CN1850849A - 25-hydroxy dioscin ketone, and its preparing method and use - Google Patents
25-hydroxy dioscin ketone, and its preparing method and use Download PDFInfo
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- CN1850849A CN1850849A CNA2006100270665A CN200610027066A CN1850849A CN 1850849 A CN1850849 A CN 1850849A CN A2006100270665 A CNA2006100270665 A CN A2006100270665A CN 200610027066 A CN200610027066 A CN 200610027066A CN 1850849 A CN1850849 A CN 1850849A
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- dioscin
- ketone
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention discloses a 25-hydroxide radical canaigre soap alkone and the manufacture method and the application. It uses canaigre ssapogenin as raw material to take hydroxylating through streptomycete at 25 tertiary carbon site to gain 25-hydroxide radical canaigre soap alkone. It could be used to make new compound and drug to anti malaria and restrict the growth of tumor.
Description
Technical field
The invention belongs to bio-organic worker field, relate to the 25-hydroxy dioscin ketone, the application of the preparation method of 25-hydroxy dioscin ketone and 25-hydroxy dioscin ketone.
Background technology
Diosgenin (diosgenin) is that diosgenin is the product that 3 glycosyls are fallen in the dioscin hydrolysis, to the extensive screening of natural product active ingredient, it is found that diosgenin and analog thereof (or derivative) have pharmacologically active widely along with both at home and abroad.Has broad-spectrum anti-tumor activity as diosgenin; Many functions such as cardiac vascular activity, as the Diaoxinxuekang that goes on the market in recent years, perhexiline etc., major ingredient are dioscin (unit); Its derivative dioscin ketone has antimalarial active etc.
In addition, steroid drugs plays very important regulatory function to body.From last century the fifties so far, diosgenin is the desirable feedstock of producing steroid drugs always, the steroid hormone medicine of the whole world more than 2/3rds directly produced as basic material with diosgenin, in fact be that all steroid drugss almost can be synthesized in the basis with the diosgenin, the structure of these steroid drugss often difference is trickle, but can show different activity.
The steroidal compounds structure is very complicated, contains several asymmetric centers, and especially its active height depends on substituting group more, and the substituting group of specific site particular configuration often.The major limitation that chemical synthesis is applied to steroidal compounds is that its selectivity is relatively poor, can't or be difficult in specific position and introduce the substituting group of particular configuration, just because of microbe transformation method being applied in the production of steroid drugs, solve the organic chemist and be difficult to the synthesizing steroid compound, the privileged site that particularly is difficult on some steroid drugss is introduced this difficult problem of particular functional group's (chemo-selective and stereoselectivity), making industrialization produce various steroid hormones becomes possibility, thereby has established important basis for the development of steroidal medicine industry.For example, 11 hydroxylations and 1 dehydrogenation are to produce the requisite two important reactions of step of most efficient steroid drugs, and wherein 11 hydroxylatings are that the organic chemistry method is difficult to realize owing to relate to regioselectivity and stereoselectivity problem; And 1 dehydrogenation reaction makes 1 dehydrogenation of microbial method highly selective become inevitable choice because the chemical method reactivity is low and reaction needed high toxicity catalyzer, and problem such as environmental pollution is serious.
Because the important physiologically active and the vital role in the steroidal medicine industry thereof of diosgenin, from the sixties in last century, the work that utilizes the microbial transformation diosgenin was all carried out in external many laboratories, attempted directly to obtain useful medicine or intermediate to shorten steroid hormone medicine production step from diosgenin through microbial transformation.
Therefore, what development research was new utilizes the new compound of microbial transformation by diosgenin, will have crucial meaning, also be pharmacy field the problem very paid close attention to.
Summary of the invention
The technical issues that need to address of the present invention disclose a kind of 25-hydroxy dioscin ketone and preparation method thereof and application.
