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CN115252611B - Amide compound, application thereof and anti-tumor pharmaceutical composition - Google Patents

Amide compound, application thereof and anti-tumor pharmaceutical composition Download PDF

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CN115252611B
CN115252611B CN202210778852.8A CN202210778852A CN115252611B CN 115252611 B CN115252611 B CN 115252611B CN 202210778852 A CN202210778852 A CN 202210778852A CN 115252611 B CN115252611 B CN 115252611B
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compounds
tumor
amide
cells
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CN115252611A (en
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余建清
韦玉璐
万倩
刘清钰
徐婕
刘星星
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Wuhan University WHU
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • A61K36/185—Magnoliopsida (dicotyledons)
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Abstract

The invention relates to the technical field of medicines, in particular to an amide compound, application thereof and an anti-tumor pharmaceutical composition. The amide compounds are separated from Piper longum and Piper nigrum belonging to the genus Piper, belonging to natural products, and have effects of increasing sensitivity of several chemotherapeutics, reversing tumor cell drug resistance, and promoting apoptosis. The 22 kinds of amide compounds can be used as sensitizer of chemotherapeutic drugs, can be used together with anti-tumor drugs (chemotherapeutic drugs), can enhance the anti-tumor effect of the chemotherapeutic drugs, reverse tumor cell drug resistance, and provide a new way and a new means for solving the problem of tumor drug resistance. The 22 kinds of amide compounds have the functions of increasing the sensitivity of taxol, vincristine and doxorubicin to tumor cells and reversing the drug resistance of the tumor cells.

Description

Amide compound, application thereof and anti-tumor pharmaceutical composition
Technical Field
The invention relates to the technical field of medicines, in particular to an amide compound, application thereof and an anti-tumor pharmaceutical composition.
Background
Cancer is a major cause of death in the world population and is also an important obstacle to improving life expectancy. Paclitaxel, the first chemical from natural plants to treat cancer, inhibits tubulin depolymerization, causes cell cycle arrest, and promotes tumor apoptosis. Paclitaxel chemotherapy drugs are currently in clinical use as antitumor drugs. With the widespread use of chemotherapeutic agents, many patients develop resistance, poor prognosis of cancer, and ultimately death. Therefore, the search for compounds with the effect of reversing the drug resistance of the taxol medicaments has extremely important significance. Vincristine is also a chemotherapeutic agent acting clinically on the tubulin system. Unlike the mechanism of action of paclitaxel, vincristine inhibits tubulin to form microtubules, mediating cell cycle arrest, leading to cell death. Doxorubicin is a clinically common antibiotic broad-spectrum antitumor drug, can inhibit synthesis of RNA and DNA, and belongs to a periodic nonspecific drug. In the treatment of tumor patients, single-drug treatment is easy to cause drug resistance of the patients, and development of new drug and chemotherapeutic drug combined treatment is beneficial to overcoming drug resistance, reducing single-drug dose toxicity and improving drug curative effect.
The amide compound is the main chemical component of the piper plant, has obvious activity and high bioavailability. The research shows that the amide compound has various biological activities such as anti-inflammatory, analgesic, anti-tumor and the like, and is an important source of natural medicine bioactive components. The amide compounds of Piperaceae plants of Piper are very abundant.
Disclosure of Invention
The invention aims at providing an application of an amide compound in preparing a chemotherapeutic drug sensitizer.
The second object of the present invention is to provide an antitumor pharmaceutical composition.
The invention also aims to provide an amide compound which has the effects of increasing the sensitivity of a plurality of chemotherapeutic drugs, reversing the drug resistance of tumor cells and promoting apoptosis.
The scheme adopted by the invention for achieving one of the purposes is as follows: an application of an amide compound, which is used for preparing an anti-tumor chemotherapeutic sensitizer, wherein the amide compound is any one of the following compounds 1-22:
preferably, the chemotherapeutic agent is a cell cycle specific agent or a cell cycle non-specific agent.
Preferably, the chemotherapeutic drug comprises any one of vincristine, doxorubicin, paclitaxel and derivatives thereof.
