CN113797195B - Application of 3-aryl coumarin compound, anti-cancer sensitization composition and anti-cancer composition - Google Patents
Application of 3-aryl coumarin compound, anti-cancer sensitization composition and anti-cancer composition Download PDFInfo
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- CN113797195B CN113797195B CN202110959473.4A CN202110959473A CN113797195B CN 113797195 B CN113797195 B CN 113797195B CN 202110959473 A CN202110959473 A CN 202110959473A CN 113797195 B CN113797195 B CN 113797195B
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- cancer
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- topotecan hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses application of a 3-aryl coumarin compound shown in a structural formula (I), and an anti-cancer sensitization composition and an anti-cancer composition containing the compound. Compared with the prior art, the 3-aryl coumarin compound has good anti-cancer sensitization effect, can obviously reduce the use dosage of topotecan hydrochloride when used together with the topotecan hydrochloride, reduces the toxic and side effects of the topotecan hydrochloride, and has good popularization and application values.
Description
Technical Field
The invention relates to the field of drug production, and particularly provides application of a 3-aryl coumarin compound, an anti-cancer sensitization composition and an anti-cancer composition.
Background
Topotecan hydrochloride (yellow needle crystal or crystalline powder, water-soluble semisynthetic derivative of camptothecin) is an inhibitor of topoisomerase I, which can be used to treat all solid tumors by inhibiting DNA damage caused by single-strand-break DNA reassociation, whose cytotoxicity affects the S-phase of cancer cell division. Topotecan hydrochloride is used as a common antitumor drug, has a wide antitumor spectrum (can be used for treating various cancers including small cell lung cancer, ovarian cancer, breast cancer, non-small cell lung cancer, colon cancer and neuroblastoma), but has the defects of poor selectivity, strong toxic and side effects, single target, easy generation of drug resistance and the like.
The 3-aryl coumarin has certain antitumor activity, and 3-aryl coumarin compounds with good antitumor activity are synthesized by modifying the 3-aryl coumarin in the prior art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an application of a 3-aryl coumarin compound.
The technical scheme adopted by the invention for solving the technical problems is as follows: the application of the 3-aryl coumarin compound shown in the structural formula (I) in preparing an anti-cancer sensitizer,
the cancer is colon cancer and lung cancer.
The applicant finds that when the 3-aryl coumarin compound shown in the formula (I) is used together with topotecan hydrochloride, the use dosage of the topotecan hydrochloride can be obviously reduced, and the toxic and side effects of the topotecan hydrochloride can be reduced.
The invention further aims to provide an anti-cancer sensitization composition.
The effective component of the anti-cancer sensitization composition comprises a 3-aryl coumarin compound shown in a structural formula (I).
Still a further technical task of the present invention is to provide an anticancer composition with low toxic and side effects.
The active ingredients of the anticancer composition comprise 3-aryl coumarin compounds shown in a structural formula (I) and topotecan hydrochloride.
Preferably, the molar ratio of the topotecan hydrochloride to the 3-aryl coumarin compound is 1:1-1: 4. In particular, when used for the preparation of a medicament for the treatment of colon cancer, the ratio of the two is preferably 1:2 to 1: 4; when used in the preparation of a medicament for the treatment of lung cancer, the ratio of the two is preferably 1:1 to 1: 2.
The anti-cancer sensitization composition or the anti-cancer composition also comprises one or more pharmaceutically acceptable carriers. The carrier comprises diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.
The anticancer sensitization composition or the anticancer composition can be used in the forms of oral administration or non-oral administration, and can be introduced into the body such as muscle, intracutaneous, subcutaneous, vein and mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.
For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, ointment, cream, etc.; making into liquid preparation such as water or oil suspension or other liquid preparations such as oral liquid. For non-oral administration, it can be made into injection, etc.
Compared with the prior art, the application of the 3-aryl coumarin compound, the anticancer sensitization composition and the anticancer composition have the following outstanding beneficial effects:
the 3-aryl coumarin compound is used as a sensitizer of an anti-cancer drug for the first time, so that the application field of the 3-aryl coumarin compound is expanded;
(II) the 3-aryl coumarin compound and the topotecan hydrochloride can be used together, so that the dosage of the topotecan hydrochloride is greatly reduced, and the toxic and side effects of the topotecan hydrochloride are reduced;
and (III) the 3-aryl coumarin compound shown in the formula (I) has a simple preparation method and is convenient to popularize and apply.
Detailed Description
The present invention is further illustrated by the following examples, which are not to be construed as limiting the invention.
Unless otherwise specified, the contents of the components used below are in weight percent; the experimental methods used are all conventional methods; the reagents, biological materials, etc. used are commercially available.