25-hydroxy dioscin ketone of the present invention, its chemical name are 3-ketone-4-alkene-25-hydroxyl spiral shell steroid, and English name is 25-hydroxyspirost-4-en-3-one or isonuatigenone, and its general structure is:
The preparation method of 25-hydroxy dioscin ketone of the present invention comprises the steps:
(1) cultivates streptomycete (Streptomyces spp), preferred streptomycete is Wei Jini streptomycete (Streptomyces virginiae) or streptomyces lavendulae (Streptomyceslavendulae), described streptomycete can be adopted commercially available commercially produced product, or the bacterial classification that provides at Chinese microbial preservation center is provided;
Said microorganism is 25-35 ℃ for the streptomycete culture temperature, and incubation time is 12～120 hours, preferably is cultured to logarithmic phase latter stage at 28-30 ℃, can adopt conventional substratum, and preferred ingredients is as follows:
Every liter of ammonium chloride 3 gram; Every liter of dipotassium hydrogen phosphate 1.55 gram; Every liter of SODIUM PHOSPHATE, MONOBASIC 0.85 gram; Every liter of glucose 3 gram; Every liter of yeast powder 3 gram; Every liter of corn steep liquor 3 gram; Every liter of cyclodextrin 3 gram.
(2) in the mixture of the cultured microorganism of the mixture of diosgenin and solvent being dropped into step (1) and substratum, 25～35 ℃ are continued cultivation 12～120 hours;
Said solvent is selected from a kind of or its mixture in ethanol, methyl alcohol, acetone, dimethyl sulfoxide (DMSO) or the nonionic surface active agent.Wherein: the concentration of diosgenin is 0.1～1g/ml;
The input amount of the mixture of diosgenin and solvent, by volume are 0.01～0.5% of cultured microorganism and substratum;
(3) from cultured products, collect the 25-hydroxy dioscin ketone.
Reaction expression is as follows:
Evidence, 25-hydroxy dioscin ketone of the present invention has antimalarial active, external plasmodium falciparum (Plasmodium falciparum) is had inhibitory or killing effect; The 25-hydroxy dioscin ketone has the activity that suppresses tumor growth in addition, in the cell in vitro experiment, the growth of multiple cancer cells is had restraining effect.
Compound 25-hydroxy dioscin ketone of the present invention can generate other steroidal compounds through the microbial transformation degraded;
Described other steroidal compounds comprises 1 dehydrogenation-25-hydroxyl dioscin ketone, 16-hydroxyl progesterone, ADD (androstane-1,4-diene-3,17-diketone) or AD (androstane-4-alkene-3,17-diketone).
By above-mentioned disclosed technical scheme as seen, the present invention is a raw material with diosgenin [spirost-5-en-3 beta-ol or diosgenin], by microorganism particularly the Wei Jini streptomycete (Streptomyces virginiae) in the streptomycete (Streptomyces spp.) carry out hydroxylating production (I) new compound 25-hydroxy dioscin ketone [25-hydroxyspirost-4-en-3-one or isonuatigenone] in 25 tertiary carbon sites with novel of streptomyces lavendulae (Streptomyces lavendulae), the new compound that is obtained has antimalarial active and suppresses the activity of tumor growth, points out mixture of the present invention will can be used in the medicine of preparation antimalarial and inhibition tumor growth; Be that precursor can be realized obtaining 1 dehydrogenation-25-hydroxyl dioscin ketone, 16-hydroxyl progesterone, ADD or AD by microbial method with this compound in addition.Compound of the present invention is compared with other compounds of the same type, has the following advantages: 1) be the polar derivative of antimalarial natural product dioscin ketone, the solubleness in solvent is improved; 2) for utilizing microbial method at the F of diosgenin on the ring for the first time, introduce an active group, the further modification diosgenin that is introduced as of this active group provides possibility; 3) can be lived by microbial transformation, realize the E of diosgenin, the degraded of F ring generates valuable drug or pharmaceutical intermediate.
Embodiment
General rule
Agents useful for same is commercially available, and purity is analytical pure.Reaction process, intermediate and degree of purity of production are confirmed with TLC and HPLC.EI-MS measures with the MicromassGCT TM mass spectrograph of Micromass Ltd.; Infrared spectra (IR) adopts the Magna-IR550 Fourier infrared spectrograph of U.S. Nicolet company to measure; The AVANCE500 of the German Bruker of nuclear-magnetism (NMR) employing company measures; The micro-fusing point instrument of the X75 that fusing point adopts Beijing instrument photoelectric instrument factory of section to produce is measured, and does not proofread and correct; Silica gel for chromatography is produced by Haiyang Chemical Plant, Qingdao.