Preferably, the tumor comprises at least one of uterine cancer, ovarian cancer, breast cancer, liver cancer, lung cancer, nasopharyngeal cancer, gastric cancer, colorectal cancer, pancreatic cancer, skin cancer, renal cancer, esophageal cancer.
The scheme adopted by the invention for achieving the second purpose is as follows: an antitumor pharmaceutical composition comprises a chemotherapeutic drug and a sensitizer, wherein the chemotherapeutic drug comprises any one of vincristine, doxorubicin, taxol and derivatives thereof, and the sensitizer is any one of amide compounds 1-22.
Preferably, the dosage form of the medicine is at least one of oral liquid, tablets, injection, capsules, granules and powder.
Preferably, the pharmaceutical composition is administered orally or by injection.
The scheme adopted by the invention for achieving the third purpose is as follows: an amide compound isolated from Piper longum and Piper nigrum of Piperaceae, wherein the structural formula is any one of the compounds 1-12.
The invention has the following advantages and beneficial effects:
the 22 kinds of amide compounds are separated from Piper longum and Piper nigrum belonging to the genus Piper and belong to natural products, and all the compounds have the functions of increasing the sensitivity of several chemotherapeutics, reversing tumor cell drug resistance and promoting apoptosis.
The 22 kinds of amide compounds can be used as sensitizer of chemotherapeutic drugs, can be used together with anti-tumor drugs (chemotherapeutic drugs), can enhance the anti-tumor effect of the chemotherapeutic drugs, reverse tumor cell drug resistance, and provide a new way and a new means for solving the problem of tumor drug resistance.
The 22 kinds of amide compounds have the functions of increasing the sensitivity of taxol, vincristine and doxorubicin to tumor cells and reversing the drug resistance of the tumor cells.
Drawings
FIG. 1 shows the synergistic and sensitization of cervical cancer taxol-resistant cells (HeLa/PTX) by the combination of novel compounds 1-12 (10. Mu.M) and taxol in the present invention;
FIG. 2 shows the synergistic and sensitization of cervical cancer paclitaxel resistant cells (HeLa/PTX) by the combination of known compounds 13-21 (10. Mu.M) and paclitaxel according to the present invention;
FIG. 3 shows the synergistic and sensitization of cervical cancer cells (HeLa) by the combination of Compounds 1, 5, 7, 15, 17 and 21 (10. Mu.M) with paclitaxel;
FIG. 4 shows the synergistic and sensitization of cervical cancer cells (HeLa) by compounds 1, 9, 10, 16, 18 and 19 (10. Mu.M) in combination with vincristine;
FIG. 5 shows the synergistic and sensitization of cervical cancer cells (HeLa) by compounds 2, 4, 6, 10, 13 and 18 (10. Mu.M) in combination with doxorubicin;
FIG. 6 shows the synergistic and sensitization of ovarian cancer cells (SKOV-3) by compounds 2, 5, 8, 14 and 17 (10. Mu.M) in combination with paclitaxel;
FIG. 7 shows the synergistic and sensitization of ovarian cancer cells (SKOV-3) by compounds 3, 6, 11, 16 and 20 (10. Mu.M) in combination with vincristine;
FIG. 8 shows the synergistic and sensitization of ovarian cancer cells (SKOV-3) by compounds 1, 10, 12, 18 and 19 (10. Mu.M) in combination with doxorubicin;
FIG. 9 shows the synergistic and sensitization of hepatoma cells (HepG 2) by the combination of compounds 10 and 16 (10. Mu.M) with paclitaxel;
FIG. 10 shows the synergistic and sensitizing effects of compounds 10 and 16 (10. Mu.M) in combination with doxorubicin on hepatoma cells (HepG 2);
FIG. 11 is a graph showing that compounds 3 and 15 (10. Mu.M) in combination with paclitaxel promote apoptosis of paclitaxel-resistant cells cervical cancer paclitaxel-resistant cells (HeLa/PTX);
FIG. 12 shows the synergistic and sensitization of cervical cancer cells (HeLa) and ovarian cancer cells (SKOV 3) with the combination of compound 22 (10. Mu.M) and doxorubicin or vincristine.
