CN103641839A - Compounds with anti-tumor effect in zephyranthes candida and separation preparation method and application thereof - Google Patents

Compounds with anti-tumor effect in zephyranthes candida and separation preparation method and application thereof Download PDF

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CN103641839A
CN103641839A CN201310560305.3A CN201310560305A CN103641839A CN 103641839 A CN103641839 A CN 103641839A CN 201310560305 A CN201310560305 A CN 201310560305A CN 103641839 A CN103641839 A CN 103641839A
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candidine
compound
compounds
leukemia
chloroform
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CN103641839B (en
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张勇慧
姚广民
王富乾
张锦文
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Huazhong University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D491/12—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 three hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D491/12—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 three hetero rings
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Abstract

The invention discloses compounds with anti-tumor effect separated from zephyranthes candida, a separation preparation method and an application thereof, and particularly discloses the activity and structure of alkaloid compounds derived from plant zephyr-lily, including compounds of N-phenethyl crinidine, zephyranthine A, and zephyranthine B, the separation preparation method and related activities thereof. Study confirms that the compounds have inhibition activity on cell proliferation of leukemia HL-60, K562, lung cancer A-549, liver cancer HepG2, and colon cancer HT-29 tumor cells, and can be used as medicaments for treating tumor diseases such as leukemia, lung cancer, liver cancer, colon cancer and the like.