Embodiment 1
The preparation of 25-hydroxy dioscin ketone:
The microorganism of adopting: Wei Jini streptomycete (Streptomyces virginiae) IBL-14, preserving number is CCTCC M206045.
The Wei Jini streptomycete is cultured to growth logarithm latter stage in 29 ℃, adding concentration is that diosgenin to the final concentration that 0.4g/ml is dissolved in the hot ethanol is 0.0015mol/L, transform 48 hours, stopped reaction, with equal volume of ethyl acetate three times, concentrate extraction liquid, concentrating under reduced pressure, cross silicagel column, every liter of reaction solution can obtain the 25-hydroxy dioscin ketone of 0.0050mol.
The component and the content of substratum are as follows:
Every liter of ammonium chloride 3 gram; Every liter of dipotassium hydrogen phosphate 1.55 gram; Every liter of SODIUM PHOSPHATE, MONOBASIC 0.85 gram; Every liter of glucose 3 gram; Every liter of yeast powder 3 gram; Every liter of corn steep liquor 3 gram; Every liter of cyclodextrin 3 gram.
Products therefrom is identified:
Colourless acicular crystal; Mp234-236 ℃;
IR(KBr)cm
-1：3450，2964，2939，2878，2857，1658，1619，1452，1379，1337，1300，1268，1226，1187，1052，1032，984，958，937，895，8010，dnC-MS(ESI)429(M+H)；MS(EI)m/z(％)：428(0.19)(M+，C27H40O4)，397(66.90)，343(3.43)，340(94.49)，298(13.63)，283(2.11)，269(100.00)，155(73.85)；
1H?NMR(CDCl3)δ：5.74(1H，S，H-4)，4.41(1H，dd，J
1＝14.94Hz，J
2＝7.51Hz，H-16)，3.73(1H，d，J＝11.42Hz，H-26ax)，3.26(1H，dd，J1＝11.37Hz，J2＝2.40Hz，H-26eq)，1.20(3H，S，H-19)，1.12(3H，S，H-27)，1.03(3H，d，J＝6.90Hz，H-21)，0.83(3H，S，H-18)；
13C?NMR(CDCl
3)δ：200.1(C3)，171.7(C5)，124.6(C4)，109.8(C22)，81.8(C16)，69.7(C26)，67.3(C25)，62.5(C17)，56.3(C14)，54.4(C9)，42.2(C20)，41.1(C13)，40.2(C12)，39.3(C10)，36.3(C1)，35.9(C8)，34.6(C2)，33.4(C6)，33.4(C24)，32.8(C7)，32.3(C15)，27.7(C23)，25.4(C27)，21.5(C11)，18.0(C19)，17.0(C18)，15.1(C21)。
Embodiment 2
The preparation of 25-hydroxy dioscin ketone:
The microorganism of adopting: Wei Jini streptomycete (Streptomyces virginiae) is selected from DSMZ.
The Wei Jini streptomycete is cultured to growth logarithm latter stage in 29 ℃, adding concentration is that diosgenin to the final concentration that 0.4g/ml is dissolved in the hot ethanol is 0.0015mol/L, transform 48 hours, stopped reaction, with equal volume of ethyl acetate three times, concentrate extraction liquid, concentrating under reduced pressure, cross silicagel column, every liter of reaction solution can obtain the 25-hydroxy dioscin ketone of 0.0040mol.
The component of substratum and content are as example 1.
Embodiment 3
The preparation of 25-hydroxy dioscin ketone:
The microorganism of adopting: streptomyces lavendulae (Streptomyces lavendulae) is selected from DSMZ.
Streptomyces lavendulae is cultured to growth logarithm latter stage in 28 ℃, adding concentration is that diosgenin to the final concentration that 0.4g/ml is dissolved in the hot ethanol is 0.0015mol/L, transform 48 hours, stopped reaction, with equal volume of ethyl acetate three times, concentrate extraction liquid, concentrating under reduced pressure, cross silicagel column, every liter of reaction solution can obtain the 25-hydroxy dioscin ketone of 0.0040mol.
