CN109320534B - Oxidized bicuculline rare earth complex and synthesis method and application thereof - Google Patents

Oxidized bicuculline rare earth complex and synthesis method and application thereof Download PDF

Info

Publication number
CN109320534B
CN109320534B CN201811453270.2A CN201811453270A CN109320534B CN 109320534 B CN109320534 B CN 109320534B CN 201811453270 A CN201811453270 A CN 201811453270A CN 109320534 B CN109320534 B CN 109320534B
Authority
CN
China
Prior art keywords
rare earth
oxidized
compound
bicuculline
chloroform
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201811453270.2A
Other languages
Chinese (zh)
Other versions
CN109320534A (en
Inventor
顾运琼
梁宏
陈振锋
刘延成
黄克斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guilin Rongtong Technology Co ltd
Original Assignee
Guangxi Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangxi Normal University filed Critical Guangxi Normal University
Priority to CN201811453270.2A priority Critical patent/CN109320534B/en
Publication of CN109320534A publication Critical patent/CN109320534A/en
Application granted granted Critical
Publication of CN109320534B publication Critical patent/CN109320534B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an oxidized bicuculline rare earth complex and a synthetic method and application thereof. The rare earth complex is obtained by dissolving oxidized bicuculline and rare earth metal salt in a solvent system and then carrying out coordination reaction under the heating condition; wherein the rare earth metal salt is LaCl3·6H2O、CeCl3·6H2O、SmCl3·6H2O or NdCl3·6H2O; the solvent system is a combination of chloroform and one selected from methanol or ethanol, wherein the volume ratio of the chloroform to the methanol or the ethanol is 2: 1-3.5: 1. in vitro tests show that the oxidized dicentrine-lanthanum rare earth complex shows better in vitro anti-tumor activity than cisplatin on SKOV3/DDP tumor cell strains, and has potential medicinal value.