Detailed Description
For a better understanding of the present invention, the following examples are further illustrative of the present invention, but the contents of the present invention are not limited to the following examples only.
In the specific implementation of the invention, the preparation method of the amide compound with the effect of increasing the chemotherapeutic drug in the pepper plant comprises the following steps:
example 1:
extracting root of Piper longum with 95% ethanol, concentrating under reduced pressure to collect extract, and primarily separating into 4 components with macroporous resin. And repeatedly separating the component 1 by gel and normal-reverse phase silica gel column chromatography to obtain compounds 1 and 9. And repeatedly separating the component 2 by forward silica gel and gel column chromatography to obtain compounds 10 and 11. And repeatedly separating the component 3 by gel chromatography and normal-reverse phase silica gel column chromatography, and separating by high performance liquid chromatography to obtain the compound 12. Component 4 was subjected to gel chromatographyThe compounds 13 and 22 were isolated by column chromatography on silica gel. Compounds 1 and 9-12 are novel compounds, which 13 The C NMR data are shown in Table 1.
Example 2:
extracting pepper stem with 95% ethanol for 4 times, concentrating under reduced pressure to collect extract, and primarily separating with small-pore resin to obtain 4 components; the component 1 is repeatedly separated by normal phase silica gel, gel and reverse phase silica gel column chromatography to obtain the compounds 2 and 3. Separating component 2 by gel chromatography, normal phase silica gel column chromatography and high performance liquid chromatography to obtain compounds 4, 5 and 6. Separating the component 3 by gel chromatography, separating by normal and reverse phase silica gel column chromatography to obtain a compound 7, and separating by high performance liquid chromatography to obtain a compound 8. And separating the component 4 by macroporous resin, normal-reverse phase silica gel and gel chromatography to obtain compounds 14 and 15. Compounds 2-8 are novel compounds, which 1 The H NMR data are shown in Table 2.
Example 3:
extracting fructus Piperis with 95% ethanol, concentrating under reduced pressure to obtain extract, and separating with macroporous resin to obtain 3 components. Component 1 was first separated by gel chromatography and then repeatedly separated using a reverse phase silica gel column chromatography to give compounds 16 and 17. Component 2 was repeatedly separated by reverse phase silica gel and gel column chromatography to give compounds 18 and 19. The component 3 is repeatedly separated by gel chromatography and normal-reverse phase silica gel column chromatography, and then separated by high performance liquid chromatography to obtain compounds 20 and 21.
Table 1. 13 C NMR(100MHz)Spectroscopic Data for Compounds 1and 9-12in CDCl 3.
Table 2. 1 H(400MHz)NMR[δ,mult(J in Hz)]Data for Compound 2-8
a Recorded in CDCl 3 , b Recorded in pyridine-d 5 .
Example 4: the amide compound and the taxol are combined to have synergistic and sensitization effects on cervical cancer taxol resistant cells (HeLa/PTX)
Cervical cancer paclitaxel resistant cells (HeLa/PTX) were cultured in DMEM high-sugar medium. After 72 hours of treatment of HeLa/PTX cells with a dimeric amide compound in combination with paclitaxel, 100. Mu.L of fresh medium was changed, 20. Mu.L of MTT (5 mg/mL) solution was added to each well and incubated for 4 hours, the supernatant was removed, 100. Mu.L of DMSO was added to each well, and OD was measured at 570nm using an microplate reader. The effect of the combination of compounds 1-21 with paclitaxel is shown in figures 1 and 2.
FIG. 1 shows the synergistic and sensitization of cervical cancer taxol-resistant cells (HeLa/PTX) with the combination of novel compounds 1-12 (10. Mu.M) and taxol.
FIG. 2 shows the synergistic and sensitization of cervical cancer taxol-resistant cells (HeLa/PTX) by the combination of known compounds 13-21 (10. Mu.M) with taxol.
As can be seen from the figures: the effect of the amide compound or taxol on the activity of cells is small, and the compound 1-21 can obviously inhibit the survival rate of cells when being combined with taxol. Cell viability = drug treated OD/control OD x 100%.