Description

In green onion lotus, there is compound and method for separating and preparing and the application of antitumor action
Technical field
The invention belongs to medical technical field, relate to antineoplastic compound compound, be specifically related to antineoplastic compound compound separation purge process, structural identification, the contents such as anti-tumour cell proliferative effect experiment.
Background technology
The early acute children's grain of people leukemia is to take promyelocyte hyperplasia as main acute leukemia, is a kind of specific type of acute myelocytic leukemia (AML), by FAB cooperative groups, is decided to be acute myelocytic leukemia M3 type.Acute promyelocytic leukemia is much clinically, and morbidity crowd be take between 30～38 years old young person as main.China sickness rate than western countries, exceed 10%, some areas (oil field, northeast) sickness rate in AML proportion up to 20%～30%.
The herb of green onion lotus (Zephyranthes candida) Shi Suan section Zephyranthes per nnial herb green onion lotus (Zephyranthes candida (Lindl.) Herb).In Japan, also claim " beautiful curtain ", originate in South America, the extensive introducing culture of south China, aboundresources.Among the peoplely with complete stool, be used as medicine, have function calming the liver to stop the wind, heat radiation removing toxic substances; For acute infantile convulsion wind, epilepsy; Red and swollen for carbuncle sore outward.The plant Zephyranthes parul belonging to together in Peru is used as treating tumour, and green onion lotus is widely used in treating diabetes in Africa as medicinal plant.
Summary of the invention
We are under the guidance of antitumor activity screening, green onion lotus antitumor activity component has been carried out to systematic study, separation has obtained compound 1-16, and wherein N-methylcrinasiadine, N-ethoxycarbonylethyl crinasiadine, N-ethoxycarbonylpropyl crinasiadine, N-phenethyl crinasiadine, N-isopentenyl crinasiadine, O-methylnerinine, 3-methyl-3,4-dihydroplicane, Candidine A and Candidine B are new compound.Structural formula is as shown in (I).By these 16 compounds, to 5 kinds of human body tumour cell antitumor activities, find that 3,5,6,7,8 pairs of leukemia HL-60s of compound, K562, lung cancer A-549, liver cancer HepG2 and the cell proliferation of colorectal carcinoma HT-29 tumour cell have the activity of inhibition.
The present invention relates to the separation preparation of related alkaloids compound in green onion lotus and it has the activity that suppresses leukemia HL-60, K562, lung cancer A-549, liver cancer HepG2 and the cell proliferation of colorectal carcinoma HT-29 tumour cell.Can be used as the medicine of the tumor diseases such as treatment leukemia, lung cancer, liver cancer, colorectal carcinoma.
Figure BDA0000412330480000021
Figure BDA0000412330480000031
Task of the present invention is to provide the compound having with structure shown in Formula Il,
Figure BDA0000412330480000041
Wherein
R 1can be following aromatic ring or heterocycle: pyrroline, 2-pyrroline, 1-pyrroline, 2-oxazoline, 3-oxazoline, 2-tetrahydroglyoxaline, pyrazoline, pyrroles, imidazoles, benzoglyoxaline, pyrazoles, indazole, pyridine, dihydro-pyrimidin, pyrimidine, phenyl ring;
R 2-R 10can be identical or different, can be respectively, simultaneously or alkoxyl group, carbonyl, carboxyl, aldehyde radical or the amino of the hydrogen of respectively doing for oneself, hydroxyl, the alkyl containing 1-8 carbon, halogen, nitro, a 1-8 carbon;
N is the number of methylene radical, can be 0-7.
Another task of the present invention is to provide the compound with structure shown in following formula III,
Figure BDA0000412330480000042
Wherein
R 1can be following aromatic ring or heterocycle: pyrroline, 2-pyrroline, 1-pyrroline, 2-oxazoline, 3-oxazoline, 2-tetrahydroglyoxaline, pyrazoline, pyrroles, imidazoles, benzoglyoxaline, pyrazoles, indazole, pyridine, dihydro-pyrimidin, pyrimidine, phenyl ring;
R 1-R 10can be identical or different, can be respectively, simultaneously or alkoxyl group, carbonyl, carboxyl, aldehyde radical or the amino of the hydrogen of respectively doing for oneself, hydroxyl, the alkyl containing 1-8 carbon, halogen, nitro, a 1-8 carbon;
X can be the acid ion of any halogen or organic acid acid ion or mineral acid, and described organic acid acid ion or the acid ion of mineral acid can be SO 4 2-, NO 3 -, PO 3 2-, HCO 2 -, CH 3cO 2 -, CO 2 2-, oxalate denominationby, citrate ion, malate ion or lactate ion.
Another task of the present invention is to provide tool compound N-styroyl crinidine alkali, Candidine A and Candidine B, and its structural formula is respectively:
Figure BDA0000412330480000051
Above-claimed cpd provided by the invention has antitumor action, can be used for preparing antitumor drug, specifically can be used for the medicine of preparation treatment leukemia, lung cancer, liver cancer or colorectal carcinoma.
The present invention also provides the structure of plant origin and separation purification method and derivative and the analogue of compound 1-16.
One embodiment of the present of invention provide the method for separating and preparing of N-phenethyl crinasiadine, Candidine A, Candidine B.
An alternative embodiment of the invention provides the experimental data of compound 1-16 to the inhibition activity of the active cells of blood sick HL-60, K562, lung cancer A-549, liver cancer HepG2 and the cell proliferation of colorectal carcinoma HT-29 tumour cell.The anti-tumor activity of compound 1-16 is evaluated leukemia HL-60, K562, lung cancer A-549, liver cancer HepG2 and five kinds of human body tumour cells of colorectal carcinoma HT-29 by mtt assay.Result shows: compound N styroyl crinidine alkali and Candidine A and Candidine B have remarkable inhibiting activity to leukemia HL-60, K562, lung cancer A-549, liver cancer HepG2 and five kinds of human body tumour cells of colorectal carcinoma HT-29, are all better than positive control drug cis-platinum.
Another embodiment of the present invention has carried out the mensuration of LD50 to compound Candidine A and Candidine B, result show compound Candidine A and Candidine B toxicity rank very low or nontoxic, oral safety.
Accompanying drawing explanation
Fig. 1: the separated preparation flow figure of N-phenethyl crinasiadine, Candidine A, Candidine B.
Fig. 2: Candidine A and Candidine B X-Ray figure,
Embodiment
The separation preparation of embodiment 1:N-styroyl crinidine alkali, Candidine A, Candidine B