Description

Oxidized bicuculline rare earth complex and synthesis method and application thereof
Technical Field
The invention relates to the field of metal coordination compounds, in particular to an oxidized bicuculline rare earth complex as well as a synthesis method and application thereof.
Background
The leontopodine is mainly derived from Paeoniaceae plant Paeonia veitchii (Dicentra spectabilis), and can be used for preventing Leptospermum stringoides (Stephania Dicentrifera) of Lagenaceae, named as "Tongkongning" or "Carnitine". Researchers separate the bioactive aporphine, isoquinoline and bisisoquinoline alkaloids from O.leucoxylon by a separation method, and the compounds contain the Paeonine which has the biological activities of anti-tumor, analgesia, sedation and antibiosis. S-lotus budThe paeoniflorin can be separated from black-shell nana (Lindera megaphylla (Lauraceae)), and the antineoplastic research on the paeoniflorin shows that the paeoniflorin has more obvious antineoplastic activity on human hepatoma HuH-7. In the research on the in vitro activity of twenty-one human tumor cells from seven different tissues, the S-dicentrine shows different degrees of antitumor activity and IC (integrated Circuit) on all the tumor cells50The values ranged from 0.4. mu.M for esophageal cancer cell HCE-6 to 29. mu.M for hepatoma HA22T, and experiments demonstrated that S-Dicentrine HAs some inhibitory activity against various cancer cells (Huang R L, Chen C, Huang Y L, Ou J C, Hu C P, Chen C F, Chang C.anti-Tumor Effects of d-directed protein from the Root of Lindera megaphyl. planta Med,1998,64(3), 212-215.). Such as adrenergic receptor action activity, ion channel action activity, cytotoxicity, antioxidant activity, anti-platelet aggregation activity, anti-trypanosome activity, and the like.
The oxidized dicentrinone (namely, the oxidized dicentrine, which is called DCO for short) has the activity of killing leishmania (proto) and trypanosomes, and the DCO has better inhibitory activity on Trypanococcal, Antisemihmanial and rad 52 to repair deletion type RS322 yeast strains. Meanwhile, oxypeucastamine is an inhibitor of topoisomerase I, II and is also less toxic to cells (Zhou B, Johnson R K, Matern M R, Wang X, Hecht S M.isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxyethylene. J.Nat.Prod.2000,63,217-221. Stevigny C, Baily C, Quetin-Leclerq.Cytoxic and Antituer Potentialities of Aporphinic Alkaloids. Current. Med.Chem.Chem-Ti-Cancer Agents,2005,5(2),173- -182 (10)). However, no reports related to the rare earth complex using DCO as a ligand and a synthetic method thereof are found at present.
Disclosure of Invention
The invention aims to solve the technical problem of providing oxidized bicuculline rare earth complexes with novel structures, and a synthetic method and application thereof.
The oxidized dicentrine rare earth complex is a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0001887176840000021
wherein Ln is La, Ce, Sm or Nd.
The synthesis method of the oxidized bicuculline rare earth complex comprises the following steps: dissolving a compound shown as a formula (II) and rare earth metal salt in a solvent system, and carrying out coordination reaction under a heating condition to obtain a corresponding target compound; wherein the content of the first and second substances,
the rare earth metal salt is LaCl3·6H2O、CeCl3·6H2O、SmCl3·6H2O or NdCl3·6H2O；
The solvent system is a combination of chloroform and one selected from methanol or ethanol, wherein the volume ratio of the chloroform to the methanol or the ethanol is 2: 1-3.5: 1;
Figure BDA0001887176840000022
the more specific synthesis method of the oxidized Paeonia nucifera alkali rare earth complex comprises the following steps: taking the compound shown in the formula (II) and rare earth metal salt, adding a solvent system for dissolving, placing the obtained mixed solution into a container, freezing, vacuumizing, sealing by melting, and then reacting at 80-120 ℃ to obtain the corresponding target compound.
In the above synthesis method, the molar ratio of the compound represented by the formula (ii) to the rare earth metal salt is a stoichiometric ratio, and in practice, the molar ratio of the compound represented by the formula (ii) to the rare earth metal salt is usually selected to be 1: 1.2-1: 2.0.
in the above-mentioned synthesis method, the amount of the solvent system to be used may be determined as required, and usually, the raw material to be reacted is dissolved in 10 to 25mL of the solvent system based on 1mmol of the compound represented by the formula (II). In the composition of the solvent system, the volume ratio of chloroform to methanol or ethanol is preferably 3: 1.
in the above synthesis method, the container is usually a thick-walled glass tube; when the reaction is carried out at the temperature of 80-120 ℃, the reaction time is usually controlled to be 48-72h, and the yield can reach more than 65%; and can be controlled to be more than 72h according to requirements. The reaction is more preferably carried out at 100-120 ℃.
The compound shown in the formula (II) involved in the synthesis method is oxidized bicuculline, can be separated from related plants, and can also be synthesized by designing a synthesis route.