Example 5: synergistic and sensitization of cervical cancer cells (HeLa) by amide compounds and several chemotherapeutics in the invention
Cervical cancer cells (HeLa) were cultured in DMEM high sugar medium. After treatment of HeLa cells with a combination of dimeric amide compound with taxol, vincristine or doxorubicin for 72 hours, 20. Mu.L of MTT (5 mg/mL) solution was added per well, incubated for 4 hours, the supernatant was removed, 100. Mu.L of DMSO was added per well, and OD was measured at 570nm using an ELISA reader. Cell viability = drug treated OD/control OD x 100%.
FIG. 3 shows the synergistic and sensitization of cervical cancer cells (HeLa) by the combination of compounds 1, 5, 7, 15, 17 and 21 (10. Mu.M) with paclitaxel.
FIG. 4 shows the synergistic and sensitization of cervical cancer cells (HeLa) by the combination of Compounds 1, 9, 10, 16, 18 and 19 (10. Mu.M) with vincristine.
FIG. 5 shows the synergistic and sensitization of cervical cancer cells (HeLa) by the combination of compounds 2, 4, 6, 10, 13 and 18 (10. Mu.M) with doxorubicin.
As can be seen from the figures: the amide compound has no obvious inhibiting effect on the activity of cervical cancer cells, but can obviously increase the inhibiting effect of three chemotherapeutics including taxol, vincristine and doxorubicin on the activity of cervical cancer cells.
Example 6: synergistic and sensitization of ovarian cancer cells (SKOV 3) by amide compounds and chemotherapeutic drugs in the invention
Ovarian cancer cells SKOV-3 were cultured in DMEM/F12 medium. After treatment of ovarian cancer cells SKOV-3 for 72 hours with a combination of dimeric amide compound and paclitaxel, vincristine or doxorubicin, 20. Mu.L of MTT (5 mg/mL) solution was added to each well and incubated for 4 hours, the supernatant was removed, 100. Mu.L of DMSO was added to each well, and the OD value was measured at 570nm using an ELISA reader. Cell viability = drug treated OD/control OD x 100%.
FIG. 6 shows the synergistic and sensitization of ovarian cancer cells (SKOV-3) by compounds 2, 5, 8, 14 and 17 (10. Mu.M) in combination with paclitaxel.
FIG. 7 shows the synergistic and sensitization of ovarian cancer cells (SKOV-3) by compounds 3, 6, 11, 16 and 20 (10. Mu.M) in combination with vincristine.
FIG. 8 shows the synergistic and sensitization of ovarian cancer cells (SKOV-3) by the combination of Compounds 1, 10, 12, 18 and 19 (10. Mu.M) with doxorubicin.
As can be seen from the figures: the amide compound has no obvious inhibiting effect on ovarian cancer cells, but can obviously increase the inhibiting effect of three chemotherapeutics including taxol, vincristine and doxorubicin on ovarian cancer cells.
Example 7: synergistic and sensitization effects of amide compounds and chemotherapeutics on liver cancer cells (HepG 2) in the invention
Liver cancer cells (HepG 2) were cultured in RPMI 1640 medium. After treating liver cancer cells HepG2 for 72 hours by adopting the combined action of a dimeric amide compound and taxol or doxorubicin, adding 20 mu L of MTT (5-mg/mL) solution into each hole for incubation for 4 hours, removing the supernatant, adding 100 mu L of DMSO into each hole, and measuring the OD value at 570nm by using an enzyme-labeled instrument. Cell viability = drug treated OD/control OD x 100%.
FIG. 9 shows the synergistic and sensitization of hepatoma cells (HepG 2) by the combination of compounds 10 and 16 (10. Mu.M) with paclitaxel.
FIG. 10 shows the synergistic and sensitization of hepatoma cells (HepG 2) by the combination of Compounds 10 and 16 (10. Mu.M) with doxorubicin.
As can be seen from the figures: the amide compound has no obvious inhibiting effect on the activity of liver cancer cells, but can obviously increase the inhibiting effect of two chemotherapeutics taxol and doxorubicin on the activity of liver cancer cells.
