CN110526925A - A kind of separation method of 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative and its application - Google Patents
A kind of separation method of 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative and its application Download PDFInfo
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Abstract
This programme discloses 25 β of one kind--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative separation method of mibemycin derivative technical field, step are as follows: one, using ethyl acetate extracting streptomycete FJS 31-2 secondary metabolite, obtain ethyl acetate extract medicinal extract；Two, ethyl acetate extract medicinal extract is carried out mixing sample, component Fr.1~Fr.6 of opposed polarity section is then obtained with petroleum ether-acetone gradient elution with petroleum ether wet method dress post with silica gel；Fr.4 is eluted through ODS-A column chromatographic grade, obtains 3 components Fr.4-1, Fr.4-2 and Fr.4-3；Component Fr.4-2 is passed through into sephadex Sephadex LH -20 column chromatography for separation again, further pass through semipreparative high performance liquid chromatography instrument, using acetonitrile-water as mobile phase, the component that retention time is 17.990min is collected, recycling design obtains 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative.25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative of this programme preparation can be applied to preparation anti-melanin tumor medicine.
Description
Technical field
The invention belongs to mibemycin derivative technical fields, in particular to one kind 25 β--23 β of secondary cyclobutenyl-isobutyl
The separation method of acyloxy mibemycin derivative and its application.
Background technique
Mibemycin (Milbemycins) is that a series of very similar 16-membered ring macrolides in structure are anti-
Raw element, can be generated by several streptomycetes, have the biological activities such as strong desinsection and mite killing.First Mir was found from 1967
Since the mould chlorins compound of shellfish, other similar compounds of a large amount of structures are reported.Have multiple mibemycin classes in the world
Drug realizes commercialization, is widely used as veterinary medicine or crop protection pesticide.
Whether there is hydrogenation benzo furan structure in mibemycin class compound, it can be simply divided into α-type and β-type
Two class formations, wherein being significantly larger than β-type with the activity of α-type structure, therefore people mainly concentrate the research of such compound
In α-type.In addition, causing due to having stronger desinsection, mite killing, the bioactivity of expelling parasite in mibemycin class compound
Currently the research application of mibemycin class compound is concentrated mainly on the pesticide or veterinary drug of Resistant.It is mould for Mir shellfish
Chlorins compound is rarely reported in the application of anti-tumor aspect.
Summary of the invention
The invention is intended to provide one kind 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative separation side
Method isolates 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative to extract from streptomycete FJS 31-2,
And 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative antitumor application thereof is studied.
25 β of one of this programme--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative separation method,
25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative is produced from the cometabolism of streptomycete FJS 31-2
It is isolated in object；The deposit number of streptomycete FJS 31-2 are as follows: CGMCC 4.7321.
Depositary institution's title of streptomycete FJS 31-2: in China Committee for Culture Collection of Microorganisms's common micro-organisms
The heart, preservation date: on June 2nd, 2016, classification naming: streptomycete Streptomyces sp, depositary institution address: court, Beijing
The institute 3 of positive area's North Star West Road 1.
25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative separation method specifically includes the following steps:
Step 1: obtaining ethyl acetate extraction using the secondary metabolite of ethyl acetate extracting streptomycete FJS 31-2
Object medicinal extract；
Step 2: carrying out mixing sample to ethyl acetate extract medicinal extract using the silica gel of 80~100 mesh, then with 200~300
Purpose silica gel is with petroleum ether wet method dress post, with petroleum ether-acetone gradient elution, obtain the component Fr.1 of opposed polarity section~
Fr.6；Fr.4 chromatographs (methanol-water 70:30~90:10) gradient elution through ODS-A column, obtains 3 components Fr.4-1, Fr.4-2
And Fr.4-3；Component Fr.4-2 is separated by sephadex Sephadex LH -20 column chromatography (chloroform-methanol 1:1) again,
Further by semipreparative high performance liquid chromatography instrument, with acetonitrile-water (72:28, v/v) for mobile phase, retention time is collected
For the component of 17.990min, recycling design obtains white amorphous powder compound: 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy
Mibemycin derivative.