The invention also comprises the application of the compound or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Compared with the prior art, the invention takes the oxidized peoniflorine as an active ligand, and the oxidized peoniflorine is coordinated and reacted with a plurality of rare earth ions to synthesize a series of oxidized peoniflorine rare earth complexes, and by observing the growth inhibition effect of the oxidized peoniflorine rare earth complexes on a plurality of tumor cell strains, the oxidized peoniflorine-lanthanum rare earth complexes are found to show better in-vitro anti-tumor activity than cisplatin on SKOV3/DDP tumor cell strains, and have potential medicinal value.
Drawings
FIG. 1 is a crystal structure diagram (with H atoms removed) of the final product obtained in example 1 of the present invention;
FIG. 2 is a crystal structure diagram (with H atoms removed) of the final product obtained in example 2 of the present invention;
FIG. 3 is a crystal structure diagram (with H atoms removed) of the final product obtained in example 3 of the present invention;
FIG. 4 is a crystal structure diagram (with H atoms removed) of the final product obtained in example 4 of the present invention;
FIG. 5 is a crystal structure diagram (with H atoms removed) of the final product obtained in example 5 of the present invention.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
Example 1: synthesis of oxidized bicuculline
Synthesizing the oxidized bicuculline according to the following route:
Figure BDA0001887176840000041
1) synthesis of Compound (2):
72g of 3, 4-dimethoxyphenylacetic acid was dissolved in 600mL of glacial acetic acid, and after stirring at room temperature for 1 hour, 7.2g of a solution of bromine in glacial acetic acid (60mL) was added, and after further reaction for 2 hours, 200mL of ice water was added, a white precipitate was formed, and the filtrate was filtered, and after the filter cake was recrystallized from methanol, 96g of compound (2) was obtained with a yield of about 95%.
Compound (2) is a white solid, ESI-MS m/z 273.02[ (2) -H]-，13C-NMR(500MHz,DMSO)δ：41.0816(C-2)，56.2538(C-5)，56.4330(C-6)，114.9042(C-9)，115.7982(C-3)，115.9616(C-8)，127.4302(C-10)，148.5825(C-4)，148.9687(C-8)，172.0429(C-1)，1H-NMR(500MHz,DMSO)δ：3.6021(2H,S,H-2),3.7120(3H,S,H-5),3.7346(3H,S,H-6),6.9880(1H,S,H-3),7.0886(1H,S,H-8)。
2) Synthesis of Compound (3):
100g of the compound (2) was dissolved in 100mL of thionyl chloride, and the mixture was refluxed at 76 ℃ for 1.5 hours, the unreacted thionyl chloride was distilled off under reduced pressure to obtain a pale yellow liquid, 75g of piperonylethylamine was dissolved in 400mL of dichloromethane and slowly added to the pale yellow liquid, and the mixture was stirred at normal temperature for 4 hours, and dichloromethane was distilled off under reduced pressure and recrystallized from methanol to obtain about 100g of a white solid with a yield of about 80%.
Compound (3) is a white solid, ESI-MS m/z 421.96[ (3) + H]+；1H-NMR(500MHz,CDCl3)δ：2.485(2H,S,H-8)，3.269(2H,S,H-12)，3.408(2H,S,H-9)，2.485(2H,S,H-8)，3.697(6H,S,H-19,20)，6.332(1H,S,H-15)，6.374(1H,S,H-4)，6.490(1H,S,H-7)，6.611(1H,S,H-5)，6.831(H,S,H-7)。13C-NMR(500MHz,CDCl3)δ：34.828(C-12)，40.487(C-8)，43.350(C-9)，55.884(C-19，C-20)，100.5927(C-1)，107.965(C-4)，108.704(C-5)，113.524(C-14)，114.470(C-15)，115.434(C-16)，121.286(C-7)，126.336(C-13)，132.033(C-6)，145.849(C-3)，147.468(C-17)，148.525(C-2)，148.745(C-18)，169.440(C-11)。
3) Synthesis of Compound (4):
100g of compound (3) was dissolved in 1250mL of chloroform, and 180mL of phosphorus oxychloride (POCl) was added3) The reaction was refluxed for 3 hours, and after completion of the reaction, the solvent was distilled off under reduced pressure, washed with a saturated sodium bicarbonate solution, and dried to obtain an unpurified compound (4) in about 80% yield.
4) Synthesis of Compound (5):
70g of compound (4) was dissolved in 300mL of methanol, an excess of sodium borohydride (80g) was added, the reaction was stirred at room temperature for 12 hours, a 1mol/L diluted hydrochloric acid solution was slowly added to react the excess of sodium borohydride, the resultant was extracted with ethyl acetate, the organic phase was washed with a saturated sodium bicarbonate solution, and recrystallization was carried out with methanol to obtain about 78g of compound (5) with a yield of about 82%.
5) Synthesis of Compound (6):
after 50g of compound (5) was dissolved in 375mL of chloroform, 150mL of a 2mol/L aqueous sodium hydroxide solution was added thereto and stirred for 0.5h (at this time, the pH of the system was 9), an equal amount of BOC anhydride was slowly added thereto, stirring was continued for 4h, extraction was performed with chloroform, the organic phase was washed with a saturated sodium bicarbonate solution, and distillation was performed under reduced pressure to obtain 57g of compound (6) with a yield of about 96%.
6) Synthesis of Compound (7):
0.32g of tricyclohexylphosphorus, 3.15g of potassium carbonate and 0.125g of palladium acetate are dissolved in 80mL of dry DMF (the pH of the system is 9), then 5g of compound (6) are added, the mixture is refluxed at 135 ℃ for 24h under the protection of an inert gas (helium), then cooled, neutralized with 1mol/L of hydrochloric acid, extracted with chloroform, washed with a saturated sodium bicarbonate solution, dried and recrystallized with ethanol to obtain 4.3g of compound (7) with a yield of about 92%.
7) Synthesis of Compound (8):