Example 8: in the invention, the amide compound and the taxol are combined to promote the apoptosis of cervical cancer taxol resistant cells (HeLa/PTX)
After 24 hours of combined action of amide compound and taxol on Hela/PTX cells, PBS was washed twice, hoechst 33258 (5. Mu.g/mL) was stained for 30 minutes, and after PBS was washed twice, the cell morphology was observed under a fluorescence microscope and photographed. The results in FIG. 11 show that the cell morphology of the compound 3, 15 (10. Mu.M) and paclitaxel (20, 40 nM) alone treatment group was not significantly different from the control group. In contrast, cells after the combined action of compounds 3, 15 with paclitaxel (20, 40 nM) were significantly disintegrated and apoptotic bodies were present.
FIG. 11 is a graph showing that compounds 3 and 15 (10. Mu.M) in combination with paclitaxel promote apoptosis of paclitaxel-resistant cells cervical cancer paclitaxel-resistant cells (HeLa/PTX).
As can be seen from the figures: when amide compounds or taxol are independently acted on cervical cancer drug-resistant cells, the cell nucleus is not changed obviously. When the compound is combined with paclitaxel, the nucleus begins to shrink, apoptotic bodies appear, and cells undergo apoptosis.
Example 9: synergistic and sensitization effects of the amide compound 22 on cervical cancer cells (HeLa) and ovarian cancer cells (SKOV 3) by combining with doxorubicin and vincristine.
After treatment of HeLa cells with compound 22 in combination with vincristine or doxorubicin for 72 hours, 20. Mu.L of MTT (5 mg/mL) solution was added per well, incubated for 4 hours, the supernatant was removed, 100. Mu.L of DMSO was added per well, and OD was measured at 570nm using an ELISA reader. Cell viability = drug treated OD/control OD x 100%.
FIG. 12 shows the synergistic and sensitization of cervical cancer cells (HeLa) and ovarian cancer cells (SKOV 3) with the combination of compound 22 (10. Mu.M) and doxorubicin or vincristine. From the figure, it can be seen that the compound 22 can obviously increase the inhibition effect of two chemotherapeutics vincristine and doxorubicin on the activity of cervical cancer cells and ovarian cancer cells.
While the invention has been described with respect to the preferred embodiments, it will be understood that the invention is not limited thereto, but is capable of modification and variation without departing from the spirit of the invention, as will be apparent to those skilled in the art.

Claims (5)

1. An application of an amide compound is characterized in that: preparing an anti-tumor chemotherapeutic sensitizer by adopting an amide compound, wherein the amide compound is any one of the following compounds 1-22:
compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
Compound 18
Compound 19
Compound 20
Compound 21
Compound 22;
the chemotherapeutic medicine is any one of vincristine, doxorubicin and paclitaxel; the tumor is at least one selected from cervical cancer, ovarian cancer and liver cancer.
2. An antitumor pharmaceutical composition, characterized in that: comprises a chemotherapeutic drug and a sensitizer, wherein the chemotherapeutic drug is any one of vincristine, doxorubicin and taxol, and the sensitizer is any one of the amide compounds 1-22 in claim 1.
3. The antitumor pharmaceutical composition according to claim 2, characterized in that: the dosage form of the medicine is at least one of oral liquid, tablet, injection, capsule, granule and powder.
4. The antitumor pharmaceutical composition according to claim 2, characterized in that: the administration mode of the pharmaceutical composition is oral administration or injection administration.
5. An amide compound, characterized in that: the amide compound is separated from Piper longum and Piper nigrum, and has a structural formula as any one of the compounds 1-12 in claim 1.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107827864A (en) * 2017-11-30 2018-03-23 宁夏医科大学 Pepper Bi roots of grass compositions dichloromethane extracts regiochemistry method of separating component and purposes
CN109875998A (en) * 2019-01-24 2019-06-14 武汉大学 Amide alkaloid is preparing application and antineoplastic pharmaceutical compositions in tumor chemotherapeutic drug sensitizer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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