Green onion lotus is dried herb (10kg) and pulverizes rear with 95% ethanol (containing 2%HCl) 25L cold soaking extraction three times, the 4th heating and refluxing extraction, united extraction liquid is used the aqueous solution 3L suspendible containing 2%HCl after reclaiming solvent, 3L chloroform extraction four times, water adjusts pH value to alkalescence with strong aqua, with 3L chloroform extraction four times, chloroform layer reclaims solvent and obtains total alkali again.Total alkali with in press chromatographic system through silica gel column chromatography, chloroform obtains five parts to methyl alcohol gradient elution, first part is through purification on normal-phase silica gel, reversed-phase silica gel column chromatography, gel chromatography obtain N-phenethyl crinasiadine separated with high performance liquid chromatography.The 5th part was entered reversed-phase silica gel column chromatography, and water, to methyl alcohol gradient elution, obtains three parts, and the 3rd part obtaining the crystallization (in methyl alcohol) of Candidine A and the Candidine B of compound through silica gel column chromatography repeatedly, and schema is shown in Fig. 1.
Through NMR and X-Ray test, resolve the absolute configuration (seeing Fig. 2) that has obtained Candidine A and Candidine B, wherein the ratio of Candidine A and Candidine B is 7:3.
N-phenethyl crinasiadine (N-phenethyl crinasiadine): colourless powder, be soluble in chloroform, be insoluble to methyl alcohol.UV(CDCl 3)λmax(logε)270(4.08)，313(3.91)，341(3.76)，372(3.13)nm；IR?v max2957，2924，2855，1747，1631，1600，1462，1310，1039，751cm -1；HRESIMS?m/z344.1282[M+H] +(calcd?for?C 22H 18NO 3 +，344.12812)。
1H?NMR(400MHz，CDCl 3)δ8.12(1H，dd，J＝8.0，0.8Hz，H-1)，7.93(1H，s，H-7)，7.65(1H，s，H-10)，7.52(1H，dd，J＝8.4，1.2Hz，H-3)，7.46(1H，d，J＝7.9Hz，H-4)，7.38(2H，t，J＝7.0Hz，H-15，17)，7.34(2H，d，J＝7.3Hz，H-14，18)，7.29(1H，ddd，J＝8.4，7.0，1.2Hz，H-2)，7.25(1H，t，J＝7.5Hz，H-16)，6.12(2H，s，H-OCH 2O)，4.58(2H，t，J＝8.3Hz，H-11)，3.07(2H，t，J＝8.6Hz，H-12)。
13C?NMR(101MHz，CDCl 3)δ160.8(s，C-6)，152.5(s，C-9)，148.7(s，C-8)，138.8(s，C-13)，136.6(s，C-4a)，130.7(s，C-6a)，129.2(d，C-3)，129.0(d，C-14，18)，128.9(d，C-15，17)，126.9(d，C-16)，123.2(d，C-1)，122.2(d，C-2)，121.5(s，C-10b)，119.7(s，C-10a)，114.7(d，C-4)，106.7(d，C-7)，101.9(t，C-OCH 2O))，100.3(d，C-10)，44.6(t，C-11)，33.6(t，C-12)。
Candidine A and Candidine B (Candidine A and Candidine B): colourless prismatic crystal, be soluble in methyl alcohol, water, is insoluble to chloroform, and there is uv-absorbing at ultraviolet 254nm place.m.p.237℃，[α]25℃D+5.23°(c0.745，CH3OH)；UV(MeOD)λmax(logε)205(2.16)，245(1.44)，290(1.47)，360(0.51)，370(0.56)nm；IR?v max3239，3003，1509，1489，1252，1132，1030，937，825cm -1；HRESIMS?m/z332.1488([M-Cl -] +calcd?for?C 18H 23NO 5 +，332.1493).
Candidine A (Candidine A) 1h NMR (400MHz, MeOD) δ 7.03 (1H, s, H-10), 6.92 (1H, s, H-7), 6.42 (1H, m, H-1), 6.41 (1H, m, H-2), 6.04 (1H, s, H-6), 6.03 (2H, s, H-OCH 2o), 4.58 (1H, dd, J=12.7,6.1Hz, H-12 β), 4.16 (1H, dd, J=13.3,4.6Hz, H-4a), 4.04 (1H, s, H-3), 4.02 (1H, s, H-11), 3.40 (3H, s, H-OMe), 3.25 (1H, m, H-12 α), 3.23 (3H, s, H-NMe), 2.51 (1H, ddd, J=14.82,13.24,3.40, Hz H-4). 13c NMR (101MHz, MeOD) δ 150.77 (C-8), 149.13 (C-9), 133.95 (C-10a), 131.09 (C-1), 126.88 (C-2), 125.22 (C-6a), 109.11 (C-7), 104.38 (C-10), 103.42 (C-OCH 2o), 96.10 (C-6), 77.94 (C-11), 72.33 (C-3), 71.72 (C-4a), 62.82 (C-12), 57.02 (C-OMe), 53.22 (C-10b), 43.69 (C-NMe), 26.1 (C-4).
Candidine B (Candidine B) 1h NMR (400MHz, MeOD) δ 7.07 (1H, s, H-10), 6.86 (1H, s, H-7), 6.42 (1H, m, H-1), 6.41 (1H, m, H-2), 6.03 (2H, s, H-OCH 2o), 5.64 (1H, s, H-6), 4.16 (1H, dd, J=13.3,4.6Hz, H-4a), 4.20 (1H, m, H-12 β), 4.04 (1H, s, H-3), 4.02 (1H, s, H-11), 3.63 (1H, d, J=13.5Hz, H-12 α), 3.40 (3H, s, H-OMe), 3.23 (3H, s, H-NMe), 2.40 (1H, m, H-4). 13c NMR (101MHz, MeOD) δ 151.08 (C-8), 149.13 (C-9), 133.95 (C-10a), 131.27 (C-1), 126.51 (C-2), 124.15 (C-6a), 109.88 (C-7), 104.38 (C-10), 103.42 (C-OCH 2o), 96.69 (C-6), 78.06 (C-11), 72.44 (C-3), 65.26 (C-4a), 68.57 (C-12), 57.02 (C-OMe), 53.80 (C-10b), 44.28 (C-NMe), 25.5 (C-4).
Embodiment 2: compound 1-16 is active to the inhibition of the active cells of blood sick HL-60, K562, lung cancer A-549, liver cancer HepG2 and the cell proliferation of colorectal carcinoma HT-29 tumour cell.
The anti-tumor activity of compound 1-16 is evaluated leukemia HL-60, K562, lung cancer A-549, liver cancer HepG2 and five kinds of human body tumour cells of colorectal carcinoma HT-29 by mtt assay.Result is as shown in table 1 below:
The half growth inhibitory concentration IC50 (μ M) of table 1 compound to different tumor cell lines
Figure BDA0000412330480000071
Figure BDA0000412330480000081
Experiment conclusion: compound N styroyl crinidine alkali and Candidine A and Candidine B have remarkable inhibiting activity to leukemia HL-60, K562, lung cancer A-549, liver cancer HepG2 and five kinds of human body tumour cells of colorectal carcinoma HT-29, are all better than positive control drug cis-platinum.
Embodiment 3: the mensuration of compound Candidine A and Candidine B (7:3) LD50
The mensuration of compound Candidine A and Candidine B LD50: 12 of regular grade kunming mices, 20 ± 2g, male and female half and half, adaptability is fed rear fasting 12 hours, is assigned to immediately the oral acute toxicity that high dose group is investigated III-6, every group of male and female half and half.Gavage, observes the diet of animal in a week, activity, the situations such as Mao Ze and living or death.After gastric infusion, animal appearance and behavior are acted normally, and without any toxic reaction, none is poisoned to death.Result shows when 40 times of effective reference dose, without any toxic reaction, to think that compound Candidine A and Candidine B toxicity rank are very low or nontoxic, and oral safety, no longer improves dosage and do toxicity test.
Therefore, compound Candidine A and Candidine B toxicity rank are very low or nontoxic, oral safety.
Embodiment 4: the preparation of compound Candidine A and Candidine B (7:3) tablet and method
Main medicinal raw material comprises: active substance Candidine A and Candidine B (7:3), the thinner of medicinal tablets, tablet lubricants, tackiness agent and disintegrating agent.Thinner can be selected one or more combinations in micro-starch, glycosides propylhomoserin, Sodium Hydroxymethyl Stalcs; Tackiness agent can be selected a kind of in starch slurry, PVP rubber cement, gelatine size; A kind of in the selectable talcum powder of lubricant, Magnesium Stearate.Tablet stability is good.
Get Candidine A and Candidine B (7:3) 100mg, starch 24g, Microcrystalline Cellulose 24g, Sodium Hydroxymethyl Stalcs 64g, glycine 10g is porphyrize respectively, crosses 80 mesh sieves, the addition of equivalent mixes, and with starch slurry (5%), makes softwood, with 30 mesh sieve filters, granulates, put under 70 ℃ of conditions dry, with adding Magnesium Stearate 0.15g after the whole grain of 40 mesh sieve filter, mix compressing tablet again, packing, obtains.