The compound numbers and structural formulas involved in the examples of the present invention are as follows:
[ preparation examples ]
The preparation process of the compound I, namely 3- (4' -hydroxyphenyl) -6-hydroxycoumarin, is as follows:
in a 100mL three-necked reaction vessel, 1.52g (10mmol) of 4-hydroxyphenylacetic acid, 1.38g (10mmol) of 2, 5-dihydroxybenzaldehyde, 5.56g (55mmol) of triethylamine and 6.12g (60mmol) of acetic anhydride were charged, followed by magneton addition, and the reaction was carried out in a microwave reactor with a microwave power of 100W and a reaction time of 70min under stirring. Pouring into 50ml water immediately after the reaction is finished, stirring, precipitating a large amount of solid, standing, filtering, washing a filter cake with water until the washing liquid is nearly neutral, and recrystallizing with ethyl acetate/petroleum ether after being dried to obtain the light yellow needle-shaped solid.
Adding the obtained solid into a 100mL three-mouth reaction bottle, adding 10mL ethanol, heating and stirring until the solid is completely dissolved, then adding 40mL 10% hydrochloric acid, stirring uniformly, heating to 80 ℃, and carrying out reflux reaction for 3 h. And (3) after the TCL monitoring reaction is finished, pouring the reaction solution into 50ml of ice water, stirring, precipitating a large amount of solid, standing, carrying out suction filtration, recrystallizing the filter cake with ethanol/water, and carrying out vacuum drying to obtain the compound I.
[ sensitization Activity measurement ]
1. Cell culture
Cells were selected for H1299 (non-small cell lung cancer cells) and cultured in 1640 medium in 10% serum.
Cells were selected for HCT116 (colon cancer cells) and cultured in 1640 medium with 10% serum.
2. Cytotoxicity test
2.1H 1299 cytotoxicity assay
H1299 cells were plated in 96-well plates at 7000 cells/100 ul per well and cultured overnight. Then 100ul of medicated medium of different concentrations was added for further treatment for 48 h. The concentration gradient of compound II (topotecan hydrochloride) is 0.78, 1.56, 3.125, 6.25, 12.5 and 25uM respectively. The concentration of the compound I is 50-100 uM. After 48h, 10uLMTT is added into each well, and the mixture is incubated for 4h at 37 ℃ without light protection. The culture broth was discarded and 150ul DMSO was added to each well. Shaking for 10min until the blue-violet crystal is completely dissolved. The absorbance at 490nm was measured with an enzyme-labeled analyzer. Cell activity (100%) (mean OD value of drug group/mean OD value of normal group) 100%.
2.2 HCT116 cytotoxicity assay
HCT116 cells were plated in 96-well plates at 7000 cells/100 ul per well and cultured overnight. Then 100ul of different concentrations of the dosed media were added and further treated for 48 h. The concentration gradient of compound II (topotecan hydrochloride) was 0.195, 0.39, 0.78, 1.56, 3.125, 6.25uM, respectively. The concentration of the compound I is 25-50 uM. After 48h, 10uLMTT is added into each well, and the mixture is incubated for 4h at 37 ℃ without light protection. The culture medium was discarded and DMSO was added to the wells at 150. mu.l/well. Shaking for 10min until the crystal is completely dissolved. The absorbance at 490nm was measured with a microplate reader. Cell activity (100%) (mean OD value of drug group/mean OD value of normal group) 100%.
3. Analysis of results
3.1 data on the Effect of lung cancer H1299 cells
When the topotecan hydrochloride single medicine is applied: IC of TPT 50 =16.053±0.75uM
When the compound I is applied singly: IC of Compound I 50 =370.675±84uM
When topotecan hydrochloride is used in combination with the compound I (the concentration is 100 uM):
TPT+100uMⅠ:IC 50 =5.214±0.46uM
when topotecan hydrochloride is used in combination with compound i (at a concentration of 50 uM):
TPT±50uMⅠ:IC 50 =10.038±1.1uM
the results show that: the topotecan hydrochloride and the compound I are combined to treat the lung cancer, so that the apoptosis of lung cancer cells can be increased, the effective concentration of the topotecan hydrochloride in application is reduced, and the effect of anti-cancer sensitization is achieved.
3.2 data on the action of HCT116 cells on colon cancer
When the topotecan hydrochloride single medicine is applied: IC of TPT 50 =3.467±0.0017uM
When the compound I is applied singly: IC of Compound I 50 =296.5±0.4467uM
Topotecan hydrochloride in combination with compound i (50 uM concentration):
TPT+50uMⅠ:IC 50 =0.391±0.004uM
topotecan hydrochloride in combination with compound i (25 uM concentration):
TPT±25uMⅠ:IC 50 =1.64±0.014uM
the results show that: when the combined application concentration of the compound I is 25uM, the dosage of the topotecan hydrochloride is reduced by half, and the same treatment effect can be achieved. When the combined administration concentration of the compound I is 50uM, the same treatment effect is achieved, the administration concentration of the topotecan hydrochloride is only 1/9 in single-drug treatment, the dosage of the topotecan hydrochloride is greatly reduced, and the adverse reaction of the drug is reduced, so that the compound I and the topotecan hydrochloride are combined to play a good role in anti-cancer sensitization.
Claims (2)
2. the anti-cancer composition of claim 1, wherein the molar ratio of topotecan hydrochloride to 3-arylcoumarin is from 1:1 to 1: 4.
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