This programme the utility model has the advantages that this method is easy to operate, micro constitutent not easily runs off and controllability and favorable reproducibility.
Active testing proves that isolated 25 β--23 β of the secondary cyclobutenyl-isobutyl acyloxy mibemycin of the present invention spreads out
Biology has good melanoma effect.Therefore, the present invention provides one kind 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy
Application of the mibemycin derivative in the drug or composition for preparing melanoma.
Further, 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative structural formula are as follows:
Detailed description of the invention
Fig. 1 is 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative in the present invention1H-NMR nuclear magnetic spectrogram；
Fig. 2 is 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative in the present invention13C-NMR nuclear magnetic spectrogram；
Fig. 3 be the present invention in 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative 13C-NMR and
DEPT135 and DEPT90 compares spectrogram；
Fig. 4 is 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative mass spectrogram in the present invention；
Fig. 5 is 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative high resolution mass spec figure in the present invention；
Fig. 6 is melanoma cancer cells strain primary dcreening operation figure；
Fig. 7 is that 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative inhibits the half of melanoma
Concentration (IC50) figure；
Fig. 8 is that 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative acts on melanoma cancer cells
Effect picture afterwards.
Specific embodiment
It is further described below by specific embodiment:
Separation and Extraction
A kind of separation method of 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative, comprising the following steps:
Step 1: extracting deposit number using ethyl acetate are as follows: the secondary generation of the streptomycete FJS 31-2 of CGMCC 4.7321
It thanks to product, obtains ethyl acetate extract medicinal extract；
Step 2: carrying out mixing sample to ethyl acetate extract medicinal extract using the silica gel of 80~100 mesh, then with 200~300
Purpose silica gel is obtained with petroleum ether wet method dress post with petroleum ether-acetone (1:0,15:1,10:1,8:1,5:1,3:1) gradient elution
To component Fr.1~Fr.6 of opposed polarity section；Fr.4 is chromatographed through ODS-A column with methanol-water (70:30,80:20,90:10) ladder
Degree elution, obtains 3 components Fr.4-1, Fr.4-2 and Fr.4-3；Component Fr.4-2 is passed through into sephadex Sephadex again
LH -20 column chromatographs (chloroform-methanol 1:1) separation, further by semipreparative high performance liquid chromatography instrument, with acetonitrile-water
(72:28, v/v) is mobile phase, collects the component that retention time is 17.990min, and recycling design obtains white amorphous powder
Close object: 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative.With TLC detection 254nm it is ultraviolet under it is visible and
In pink after 10% sulfuric acid ethyl alcohol chromogenic reagent, it is unfolded by solvent of chloroform-acetone 10:1 or petroleum ether-acetone 3:1
Afterwards, Rf value is 0.5.
Structural Identification:
25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative structural formula is as follows:
White amorphous powder, ESI-MS (positive) provide m/z 693 [M+Na]+, prompt the molecular weight of compound
It is 670.HR-ESI-MS map provides m/z 693.3623 [M+Na]+(calculated value 693.3609), determines compound molecule
Formula is C38H54O10, calculating degree of unsaturation is 12.
1H-NMR(CDCl3, 500MHz) and in spectrum, it can be seen that 5 groups of doublet methyl hydrogen signals, wherein 4 groups are and saturated carbon
Connected methyl hydrogen δ 0.69 (3H, d, J=6.6Hz), δ 1.00 (3H, d, J=6.7Hz), δ 1.00 (3H, d, J=6.7Hz), δ
1.197 (3H, d, J=6.9Hz), δ 1.20 (3H, d, J=6.9Hz)；1 group be connected with end olefinic carbon methyl δ 1.66 (3H,
D, J=6.7Hz)；The unimodal methyl hydrogen signal δ 1.53 (3H, s) of 3 groups of connection unsaturated carbons, δ 1.59 (3H, s), δ 1.87 (3H,
br s)；1 group of methylene hydrogen signal δ 4.68 (2H, m) being connected with oxygen.