The component of substratum and content are with example 1:
Products therefrom is identified: colourless acicular crystal; Mp234-236 ℃; MS (EI) m/z (%): 428 (0.19) (M+, C27H40O4), 397 (66.90), 343 (3.43), 340 (94.49), 298 (13.63), 283 (2.11), 269 (100.00), 155 (73.85).
Embodiment 4
The antimalarial effect of 25-hydroxy dioscin ketone
Test 25-hydroxy dioscin ketone is selected plasmodium falciparum FCB-2 for use to the activity of plasmodium falciparum, and used substratum is for being supplemented with 10% people A
+The RPMI1640 of type serum, 25mMHEPES, 25mM NaHCO3 (pH7.3).People A
+The type red corpuscle is as host cell.Culture is remained on 37 ℃, normal atmosphere, 3%O
2, 4%CO
2And 93%N
2Moist culturing room in.Compound is dissolved in the ethanol, dilutes in advance, and in 96 hole droplet plates, in 64 times of scopes, carry out three parts of titration with continuous 2 times of dilutions with perfect medium.Be added in after the parasite culture of 0.75% initial parasitemia (representing) in 2.5% the red blood cell suspension, test board was cultivated 72 hours under these conditions with infected erythrocytic percentage ratio.Radiolabeled by adding in preceding 16 hours in off-test [
3H]-xanthoglobulin and measure the growth of parasite culture.Estimate 50% inhibition concentration (IC by regression analysis
50).
The result shows that the 25-hydroxy dioscin ketone has effective restraining effect to plasmodium falciparum FCB-2, its IC
50Be 21.8 μ M, so the 25-hydroxy dioscin ketone have certain antimalarial effect.
Embodiment 5
The cancer suppressing action of 25-hydroxy dioscin ketone
The anticancer effect of test 25-hydroxy dioscin ketone selects for use human melanoma cell A375-S2 and human erythroleukemia cell K562 for testing picture.Used substratum is RPMI1640, replenishes 10% heat-inactivated fetal bovine serum, the glutamine of 2 μ M/L, 10
5U/L penicillin, the 100mg/L streptomycete is put the CO of 5% volume
2Cultivate in the case.The 25-hydroxy dioscin ketone is to the inhibition effect (IC of these two kinds of cancer cells
50Expression) measure with mtt assay, in 96 orifice plates, the K562 cell concn directly is adjusted into 1 * 10
8Individual/L, the A375-S2 cell is through digestion process, and adjusting concentration is 1 * 10
8Individual/L, every hole 100 μ L, cultivate 24, experimental group adds the 25-hydroxy dioscin ketone of 10-80 μ M respectively, handles 4 multiple holes for every group, cultivate 20h, add MTT, abandon supernatant after continuing to cultivate 4h, every hole adds 150 μ LDMSO, lucifuge vibration 10min measures absorbance with the full-automatic enzyme-linked immunologic detector in the 492nm place.
The result shows that the 25-hydroxy dioscin ketone has certain cancer resistant effect, and the 25-hydroxy dioscin ketone is to the IC of A375-S2
50Be 41 μ M, to the IC of K562
50Be 62 μ M, so the 25-hydroxy dioscin ketone have certain antitumous effect.
Embodiment 6
The 25-hydroxy dioscin ketone is by the obtainable useful products of microbiological deterioration
The 25-hydroxy dioscin ketone can further transform degraded through microorganism and generate the 16-hydroxyl progesterone, and ADD, AD.The Wei Jini streptomycete is cultured to growth logarithm latter stage in 28-30 ℃, add the 25-hydroxy dioscin ketone that is dissolved in the hot ethanol and transform 24 hours, stopped reaction, with equal volume of ethyl acetate three times, concentrate extraction liquid, concentrating under reduced pressure, cross silicagel column, can obtain the 16-hydroxyl progesterone respectively, and ADD, AD (formula III as follows).