5g of compound (7) was dissolved in 130mL of dry tetrahydrofuran, 4.4g of lithium aluminum hydride was slowly added to an ice bath, the mixture was refluxed at 50 ℃ for 24 hours under protection of an inert gas (helium), the pH of the system was adjusted to 8 with dilute aqueous ammonia, suction filtration was performed while hot, the filtrate was collected, the solvent was distilled off under reduced pressure, the obtained residue was recrystallized from ethanol, a solid was precipitated, and suction filtration was performed to obtain about 3.5g of compound (8) with a yield of about 90%.
8) Synthesis of oxidized bicuculline, compound (9):
dissolving 2g of the compound (8) in 50mL of glacial acetic acid, adding 6.5g of manganese (III) acetate, refluxing for 5h at 70 ℃, filtering a reactant, and performing rotary evaporation on a filtrate to remove a solvent to obtain a residue, namely a crude product of the oxycodone peoniflorine. The crude product was dissolved in chloroform, washed three times with saturated sodium bicarbonate solution, and then subjected to silica gel column chromatography (to remove residual catalyst) with a mixture of chloroform and methanol at a ratio of 30-32: 1, and evaporating the solvent from the eluent to obtain 1g of a high-purity yellow powder product with the yield of about 50%.
The product obtained in this example was taken up in chloroform and methanol as 3: 1, slowly volatilizing at room temperature, finding bright yellow rod-shaped crystals on the 15 th day, and selecting proper single crystals for structural characterization:
1) infrared characterization:
the product obtained in this example was analyzed by infrared analysis using a Spectrum Two FT-IR Spectrometer Fourier transform infrared Spectrometer (KBr pellet) from Perkin-Klmer, and the following infrared spectra were obtained:
IR(KBr cm-1)(Ar-H)3377(m),(-CH2-,v)2923,2851(m),(C＝O)1638(vs),(C＝C)1598,1572,1515,1424(s),(-CH2-,d)1459,(C-O)1279,1248,(C-N)1057,(-CH2-)776cm-1。
2) x-ray diffraction analysis:
placing the single crystal with proper size on a Bruker Smart Aapex2CCD surface-detecting single crystal diffractometer, and monochromating the Mo-Kalpha rays by a graphite monochromator
Figure BDA0001887176840000062
Collecting crystal data in psi/theta scanning mode at temperature of 296(2) K and theta of 1.90-25.10 deg.C by using Crystalclar program, determining unit cell parameters after least square correction, and resolving by direct method and difference Fourier synthesis methodCrystal structure, and using full matrix least square method to make correction, correcting anisotropic temperature factor of all non-hydrogen atoms, and making hydrogenation by means of theoretical calculation. All calculations were done on a PC using the SHELXTL-97 package, correcting the structure using a semi-empirical method.
The structure of the obtained crystal is shown in fig. 1, and the crystal structure parameters, part of the bond length and bond angle data are shown in the following tables 1 and 2, respectively.
Table 1: crystallographic data of oxidized bicuculline
Figure BDA0001887176840000061
Figure BDA0001887176840000071
Table 2: partial bond length angle of oxidized dicentrine
Figure BDA0001887176840000072
Therefore, it was confirmed that the product obtained in this example was oxidized bicuculline.
Example 2: [ La (DCO)2Cl3(H2O) Synthesis of Complex 1
The DCO (0.05mmol,0.017g) prepared as described in example 1 was taken with LaCl3·6H2O (0.1mmol,0.374g) was added to a 25cm Pyrex thick-walled glass tube closed at one end, and 1.5mL of CH was added dropwise3OH and 0.5mL CHCl3Freezing with liquid nitrogen, sealing the open end under vacuum condition, mixing, placing in oven at 110 deg.C for 72h, cooling, and observing the formation of dark red square crystal (Yield: 65%).
The product obtained above was characterized:
1) infrared characterization:
the product obtained in this example was analyzed by infrared analysis using a Spectrum Two FT-IR Spectrometer Fourier transform infrared Spectrometer (KBr pellet) from Perkin-Klmer, and the following infrared spectra were obtained:
IR(KBr cm-1)(N-H)3377(m),(-CH2-,v)2918(m),(C＝O)1564(vs),(C＝C)15121484 1429(s),(-CH2-,d)1462,(C-O)1284 1256,(C-N)1056,(-CH2-)776cm-1。
2) and (3) analyzing a crystal structure:
placing crystals with proper size on Bruker Smart Aapex2CCD surface-detecting single crystal diffractometer, and monochromating Mo-Kalpha rays with graphite monochromator
Figure BDA0001887176840000073
Collecting crystal data in a psi/theta scanning mode at a temperature of 296(2) K and within a range of theta being more than or equal to 1.90 degrees and less than or equal to 25.10 degrees by applying a Crystalclar program, determining unit cell parameters after least square method correction, solving a crystal structure by a direct method and a difference Fourier synthesis method, correcting anisotropic temperature factors of all non-hydrogen atoms by a full matrix least square method, and theoretically calculating hydrogenation. All calculations were done on a PC using the SHELXTL-97 package, correcting the structure using a semi-empirical method.
The structure of the obtained crystal is shown in fig. 2, and the crystal structure parameters, part of the bond length and bond angle data are shown in the following tables 3 and 4, respectively.
Table 3: crystallographic data for Complex 1
Figure BDA0001887176840000081
Table 4: partial bond length and bond angle of Complex 1
Figure BDA0001887176840000082
Therefore, it was confirmed that the product obtained in this example was the objective product [ La (DCO) ]2Cl3(H2O)。
Comparative example 2-1