13C-NMR(CDCl3, 125MHz) and 38 carbon signals are shared in map, it is composed in conjunction with DEPT90 and 135, it can be seen that its
In include: 8 quaternary carbon signals, wherein 2 ester carbonyl group carbon signals (δ 178.0,173.7) and 4 olefinic carbon signals (δ 139.6,
137.9,137.5,133.2), the carbon signal (δ 100.3,80.3) of 2 company's oxygen；17 methine carbon signals, wherein 6 olefinic carbons
Signal (δ 142.9,125.0,123.5,120.5,120.4,118.2), 7 company's oxygen carbon signal (δ 80.3,79.3,76.1,
), 75.5,68.6,68.3,67.8 4 carbon signals (δ 45.8,37.8,36.1,34.4) being connected with aliphatic chain；5 methylene
Carbon signal, the mesomethylene carbon signal (δ 48.6,36.3,36.2,34.7) of 5 company's fatty carbon chains, the mesomethylene carbon letter of 1 company's oxygen
Number (δ 68.5)；8 methyl carbon signals (δ 22.4,20.0,19.3,19.1,15.7,13.3,13.1,10.9).
By the compound1H-NMR and13C-NMR nuclear magnetic data and compound VM48130 compare (Haxell et
al. 1992；Baker et al.1996), it is found that chemical displacement value and coupling constant values are almost the same, therefore compound can be reflected
It is set to VM48130.
Detailed data is as shown in the table:
25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative1H and13C-NMR data (500 (1H)
and 125(13C)MHz,Chloroform–d)
C38H54O10, white amorphous powder.positive ESI-MS m/z 693[M+Na]+；1H NMR(CDCl3,500
MHz)δH: 5.76 (m, 1H), 5.75 (dd, J=14.4,11.2Hz, 1H), 5.45 (dq, J=6.7,1.2Hz, 1H), 5.42 (m,
1H), 5.31 (m, 1H), 5.30 (m, 1H), 4.97 (m, 1H), 4.93 (dd, J=10.6,9.5Hz, 1H), 4.68 (m, 2H),
4.29 (d, J=6.0Hz, 1H), 3.95 (d, J=6.2Hz, 1H), 3.89 (s, 1H), 3.61 (m, 1H), 3.58 (d, J=
10.4Hz, 1H), 3.27 (q, J=2.5Hz, 1H), 3.21 (d, J=9.6Hz, 1H), 2.61 (heptet, J=6.9Hz, 1H),
2.42 (m, 1H), 2.32 (br d, J=7.9Hz, 1H), 2.25 (m, 2H), 2.20 (m, 1H), 1.90 (m, 1H), 1.87 (br
S, 3H), 1.85 (m, 1H), 1.82 (m, 1H), 1.80 (m, 2H), 1.66 (d, J=6.7Hz, 3H), 1.59 (s, 3H), 1.53
(s, 3H), 1.20 (d, J=6.9Hz, 3H), 1.19 (d, J=6.9Hz, 3H), 1.19 (d, J=8.6Hz, 1H), 1.00 (d, J
=6.7Hz, 3H), 0.90 (q, J=12.4 Hz, 1H), 0.69 (d, J=6.6Hz, 3H) .The13C NMR(CDCl3,
125MHz)δC:178.0(s,C-35),173.7(s, C-1),142.9(d,C-11),139.6(s,C-8),137.9(s,C-
4),137.5(s,C-14),133.2(s,C-31),125.0(d, C-32),123.5(d,C-10),120.5(d,C-15),
120.4(d,C-9),118.2(d,C-3),100.3(s,C-21),80.3(s, C-7),80.3(d,C-25),79.3(d,C-
6),76.1(d,C-23),75.5(d,C-22),68.6(d,C-19),68.5(t,C-27), 68.3(d,C-17),67.8(d,
C-5),48.6(t,C-13),45.8(d,C-2),37.8(d,C-24),36.3(t,C-18),36.2(t, C-20),36.1(d,
C-12),34.7(t,C-16),34.4(d,C-36),22.4(q,C-28),20.0(q,C-26),19.3(q,C-37), 19.1
(q,C-38),15.7(q,C-29),13.3(q,C-33),13.1(q,C-30),10.9(q,C-34)。
25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative melanoma test
Experimental procedure:
(1) cell recovery: -80 DEG C of melanoma (B16) cancer cell line frozen are taken out, is put into rapidly in 37 DEG C of water-baths and solves
Freeze；Cell suspension is transferred in the 15mL centrifuge tube of the culture medium containing 2mL, 800rpm, is centrifuged 3min.1mL is taken to cultivate base weight