This explanation 25-hydroxy dioscin ketone can be produced the 16-hydroxyl progesterone through microbial transformation as substrate, and ADD, AD.
Embodiment 7
The 25-hydroxy dioscin ketone is by the obtainable useful products of microorganism dehydrogenation
The 25-hydroxy dioscin ketone can further transform 1 dehydrogenation through microorganism and generate 1 dehydrogenation-25-hydroxyl dioscin ketone.Arthrobacter simplex is cultured to growth logarithmic phase mid-term in 29 ℃, adds the 25-hydroxy dioscin ketone that is dissolved in the hot ethanol and transforms 24 hours, stopped reaction, with equal volume of ethyl acetate three times, concentrate extraction liquid, concentrating under reduced pressure, cross silicagel column, can obtain 1 dehydrogenation-25-hydroxyl dioscin ketone.
The component and the content of substratum are as follows:
Every liter of corn steep liquor 10 gram, every liter of glucose 6 gram, every liter of peptone 3 gram, every liter of phosphoric acid hydrogen dimethylamino 1.5 gram.
Claims (10)
1.25-hydroxy dioscin ketone is characterized in that, structural formula is:
2. prepare the method for the described 25-hydroxy dioscin ketone of claim 1, it is characterized in that, comprise the steps:
(1) cultivates streptomycete (Streptomyces spp);
(2) in the mixture of the cultured microorganism of the mixture of diosgenin and solvent being dropped into step (1) and substratum, 25～35 ℃ are continued cultivation 12～120 hours;
(3) from cultured products, collect the 25-hydroxy dioscin ketone.
3. method according to claim 2 is characterized in that, streptomycete is Wei Jini streptomycete (Streptomyces virginiae) or streptomyces lavendulae (Streptomyceslavendulae).
4. method according to claim 2 is characterized in that, said solvent is selected from a kind of or its mixture in ethanol, methyl alcohol, acetone, dimethyl sulfoxide (DMSO) or the nonionic surface active agent.
5. method according to claim 4 is characterized in that, the concentration of diosgenin is 0.1～1g/ml.
6. method according to claim 2 is characterized in that, the streptomycete culture temperature is 25-35 ℃, and incubation time is 12～120 hours.
7. method according to claim 6 is characterized in that, is cultured to logarithmic phase latter stage at 28-30 ℃.
8. method according to claim 2 is characterized in that, the input amount of the mixture of diosgenin and solvent, and by volume is 0.01～0.5% of cultured microorganism and a substratum.
9. the application of the described 25-hydroxy dioscin ketone of claim 1, it is characterized in that, said compound 25-hydroxy dioscin ketone, generate other steroidal compounds through the microbial transformation degraded, described other steroidal compounds comprises 16-hydroxyl progesterone, ADD (androstane-1,4-diene-3, the 17-diketone) or AD (androstane-4-alkene-3,17-diketone).
10. with the described 25-hydroxy dioscin ketone of claim 1, the novel drugs and the new compound that it is characterized in that preparing other antimalarial and suppress tumor growth generate 1 dehydrogenation-25-hydroxyl dioscin ketone etc. as 1 dehydrogenation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100270665A CN1850849A (en) | 2006-05-30 | 2006-05-30 | 25-hydroxy dioscin ketone, and its preparing method and use |
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|---|---|---|---|
| CNA2006100270665A CN1850849A (en) | 2006-05-30 | 2006-05-30 | 25-hydroxy dioscin ketone, and its preparing method and use |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232520A (en) * | 2013-05-13 | 2013-08-07 | 中国药科大学 | Spirosteroid compounds and preparation method and medical application thereof |
| CN115282155A (en) * | 2022-06-20 | 2022-11-04 | 天津中医药大学 | Application of diosgenin derivative in preparation of anti-cancer drugs |
-
2006
- 2006-05-30 CN CNA2006100270665A patent/CN1850849A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232520A (en) * | 2013-05-13 | 2013-08-07 | 中国药科大学 | Spirosteroid compounds and preparation method and medical application thereof |
| CN115282155A (en) * | 2022-06-20 | 2022-11-04 | 天津中医药大学 | Application of diosgenin derivative in preparation of anti-cancer drugs |
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