Example 2 was repeated except that the reaction was carried out at room temperature for 5 days without any product formed in the test tube; after further observation for 5 days, no product was formed.
Comparative examples 2 to 2
Example 2 was repeated, except that the solvent system consisted of 1.0mL CH3OH and 1.0mL CHCl3(i.e. CH)3OH and CHCl3Is 1: 1) and others are unchanged.
After cooling, no crystal was formed in the tube.
Comparative examples 2 to 2
Example 2 was repeated, except that the solvent system consisted of 2.0mL CH3OH and 0.5mL CHCl3(i.e. CH)3OH and CHCl3Is 4: 1) and others are unchanged.
After cooling, no crystal was formed in the tube.
Example 3: [ Ce (DCO)2Cl3(H2O)]Synthesis of (Complex 2)
DCO (0.05mmol,0.017g) was weighed out together with CeCl3·6H2O (0.1mmol,0.373g) was added to a 25cm Pyrex thick walled glass tube closed at one end and 1.5mL CH was added dropwise3OH and 0.5mLCHCl3Freezing with liquid nitrogen, sealing the open end under vacuum condition, mixing, placing in oven at 110 deg.C for 72h, cooling, and observing the formation of dark red square crystal (Yield: 70%).
The product obtained above was characterized:
1) infrared characterization:
the product obtained in this example was analyzed by infrared analysis using a Spectrum Two FT-IR Spectrometer Fourier transform infrared Spectrometer (KBr pellet) from Perkin-Klmer, and the following infrared spectra were obtained:
IR(KBr cm-1)(N-H)3378(m),(-CH2-,v)2917(m),(C＝O)1562(vs),(C＝C)1511,1459,1429(s),(-CH2-,d)1489,(C-O)1282,1253,(C-N)1059,(-CH2-)774cm-1。
2) and (3) analyzing a crystal structure:
placing crystals with proper size on Bruker Smart Aapex2CCD surface-detecting single crystal diffractometer, and monochromating Mo-Kalpha rays with graphite monochromator
Figure BDA0001887176840000091
Collecting crystal data in a psi/theta scanning mode at a temperature of 296(2) K and within a range of theta being more than or equal to 1.90 degrees and less than or equal to 25.10 degrees by applying a Crystalclar program, determining unit cell parameters after least square method correction, solving a crystal structure by a direct method and a difference Fourier synthesis method, correcting anisotropic temperature factors of all non-hydrogen atoms by a full matrix least square method, and theoretically calculating hydrogenation. All calculations were done on a PC using the SHELXTL-97 package, correcting the structure using a semi-empirical method.
The structure of the obtained crystal is shown in FIG. 3, and the crystal structure parameters, part of the bond length and bond angle data are shown in the following tables 5 and 6, respectively.
Table 5: crystallographic data of Complex 2
Figure BDA0001887176840000101
Table 6: partial bond length and bond angle of Complex 2
Figure BDA0001887176840000102
Therefore, it was confirmed that the product obtained in this example was the objective product [ Ce (DCO) ]2Cl3(H2O)]。
Example 4: [ Sm (DCO)2Cl3(H2O)]Synthesis of (Complex 3)
DCO (0.05mmol,0.017g) and SmCl were weighed3·6H2O (0.1mmol,0.365g) was added to a 25cm Pyrex thick walled glass tube closed at one end and 1.0mL CH was added dropwise3OH and 0.5mLCHCl3Freezing with liquid nitrogen, and sealing the open end under vacuum conditionAfter mixing uniformly, the mixture is placed in an oven to react for 72 hours at the temperature of 110 ℃, and cooling is carried out, and dark red square crystals (Yield: 65%) are observed to be generated in the tube.
The product obtained above was characterized:
1) infrared characterization:
the product obtained in this example was analyzed by infrared analysis using a Spectrum Two FT-IR Spectrometer Fourier transform infrared Spectrometer (KBr pellet) from Perkin-Klmer, and the following infrared spectra were obtained:
IR(KBr cm-1)(N-H)3350(m),(-CH2-,v)2923(m),(C＝O)1566(vs),(C＝C)1512,1462,1429(s),(-CH2-,d)1492,(C-O)1278,1251,(C-N)1059,(-CH2-)773cm-1。
2) and (3) analyzing a crystal structure:
placing crystals with proper size on Bruker Smart Aapex2CCD surface-detecting single crystal diffractometer, and monochromating Mo-Kalpha rays with graphite monochromator
Figure BDA0001887176840000112
Collecting crystal data in a psi/theta scanning mode at a temperature of 296(2) K and within a range of theta being more than or equal to 1.90 degrees and less than or equal to 25.10 degrees by applying a Crystalclar program, determining unit cell parameters after least square method correction, solving a crystal structure by a direct method and a difference Fourier synthesis method, correcting anisotropic temperature factors of all non-hydrogen atoms by a full matrix least square method, and theoretically calculating hydrogenation. All calculations were done on a PC using the SHELXTL-97 package, correcting the structure using a semi-empirical method.
The structure of the obtained crystal is shown in FIG. 4, and the crystal structure parameters, part of the bond length and bond angle data are shown in the following tables 7 and 8, respectively.
Table 7: crystallographic data of Complex 3
Figure BDA0001887176840000111
Figure BDA0001887176840000121
Table 8: partial bond length and bond angle of Complex 3
Figure BDA0001887176840000122
Therefore, the product obtained in this example was determined to be [ Sm (DCO)2Cl3(H2O)]。
Example 5: [ Nd (DCO)2Cl3(H2O)]Synthesis of (Complex 4)
DCO (0.05mmol,0.017g) was weighed into NdCl3·6H2O (0.1mmol,0.251g) was added to a 25cm Pyrex thick-walled glass tube closed at one end, and 1.75mL of CH was added dropwise3OH and 0.5mLCHCl3Freezing with liquid nitrogen, sealing the open end under vacuum condition, mixing, placing in oven at 110 deg.C for 72h, cooling, and observing the formation of dark red square crystal (Yield: 65%).