The cell of the new precipitating that suspends, and be transferred in the Tissue Culture Flask of the culture medium containing 3mL and dispel uniformly, it is placed in 37 DEG C of CO2Culture
Case culture.
(2) cell passes on: discarding the culture medium in culture bottle, PBS liquid cleans 2 times, and 0.25% trypsase of 1mL is added
Cellular morphology is observed under digestion inverted microscope, is terminated and is digested with 3mL culture medium when contraction is rounded.Gently dispel Tissue Culture Flask
Cell suspension is transferred to 15mL centrifuge tube by interior attached cell, and 800rpm is centrifuged 3min.1mL culture medium is taken to suspend again heavy
The cell in shallow lake, and be transferred in the Tissue Culture Flask of the culture medium containing 3mL and dispel uniformly, it is placed in 37 DEG C, 5%CO2It is trained in incubator
It supports.
(3) cell administration: taking out the cell of passage, discards the culture medium in culture bottle, and PBS is cleaned 2 times, and 1mL is added
0.25% trypsin digestion, when cellular contraction is rounded, 3mL culture medium terminates digestion.Cell is gently blown and beaten, cell culture is made
Attached cell in bottle sufficiently falls off, and collects cell suspension and is transferred to 15mL centrifuge tube, 800rpm is centrifuged 3min.Cell precipitation
It is 5 × 10 with culture medium adjustment cell concentration4A/mL takes 100 μ L cell suspensions, is separately added into 96 orifice plate culture holes, is placed in
37℃CO2Incubator culture is for 24 hours.When cell grows to the 80% of culture hole, successively by the drug hole be diluted to 2 μM, 4 μM,
8 concentration such as 8 μM, 16 μM, 32 μM, 64 μM, 128 μM, 256 μM are as test concentrations, parallel 6 multiple holes of each medicine group, and 37
DEG C, 5%CO2Incubator effect terminates to cultivate for 24 hours afterwards.Above-mentioned culture medium is to add 10% on the basis of 1640 basal medium
Serum and 1% dual anti-is formulated.
(4) absorbance measurement: discarding the liquid in 96 orifice plates, and PBS cleans each orifice plate to no compound and remains, and is added 90
μ L culture medium and 10 μ L cck8 reagents, 37 DEG C are continued to terminate culture after being incubated for 4h, and microplate reader measures OD value at 490nm.
(5) experimental analysis:
According to each group OD490The average and standard deviation of value can calculate place's inhibitory rate of cell growth as follows:
IC is calculated using SPSS18.0 and GraphPadPrism6.0 statistical software50。
IC50(half maximal inhibitory concentration) refers to the 503nhibiting concentration of drug.It can refer to
Show that a certain drug or substance (inhibitor) are inhibiting certain biological process, concentration or dosage when such as cell death half, IC50
Value can be used to measure the ability of drug-induced death, i.e. inducibility is stronger, and the numerical value is lower, also can be reversed and illustrate certain
Tolerance degree of the cell to drug.