Claims (5)

1. there is the compound Candidine A shown in following structural formula:
2. there is the compound Candidine B shown in following structural formula
Figure FDA0000412330470000012
3. the application of the compound described in claim 1 or 2 in preparing antitumor drug.
4. the application of the compound described in claim 1 or 2 in the medicine for the preparation for the treatment of leukemia, lung cancer, liver cancer or colorectal carcinoma.
5. the separated method of preparing Candidine A and Candidine B from green onion lotus, comprise: after the dry herb (10kg) of green onion lotus is pulverized, with 95% ethanol (containing 2%HCl) 25L cold soaking, extract three times, the 4th heating and refluxing extraction, united extraction liquid is used the aqueous solution 3L suspendible containing 2%HCl after reclaiming solvent, 3L chloroform extraction four times, water adjusts pH value to alkalescence with strong aqua, again with 3L chloroform extraction four times, chloroform layer reclaims solvent and obtains total alkali, total alkali with in press chromatographic system through silica gel column chromatography, chloroform to methyl alcohol gradient elution obtains five parts, the 5th part is through reversed-phase silica gel column chromatography, water is to methyl alcohol gradient elution, obtain three parts, the 3rd part obtaining having the crystallization (in methyl alcohol) of compound Candidine A and the Candidine B of following structural formula through silica gel column chromatography repeatedly:
Figure FDA0000412330470000021
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Publication number Priority date Publication date Assignee Title
CN107412463A (en) * 2017-04-27 2017-12-01 云南中医学院 A kind of green onion Flos Nelumbinis extract with antitumor action
CN110950878A (en) * 2017-05-27 2020-04-03 华中科技大学 Phenanthridinone derivative, and synthesis method and anti-tumor application thereof

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