The product obtained above was characterized:
1) infrared characterization:
the product obtained in this example was analyzed by infrared analysis using a Spectrum Two FT-IR Spectrometer Fourier transform infrared Spectrometer (KBr pellet) from Perkin-Klmer, and the following infrared spectra were obtained:
IR(KBr cm-1)(N-H)3357(m),(-CH2-,v)2929(m),(C＝O)1558(vs),(C＝C)1511,1456,1360(s),(C-O)1278,1248,(C-N)1067cm-1。
2) and (3) analyzing a crystal structure:
placing crystals with proper size on Bruker Smart Aapex2CCD surface-detecting single crystal diffractometer, and monochromating Mo-Kalpha rays with graphite monochromator
Figure BDA0001887176840000133
Scanning with psi/theta at a temperature of 296(2) K and in the range of 1.90 DEG theta to 25.10 DEG using a Crystalclar programCrystal data are collected, unit cell parameters are determined after least square correction, crystal structures are solved through a direct method and a difference Fourier synthesis method, correction is carried out through a full matrix least square method, anisotropic temperature factors of all non-hydrogen atoms are corrected, and hydrogenation is carried out through theoretical calculation. All calculations were done on a PC using the SHELXTL-97 package, correcting the structure using a semi-empirical method.
The structure of the obtained crystal is shown in FIG. 5, and the crystal structure parameters, part of the bond length and bond angle data are shown in the following tables 9 and 10, respectively.
Table 9: crystallographic data for Complex 4
Figure BDA0001887176840000131
Table 10: partial bond length and bond angle of Complex 4
Figure BDA0001887176840000132
Figure BDA0001887176840000141
Therefore, it was confirmed that the product obtained in this example was [ Nd (DCO)2Cl3(H2O)]。
Example 6: [ Ce (DCO)2Cl3(H2O)]Synthesis of (Complex 2)
Example 3 was repeated, except that ethanol was used instead of methanol, the reaction time was 56h, and the rest was unchanged.
After cooling, a dark red square block of crystals was observed in the tube (Yield: 70%).
The obtained crystal is identified as a target product [ Ce (DCO) through structural characterization2Cl3(H2O)]。
Example 7: [ Sm (DCO)2Cl3(H2O)]Synthesis of (Complex 3)
Example 4 was repeated, except that the solvent system consisted of 1.5mL of methanol and 0.5mL of chloroform and the reaction was carried out at 120 ℃ for 48h, otherwise unchanged.
After cooling, a dark red square block of crystals was observed in the tube (Yield: 63%).
The obtained crystal is identified as a target product [ Sm (DCO) through structural characterization2Cl3(H2O)]。
Example 8: [ Nd (DCO)2Cl3(H2O)]Synthesis of (Complex 4)
Example 5 was repeated, except that the reaction was carried out at 80 ℃ and the rest was unchanged.
After cooling, a dark red square block of crystals was observed in the tube (Yield: 65%).
The obtained crystal is determined as a target product [ Nd (DCO) through structural characterization2Cl3(H2O)]。
Experimental example: experiments on proliferation inhibition activity of DCO prepared in inventive example 1 and on various human tumor cell lines by the respective rare earth complexes prepared in inventive examples 2 to 5
The MTT method was used to evaluate the effect of drugs on the growth and proliferation of living cells. In the preliminary screening test, a series of tumor cell lines in logarithmic growth phase were prepared into a single cell suspension using a culture medium containing 10% newborn bovine serum at 190. mu.L (about 1X 10) per well4One/hole) cells are inoculated on a 96-well plate, after the cells are cultured for 12h and adhered to the wall, 10 mu L of samples with different concentrations are respectively added into each hole, 4 multiple holes are arranged in parallel for each gradient, wherein DMSO is a cosolvent, the final concentration does not exceed 1%, meanwhile, corresponding negative control groups (only cells and the same amount of DMSO in a culture solution, and no medicine) and blank control groups (only the same amount of medicine and no cells in the culture solution) are arranged, 4 multiple holes are also arranged in parallel for each gradient, and the action time of the medicine is 48 hours. After 4 hours of incubation, 10. mu.L of MTT (5mg/mL PBS) was added to each well 4 hours before the incubation was completed, the supernatant was aspirated off, 100. mu.L of DMSO was added to each well, and the mixture was shaken with a plate shaker for 10min to dissolve the crystals sufficiently, and the blank control was zeroed. Measuring with enzyme-linked immunosorbent assay at 570nm/630nm dual wavelength to remove background lightThe cell growth inhibition rate was calculated from the absorbance (A) value after the absorbance. Inhibition rate ═ 1-sample a value/control a value × 100%. Respectively calculating the IC of each tested compound to several tumor cell strains by a Bliss method for the tested compounds with better anti-tumor effect after primary screening50The value is obtained. In the experiment, IC of each compound on various tumor cell strains is calculated by a Bliss method50Values, averaged after 3 replicates of all experiments. The results are shown in table 11 below.
Table 11: IC of each complex for different cell lines50Value (μ M)
Figure BDA0001887176840000151
Note: "-" indicates that the IC was not calculated50The value is obtained.