25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative is to the half-suppressed dense of melanoma cancer cells
Degree figure is as shown in Fig. 7.
25 β of various concentration--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative is to melanoma cancer cells
Inhibiting rate such as following table
This experiment takes 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative of various concentration to black
Pigment tumor cell strain is tested through the above steps, melanoma cancer cells after experiment as shown in figure 8, in Fig. 8 nine grids from
Under above, first row from left to right indicates that 25 β used--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative is dense
Degree is respectively as follows: 0 μM, 2 μM, 4 μM；Second row from left to right indicates 25 β used--23 β of secondary cyclobutenyl-isobutyl acyloxy Mir
Shellfish adm derivative concentration is respectively as follows: 8 μM, 16 μM, 32 μM；Third row from left to right indicates the 25 β-secondary cyclobutenyl -23 used
β-isobutyl acyloxy mibemycin derivatives concentration is respectively as follows: 64 μM, 128 μM and 256 μM.In Fig. 8 in white portion 50
μM be scale, indicate cell amplify 200 times after effect picture.
As can be seen from Figure 8, when drug concentration is at 2 μM, 4 μM, 8 μM, observe in cellular morphology and quantity with it is right
According to group and no significant difference；But when drug concentration is at 16 μM, cell is not only quantitatively reduced, but also form becomes
Change, part cell disruption；When drug concentration increases to 32 μM, cell disruption, cell quantity is sharply reduced；When drug concentration increases
When greatly to 64 μM, most cells floating, number cell deaths big absolutely.
It is black after 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative acts on melanoma cancer cells
The effect figure of melanoma cancer cell is as shown in Fig. 8.
From function and effect, it is apparent that 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative pair
Melanoma cancer cells have significant inhibiting effect；It can be widely used for preparing in the drug of melanoma.
Claims (4)
1. one kind 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative separation method, it is characterised in that: 25
Secondary -23 β of cyclobutenyl of β-- isobutyl acyloxy mibemycin derivative is separated from the secondary metabolite of streptomycete FJS 31-2
It obtains；The deposit number of streptomycete FJS 31-2 are as follows: CGMCC 4.7321.
2. a kind of 25 β-- 23 β of secondary cyclobutenyl according to claim 1-isobutyl acyloxy mibemycin derivative point
From method, it is characterised in that: specifically includes the following steps:
Step 1: obtaining ethyl acetate extract leaching using the secondary metabolite of ethyl acetate extracting streptomycete FJS 31-2
Cream；
Step 2: carrying out mixing sample to ethyl acetate extract medicinal extract using the silica gel of 80~100 mesh, then with 200~300 purposes
Silica gel obtains component Fr.1~Fr.6 of opposed polarity section with petroleum ether-acetone gradient elution with petroleum ether wet method dress post；
Fr.4 through ODS-A column chromatograph (methanol-water 70:30~90:10) gradient elution, obtain 3 components Fr.4-1, Fr.4-2 and
Fr.4-3；Again by component Fr.4-2 by sephadex Sephadex LH -20 column chromatography (chloroform-methanol 1:1) separation, then
Further by semipreparative high performance liquid chromatography instrument, with acetonitrile-water (72:28, v/v) for mobile phase, collecting retention time is
The component of 17.990min, recycling design obtain white amorphous powder compound: 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy rice
That shellfish adm derivative.
3. the application of one kind 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative, it is characterised in that: 25 β-secondary
- 23 β of cyclobutenyl-application of the isobutyl acyloxy mibemycin derivative in the drug or composition for preparing melanoma.
4. a kind of 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative according to claim 3 is answered
With, it is characterised in that: 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative structural formula are as follows:
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| CN116589606A (en) * | 2022-12-01 | 2023-08-15 | 中国药科大学 | Butyrylated yeast glucan as well as preparation method and application thereof |
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