CN106588945A - Aspirin-anticancer drug conjugate, and synthetic method and application thereof - Google Patents
Aspirin-anticancer drug conjugate, and synthetic method and application thereof 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 an aspirin-anticancer drug conjugate with a structure as shown in a formula (1) which is described in the specification. In the formula (1), A is originated from an anticancer drug capable of realizing acylation with the carboxyl group of aspirin. The invention discloses a preparation method for the aspirin-anticancer drug conjugate. The preparation method comprises a step of subjecting aspirin or an aspirin precursor compound and an anticancer drug to acylation in an organic solvent so as to prepare the aspirin-anticancer drug conjugate. The invention also discloses effect of the aspirin-anticancer drug conjugate in inhibition of proliferation of tumor cells. According to the invention, aspirin is coupled with a camptothecin drug or paclitaxel drug, so synergism of aspirin and the anticancer drug further improves inhibitory effect on tumor cells; and compared with the single anticancer drug, the aspirin-anticancer drug conjugate prepared in the invention has good synergism.
Description
Technical field
The invention belongs to cancer therapy drug studying technological domain, be specifically related to a kind of aspirin cancer therapy drug conjugate and
Preparation method and applications.
Background technology
Aspirin, chemical name：2- (acetoxyl group) benzoic acid, listed in 1898, up to the present, aspirin
Using a century, become one of three big classics medicines in medical history, it is still most widely used antipyretic, analgesia in the world so far
And anti-inflammatory agent, and as comparing and evaluate the standard preparation of other drugs.And aspirin also has antithrombotic in vivo
Effect, clinically for preventing the outbreak 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 so as to 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 aspirin with the generation and progress for suppressing tumor
Effect, then causes people great interest (Effect of again as a kind of new cancer therapy drug-aspirin
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 by way of chemosynthesis with forming conjugate along platinum medicine, and can to produce
Synergy.For example, the patent documentation of Publication No. CN102942594A discloses a kind of anticarcinogen aspirin platinum and coordinates
Thing and preparation method thereof, it is former that the patent documentation is coordinated to platinum amine or heterocyclic amine by the N atoms of part and the coordination of platinum
On son, then halogen or hydroxyl, carboxylate radical or substituted carboxylic acid root are introduced by coordination, be 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
Valency platinum complexes.As the tetravalent state of platinum is than relatively inert, only has the toxic and side effects of very little to body, and change medicine
Intake approach, improve the active anticancer of medicine, with even more superior anti-tumor activity equal with cisplatin, and to drug resistance
Cell also has good lethal effect.
(the The Prodrug Platin-A such as Rakesh K.Pathak:Simultaneous Release of
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 cisplatin class medicine
Thing forms the correlational study of conjugate.
Camptothecine started clinical trial from 1961, starts the seventies to be applied to clinic, specifically can suppress
The activity of topoisomerase I, is the rising anticarcinogen of a class.The water solublity of camptothecine parent nucleus is very poor, biological utilisation
Degree is low, therefore, the correlation in terms of the camptothecin derivant that corresponding good water solubility, toxic and side effects are little and anti-tumor activity is high
Research and development is rapid.In recent years, the patent in terms of camptothecine pharmacokineticss, pharmacodynamicss, derivant and preparation research etc. is more
Up to a thousands of pieces.
Taxanes medicine suppresses depolymerization by promoting tubulin polymerization, keeps tubulin stable, suppresses cell to have
Silk division, is primarily adapted for use in ovarian cancer and breast carcinoma.At present, many formulation for paclitaxel step into clinical investigation phase.Such as Ramulus et folium taxi cuspidatae
Alcohol Vitamin E Emulsion (TOCOSOL), the medicine carry out III clinical trial phases in the approvals of Jing FDA in 2005, but the failure of an experiment.This
Outward, also polyglutamic acid paclitaxel (XyotaxTM), docosahexenoic acid paclitaxel (Taxoprexin) and paclitaxel
Microsphere (Paclimer) etc..U.S. FDA ratifies Albumin binding paclitaxel (Abraxane) controlling for metastatic breast cancer
Treat, and achieve extraordinary curative effect.Therefore taxanes medicine still has very big application prospect and development space.
There is presently no the relevant report with regard to aspirin and camptothecine or taxanes drug coupling.
The content of the invention
The present invention provides a kind of with higher inhibiting tumour cells effect aspirin cancer therapy drug conjugate.
Present invention also offers a kind of synthetic method of aspirin cancer therapy drug conjugate, the method process is simple.