Claims (4)

1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure 167874DEST_PATH_IMAGE001
(I)；
wherein Ln is La or Sm.
2. A method of synthesizing the compound of claim 1, wherein: dissolving a compound shown as a formula (II) and rare earth metal salt in a solvent system, and carrying out coordination reaction under a heating condition to obtain a corresponding target compound; wherein the content of the first and second substances,
the rare earth metal salt is LaCl3·6H2O or SmCl3·6H2O；
The solvent system is a combination of chloroform and one selected from methanol or ethanol, wherein the volume ratio of the methanol or the ethanol to the chloroform is 2: 1-3.5: 1;
Figure DEST_PATH_IMAGE002
(Ⅱ)。
3. the method of synthesis according to claim 2, characterized in that: taking the compound shown in the formula (II) and rare earth metal salt, adding a solvent system for dissolving, placing the obtained mixed solution into a container, freezing, vacuumizing, sealing by melting, and then reacting at 80-120 ℃ to obtain the corresponding target compound.
4. The method of synthesis according to claim 2, characterized in that: in the composition of the solvent system, the volume ratio of the methanol or ethanol to the chloroform is 3: 1.
CN201811453270.2A 2018-11-30 2018-11-30 Oxidized bicuculline rare earth complex and synthesis method and application thereof Active CN109320534B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811453270.2A CN109320534B (en) 2018-11-30 2018-11-30 Oxidized bicuculline rare earth complex and synthesis method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811453270.2A CN109320534B (en) 2018-11-30 2018-11-30 Oxidized bicuculline rare earth complex and synthesis method and application thereof

