He matches, aspirin (being dissolved in dimethyl sulfoxide) as a control group, every kind of medicine 4 repetition values of each concentration add 96 holes after medicine
Cell plates are put into cell incubator after 48 or 72h of culture, and the Methyl thiazoly tetrazolium assay of 30 μ L is added in every hole of 96 orifice plates
(MTT), continue to be put into cell incubator after culture 4h, culture medium is abandoned in suction, and every hole is added 100 μ L dimethyl sulfoxides, uses microplate reader
Detect the light absorption value at 490nm.Compound 1~3, SN38, taxol, Cabazitaxel, aspirin are to various tumour cells
In vitro toxicity the results are shown in Table 1~3.
1 drug 1 of table and the vitro Cytotoxicity Evaluation result (μM) for being associated with control drug
N.E. it indicates to act on tumour cell unrestraint.
2 drug 2 of table and the vitro Cytotoxicity Evaluation result (nM) for being associated with control drug
N.E. it indicates to act on tumour cell unrestraint.
3 drug 3 of table and the vitro Cytotoxicity Evaluation result (nM) for being associated with control drug
N.E. it indicates to act on tumour cell unrestraint.
Table 1~3 is the results show that with source of people colon-cancer cell system HCT-116, colon cancer cell LoVo, source of people non-small cell lung
After cancer A549 co-cultures 48h, aspirin list medicine has little effect the survival rate of tumour cell, i.e. unrestraint acts on；
SN38, taxol, Cabazitaxel can effectively inhibit the proliferation of various tumour cells.Wherein, compound 1 to HCT-116,
The IC of LoVo, A54950Value is respectively 0.07 μM, 0.11 μM, 0.13 μM, and SN38 is applied alone to HCT-116, LoVo, A549
IC50Value is respectively 0.25 μM, 0.28 μM, 0.30 μM, and coupling drug 1 thus can be calculated to HCT-116, LoVo, A549 cell
Inhibit proliferaton ability has been respectively increased 2.57,1.55,1.31 times.It is similar, compound 2 relative to taxol HCT-116,
The inhibiting effect nitrate enhancement of LoVo, A549 are respectively 2.84,3.63,1.63.Compound 3 is relative to Cabazitaxel to HCT-
116, the inhibiting effect nitrate enhancement of LoVo, A549 are respectively nitrate enhancement 2.49,2.69,4.49.
By table 1~3 it is found that compared to aspirin or SN38, taxol, Cabazitaxel, what the present invention was prepared
Aspirin anticancer drug conjugate has the function of stronger inhibition tumor cell proliferation, and nitrate enhancement is up to 2 times or more, card
The aspirin anticancer drug conjugate that the real present invention is prepared has wide antitumor application thereof prospect.
Claims (5)
1. a kind of aspirin anticancer drug conjugate, which is characterized in that shown in structure such as following formula (1-1):
2. a kind of synthetic method of aspirin anticancer drug conjugate described in claim 1 characterized by comprising will
Aspirin or aspirin precursor compound and 7-Ethyl-10-hydroxycamptothecin carry out being acylated in organic solvent anti-
It answers, the aspirin anticancer drug conjugate is prepared；The 7-Ethyl-10-hydroxycamptothecin and aspirin
Molar ratio be 1:1.
3. the synthetic method of aspirin anticancer drug conjugate according to claim 2, which is characterized in that the acyl
Glycosylation reaction is esterification, and in esterification system, one of acid binding agent, condensing agent, acylation catalyst or a variety of is added.
4. the synthetic method of aspirin anticancer drug conjugate according to claim 2, which is characterized in that described has
Solvent includes one of DMF, DMSO, acetone, pyridine, methylene chloride or a variety of.
5. aspirin anticancer drug conjugate is in the application for preparing anticancer drug described in a kind of claim 1.
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| CN109675050A (en) * | 2018-12-27 | 2019-04-26 | 浙江工业大学 | Using camptothecine as the conjugate and its preparation and application of the analog of parent nucleus and nonsteroidal anti-inflammatory drug |
| CN112250647A (en) * | 2020-06-30 | 2021-01-22 | 浙江大学 | Taxane prodrug, preparation method and application |
| CN111925362B (en) * | 2020-08-20 | 2023-06-23 | 陕西中医药大学 | Anticancer compound and synthesis method and application thereof |
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| Title |
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| BIOACTIVATION OF THE ANTICANCER AGENT CPT-11 TO SN-38 BY HUMAN HEPATIC MICROSOMAL CARBOXYLESTERASES AND THE IN VITRO ASSESSMENT OF POTENTIAL DRUG INTERACTIONS;J. GREG SLATTER,et al.,;《DRUG METABOLISM AND DISPOSITION》;19971231;第25卷(第10期);第1157-1164页 |
| EDCI/DMAP存在下7-乙基喜树碱与乙酰水杨酸的反应;蔡冉,et al.,;《化学研究与应用》;20160228;第28卷(第2期);第214-217页 |
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