Present invention also offers a kind of aspirin cancer therapy drug conjugate is in the application for preparing anti-cancer therapy drug, compared to
Traditional antitumor drug, the aspirin cancer therapy drug conjugate of the present invention have more preferable inhibiting tumour cells effect.
A kind of aspirin cancer therapy drug conjugate, its structure are as follows：
Wherein：A is from the cancer therapy drug that acylation reaction can be carried out with the carboxyl of aspirin.The cancer therapy drug
Preferably camptothecine or taxanes medicine.
The acylation reaction, can be esterification, or amidation process, and different substrates carry out corresponding acyl
Change reaction, to realize its coupling with aspirin.Preferably, the cancer therapy drug is generally containing phenolic hydroxyl group or alkane hydroxyl
The antitumor drug of base, used as further preferred, the cancer therapy drug is selected from 10-hydroxycamptothecine and its derivant, paclitaxel
(PTX) one kind in, Docetaxel (DTX), Cabazitaxel (CTX) etc..
Used as still more preferably, the cancer therapy drug is selected from SN38, paclitaxel (PTX) or card
Ba Tasai (CTX), i.e., the structure of described aspirin cancer therapy drug conjugate is respectively as shown in following formula (1-1)～(1-3)：
Present invention also offers a kind of synthetic method of above-mentioned aspirin cancer therapy drug conjugate, including：By Ah Si
Woods or aspirin precursor compound and cancer therapy drug carry out acylation reaction in organic solvent, prepare described Ah
Department's woods cancer therapy drug conjugate.
Preferably, the acylation reaction can be esterification.
Preferably, in above-mentioned preparation method, in the esterification system, condensing agent can be added, than as mentioned
Condensing agent is preferably 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides or its hydrochloride form.As reaction system is used
During the hydrochlorate of condensing agent, need to add triethylamine, DIPEA.
Preferably, in above-mentioned preparation method, in the esterification system, acylation catalyst can be added, preferably
Acylation catalyst be DMAP etc..
Above-mentioned condensing agent and catalyst etc., can add simultaneously, or add one or several, or be added without, be both needed to
Will be according to the different and different of substrate.Such as, when from basic solvent, without other acid binding agent condensing agent and can urge
Agent etc..
The organic solvent can be that DMF, DMSO, acetone, pyridine, dichloromethane are medium one or more.
The aspirin precursor compound can be aspirin chloride compounds, aspirin anhydride compound etc..
When selecting aspirin as reaction substrate, generally require in reaction system, add condensing agent and catalyst etc., to ensure
That what is reacted is carried out rapidly.When reaction substrate is aspirin acyl chlorides or anhydride, catalyst etc. can be added without.
In above-mentioned reaction, preferably, the cancer therapy drug is 1 with the mol ratio of aspirin:1.
Above-mentioned acylation reaction can be carried out at ambient temperature, it is not necessary to harsh reaction condition, easily realize the work of production
Industry.
Present invention also offers a kind of above-mentioned aspirin cancer therapy drug conjugate is in the application for preparing anti-cancer therapy drug.
Cancer therapy drug is coupled latter aspect with aspirin can improve the endocytosis of medicine, and can reduce tumor cell membrane
The affinity of upper resistance to Teat pipette, so as to cause intracellular savings concentration to increase.Such as Qinqin Cheng etc. (The ligation of
aspirin to cisplatin demonstratessignificant synergistic effects on tumor
Cells, Chem.Commun., 2014,50,7427-7430), after reporting aspirin and cisplatin medicine coupling, effectively increase
The savings concentration of the cisplatin in various tumor cells is added, so as to play more preferable Inhibit proliferaton effect.Additionally, aspirin
As a kind of NSAID (non-steroidal anti-inflammatory drug), it is the inhibitor of cyclooxygenase COX-1and COX-2；And COX-2 withers in the resistance to of tumor cell
Die and mechanism of drug resistance in play a significantly greater role；Therefore aspirin molecule is expected to increase induced by chemotherapeutic agents tumor cell and withers
The ability died.
Compared with prior art, 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 inhibitory action to tumor cell, compared with simple antitumor drug, the present invention
The suppression potentiation of the Aspirin Conjugate for obtaining is substantially all more than 2 times.In addition, the aspirin anticarcinogen of the present invention
The preparation method of thing conjugate is simple, it is not necessary to harsh reaction condition, it is easy to accomplish large production, reduce medicine into
This.