Publications (2)

Publication Number Publication Date
CN109320534A CN109320534A (en) 2019-02-12
CN109320534B true CN109320534B (en) 2021-04-06

Family

ID=65255931

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811453270.2A Active CN109320534B (en) 2018-11-30 2018-11-30 Oxidized bicuculline rare earth complex and synthesis method and application thereof

Country Status (1)

Country Link
CN (1) CN109320534B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101020699A (en) * 2006-02-16 2007-08-22 广西师范大学 Metal complex with liriodenine as ligand and its synthesis process and use
CN108524512A (en) * 2018-04-20 2018-09-14 云南中医学院 Aporphine alkaloid, the anti-inflammatory effect of its trim and salt and its application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120183600A1 (en) * 2007-01-16 2012-07-19 Chien-Hung Chen Novel composition for treating metabolic syndrome and other conditions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101020699A (en) * 2006-02-16 2007-08-22 广西师范大学 Metal complex with liriodenine as ligand and its synthesis process and use
CN108524512A (en) * 2018-04-20 2018-09-14 云南中医学院 Aporphine alkaloid, the anti-inflammatory effect of its trim and salt and its application

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Divalent later transition metal complexes of the traditional chinese medicine (TCM) liriodenine: coordination chemistry, cytotoxicity and DNA binding studies";Liu Y C. et al;《Dalton Trans》;20091106;第10813-10815、10820页 *
"The antitumoral, trypanocidal and antileishmanial activities of extract and alkaloids isolated from Duguetia furfuracea";D.B. da Silva. Et al;《Phytomedicine》;20091231;第16卷;第1061页 *
"天然药物有效成分的金属配合物研究进展";谭明雄等;《林产化学与工业》;20081231;第28卷(第6期);第93-99页 *

Also Published As

Publication number Publication date
CN109320534A (en) 2019-02-12

Similar Documents

Publication Publication Date Title
CN110713500B (en) Palladium complex using 2-benzoylpyridine thiosemicarbazone and synthetic method thereof
CN114014872B (en) Artesunate derivative and preparation method and application thereof
CN112321667B (en) Ursolic acid piperazine dithioformic acid-pyridine ruthenium complex and preparation method and application thereof
CN109320534B (en) Oxidized bicuculline rare earth complex and synthesis method and application thereof
CN102260281B (en) Oxidized glaucine rare earth chelate compound as well as synthesis method and application thereof
CN115043826B (en) Sinomenine furazan derivatives, and preparation method and application thereof
CN109020997B (en) 3-benzimidazole-6, 7-piperonyl-2 (1H) -quinolinone-zinc complex and preparation method and application thereof
CN109651413B (en) Rare earth complex with bromo-oxidized bicuculline as ligand and synthetic method and application thereof
CN115057839B (en) Eucalyptus type sesquiterpene lactone compound and preparation and application thereof
US20180186794A1 (en) Imidazopyrroloquinoline salt, method for producing the same, medicament, cosmetic, and food
CN109456335B (en) Method for synthesizing oxidized bicuculline
CN108125962B (en) Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer
CN110128452B (en) Gold complex and synthesis method and application thereof
CN108329300B (en) Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof
CN113735781A (en) Copper complex and preparation method and application thereof
CN106478692A (en) Copper-nitrate complex and its synthetic method and application with 1 (2 pyridine) 9 benzyl β carboline as part
CN110950896B (en) Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof
CN105566398B (en) A kind of oxide of high activity aporphine alkali rhodium (III) complex and its synthetic method and application
CN108623638B (en) 12-chlorobenzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof
CN109021021B (en) 11, 12-dichlorobenzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof
CN109021020B (en) 11, 12-dimethyl benzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof
CN108752384B (en) Benzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof
CN108727435B (en) 12-fluorobenzoimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof
CN109503609A (en) Bromo aoxidizes bicuculline and its synthetic method and application
CN108727434B (en) 11-trifluoromethyl benzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20220527

Address after: 541002 No. 1-9-10, Jinma Building, No. 13, Zhongshan Middle Road, Xiangshan District, Guilin City, Guangxi Zhuang Autonomous Region

Patentee after: GUILIN RONGTONG TECHNOLOGY Co.,Ltd.

Address before: 541004 No. 15 Yucai Road, Qixing District, Guilin, the Guangxi Zhuang Autonomous Region

Patentee before: Guangxi Normal University