Specific embodiment
Embodiment 1
SN38 (200mg, 0.5mmol) and aspirin (92mg, 0.5mmol), dissolving are added in 100mL round-bottomed flasks
In 10mL dry DMFs (N, N '-dimethyl Methanamide), EDC.HCl (1- (3- dimethylamino-propyls) -3- ethyl carbon is added
Diimmonium salt hydrochlorate, 107.4mg, 0.56mmol), DMAP (DMAP) (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 aqueous common salt cleaning；Organic faciess anhydrous sodium sulfate drying, filters, and collects removal of solvent under reduced pressure after filtrate；Solid post
Thin layer chromatography isolates and purifies (DCM:MeOH=100:1) product 1 is obtained after, and (213mg, yield is 76.8%).
Product1H NMR nuclear magnetic datas are as follows：
1H NMR (400MHz, CDCl3)：δ1.05-1.06(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
In 100mL round-bottomed flasks add paclitaxel (PTX) (200mg, 0.233mmol) and aspirin (47mg,
0.257mmol), be dissolved in 1 0mL dry DMFs (N, N '-dimethyl Methanamide), add EDCHCl (69mg,
0.35mmol), DMAP (DMAP) (32mg, 0.257mmol) and DIEA (DIPEA) (46mg,
0.35mmol).It is stirred overnight at room temperature, then uses water, 5% citric acid, saturated sodium bicarbonate, saturated aqueous common salt cleaning respectively；Have
Machine mutually uses anhydrous sodium sulfate drying, filters, and collects removal of solvent under reduced pressure after filtrate；Solid is isolated and purified with column chromatography chromatogram
(DCM:MeOH=200:1) product 2 is obtained after, and (172mg, yield is 72.6%).
Product1H NMR nuclear magnetic datas are 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 anhydride are added in 100mL round-bottomed flasks
(138mg, 0.395mmol), is dissolved in 10mL anhydrous pyridines.Be stirred overnight at room temperature, then oil pump pumps pyridine, after use respectively
Water, 0.1mol/L hydrochloric acid, saturated sodium bicarbonate, saturated aqueous common salt cleaning；Organic faciess anhydrous sodium sulfate drying, filters, and collects
Removal of solvent under reduced pressure after filtrate；Solid column chromatography chromatogram isolates and purifies (DCM:MeOH=100:1) product 3 is obtained after
(286mg, yield is 79%).
Product1H NMR nuclear magnetic datas are as follows：
1H NMR (400MHz, CDCl3)：δ1.21-1.25(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 is tested
For the compound 1～3 that embodiment 1-3 is prepared, vitro cytotoxicity test is carried out using mtt assay：
It is respectively directed to compound 1～3, SN38, paclitaxel, Cabazitaxel, aspirin that embodiment 1-3 prepares to make
Tested for testing sample as follows：
According to trophophase cell of listed by table 1～3, taking the logarithm, 96 well culture plates (5000 cells/wells) are inoculated in.It is put into
After constant temperature culture 24h in 37 DEG C of cell culture incubators, testing sample is added, 7 Concentraton gradient is taken, with SN38, paclitaxel, kappa
He matches, aspirin (being dissolved in dimethyl sulfoxide) as a control group, every kind of medicine 4 repetition values of each concentration are added 96 holes after medicine
After cell plates cultivate 48 or 72h in being put into cell culture incubator, the Methyl thiazoly tetrazolium assay of 30 μ L is added in every hole of 96 orifice plates
(MTT) after cultivating 4h in, continuing to be put into cell culture incubator, culture medium is abandoned in suction, and 100 μ L dimethyl sulfoxides are added per hole, microplate reader is used
Light absorption value at detection 490nm.Compound 1～3, SN38, paclitaxel, Cabazitaxel, aspirin are to various tumor cells
In vitro toxicity the results are shown in Table 1～3.
Vitro Cytotoxicity Evaluation result (μM) of 1 medicine 1 of table and association control drug
N.E. represent and tumor cell unrestraint is acted on.
The vitro Cytotoxicity Evaluation result (nM) of 2 medicine 2 of table and association control drug
N.E. represent and tumor cell unrestraint is acted on.
The vitro Cytotoxicity Evaluation result (nM) of 3 medicine 3 of table and association control drug
N.E. represent and tumor cell unrestraint is acted on.
1～3 result of table shows, with people source colon-cancer cell system HCT-116, colon cancer cell LoVo, people source non-small cell lung
After cancer A549 co-cultures 48h, aspirin list medicine is had little to no effect to the survival rate of tumor cell, i.e. unrestraint effect；
SN38, paclitaxel, Cabazitaxel can effectively suppress the propagation of various tumor 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 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 paclitaxel HCT-116,
The inhibitory action nitrate enhancement of LoVo, A549 is respectively 2.84,3.63,1.63.Compound 3 is relative to Cabazitaxel to HCT-
116th, the inhibitory action nitrate enhancement of LoVo, A549 is respectively nitrate enhancement 2.49,2.69,4.49.
From table 1～3, compared to aspirin or SN38, paclitaxel, Cabazitaxel, what the present invention was prepared
Aspirin cancer therapy drug conjugate has the effect of higher suppression tumor cell proliferation, and nitrate enhancement is demonstrate,proved up to more than 2 times
The aspirin cancer therapy drug conjugate that the real present invention is prepared has wide antitumor application thereof prospect.
Claims (10)
1. a kind of aspirin cancer therapy drug conjugate, it is characterised in that shown in structure such as following formula (1)：
In formula (1)：A is from the cancer therapy drug that acylation reaction can be carried out with the carboxyl of aspirin.
2. aspirin cancer therapy drug conjugate according to claim 1, it is characterised in that described acylation reaction is
Esterification, the cancer therapy drug are camptothecine.
3. aspirin cancer therapy drug conjugate according to claim 1, it is characterised in that described cancer therapy drug is selected from
One kind in camptothecin analogues.
4. aspirin cancer therapy drug conjugate according to claim 3, it is characterised in that described cancer therapy drug is 7-
Ethyl-10-hydroxycamptothecin.
5. aspirin cancer therapy drug conjugate according to claim 3, it is characterised in that described aspirin anticancer
The structure of drug conjugates is respectively as shown in following formula (1-1)：
6. the synthetic method of the aspirin cancer therapy drug conjugate described in a kind of claim 1, it is characterised in that include：Will
Aspirin or aspirin precursor compound and cancer therapy drug carry out acylation reaction in organic solvent, prepare institute
The aspirin cancer therapy drug conjugate stated.
7. the synthetic method of aspirin cancer therapy drug conjugate according to claim 6, it is characterised in that described acyl
Glycosylation reaction is esterification, in esterification system, adds one or more in acid binding agent, condensing agent, acylation catalyst.
8. the synthetic method of aspirin cancer therapy drug conjugate according to claim 6, it is characterised in that described has
Machine solvent includes one or more in DMF, DMSO, acetone, pyridine, dichloromethane.
9. the synthetic method of aspirin cancer therapy drug conjugate according to claim 6, it is characterised in that described is anti-
Cancer drug is 1 with the mol ratio of aspirin:1.
10. aspirin cancer therapy drug conjugate described in a kind of claim 1 is in the application for preparing anti-cancer therapy drug.
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Cited By (4)
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| CN107417661A (en) * | 2017-06-13 | 2017-12-01 | 佛山科学技术学院 | A kind of conjugate containing aspirin and its production and use |
| CN109675050A (en) * | 2018-12-27 | 2019-04-26 | 浙江工业大学 | conjugate of analogue taking camptothecin as parent nucleus and non-steroidal anti-inflammatory drug, preparation and application thereof |
| CN111925362A (en) * | 2020-08-20 | 2020-11-13 | 陕西中医药大学 | Anticancer compound and synthesis method and application thereof |
| CN112250647A (en) * | 2020-06-30 | 2021-01-22 | 浙江大学 | Taxane prodrug, preparation method and application |
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| WO2003095460A1 (en) * | 2002-05-06 | 2003-11-20 | The Stehlin Foundation For Cancer Research | Cascade esters of camptothecins and methods of treating cancer using these compounds |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417661A (en) * | 2017-06-13 | 2017-12-01 | 佛山科学技术学院 | A kind of conjugate containing aspirin and its production and use |
| CN109675050A (en) * | 2018-12-27 | 2019-04-26 | 浙江工业大学 | conjugate of analogue taking camptothecin as parent nucleus and non-steroidal anti-inflammatory drug, preparation and application thereof |
| CN112250647A (en) * | 2020-06-30 | 2021-01-22 | 浙江大学 | Taxane prodrug, preparation method and application |
| CN111925362A (en) * | 2020-08-20 | 2020-11-13 | 陕西中医药大学 | Anticancer compound and synthesis method and application thereof |
| 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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