CN1268622C - New ramification of diterpenes possessing periodic inhibitory action like matricyte of sea star egg - Google Patents
New ramification of diterpenes possessing periodic inhibitory action like matricyte of sea star egg Download PDFInfo
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- CN1268622C CN1268622C CN 200410026676 CN200410026676A CN1268622C CN 1268622 C CN1268622 C CN 1268622C CN 200410026676 CN200410026676 CN 200410026676 CN 200410026676 A CN200410026676 A CN 200410026676A CN 1268622 C CN1268622 C CN 1268622C
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- starfish
- oocyte
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Abstract
The present invention relates to a new diterpene derivative with the cycle inhibitory activity of matricyte of starfish oocyte. A new diterpene compound is obtained by separating sponge (Strongylophora strongylata) collected from the sea area of the Xibiao island in Japan by an applicant; the maturation division of starfish oocyte can be obviously suppressed in vitro, and the new diterpene derivative can not only used for preventing and treating the damage to fry livestock breeding caused by the mass propagation of the starfish in the coastal area, but also used as biochemical reagents of a cell division mechanism of a study in vitro. In addition, since the molecular action mechanisms of the oocyte maturation process of the starfish and the eukaryotic G2/M period conversion are very similar, the molecular action mechanisms depend on the activation of cyclinB/cdc2 kinase, and accordingly, the cycle inhibitory of starfish oocyte possibly has inhibiting action on the growth of tumor cells.
Description
Technical field: what the present invention relates to that separation obtains from the sponge (Pgyllospongiadendyi) that West Pacific Ocean's Palau (Palau) archipelagic sea is gathered a plurality ofly has a sea star egg parent cell cycle and suppresses active following new diterpene-kind compound.These compounds can significantly suppress the maturation division of sea star egg parent cell in vitro tests, not only can be used for preventing and treating the region following the line of the sea because of a large amount of breedings of starfish to the infringement that ocean fry aquaculture etc. causes, also can be used as the biochemical reagents of in vitro study cell fission mechanism.
Background technology and document: the ocean is a Source of life, it also is the abundantest field of physical resources on the earth, marine organisms are different from terrestrial life, because the difficult harshness (high salt, high pressure, anoxic etc.) of its living environment, for seeking survival and compete living space, a lot of marine organisms can metabolism in the evolution of long period of time process produce the secondary metabolite of some structure uniquenesses.Modern pharmacological research shows that a lot of marine organisms secondary metabolites also have better curative effect to the multiple disease of the mankind, thereby causes chemist, biologist, pharmacologist's etc. very big interest.
The research of marine drug originates in beginning of the sixties not fifties in the world.To the later stage eighties, because huge advance made, especially the high resolution NMR broad application of science and technology, the structure determination work of the minor compound that makes becomes quite easy, the research of the marine bioactivity material hot topic that becomes.The various countries scholar has carried out in succession that marine organisms are antitumor, antiviral, antimycotic, resisting cardiovascular is sick, the research of anti-AIDS isoreactivity composition.In the past few decades, about 600,010,004 2002.4
Multiple marine natural product is found, and wherein has the new compound of the active patent applied for of important biomolecule that kind more than 300 is arranged
[1,2]The generation development of unusual and a lot of diseases of cell cycle all has confidential relation, and the intravital most of cell of Mammals is in resting stage (G0 phase) under the normal circumstances, has only under certain condition (as factors stimulated growth) just to enter the G1 phase.Cell after the division mostly reenters the G0 phase or is differentiated to form sophisticated not somatoblast, and minority enters the G1 phase and divides next time.The periodicity of cell mitogen and succession explanation cell cycle are processes that is subjected to strict regulation and control, in case defective appears in certain link, just may cause uncontrolled cellular proliferation, and then produce tumour.Extensive screening cell cycle inhibitor, (Flow Cytometry, FCM), but this method needs expensive instrument, complicated operation generally to adopt the flow cytometry method.The sea star egg parent cell is because of its following feature that has, as: Fine born of the same parents' cycle regulating mechanism is similar to eukaryotic cell cycle regulating mechanism; And Fine born of the same parents' cycle spontaneously is synchronized with the early stage of initial meiosis, i.e. the G2/M phase; Immature egg cell and mature egg cell be easy to differentiate at microscopically, obtained using effectively as a kind of cell cycle inhibitor screening method of simple and convenient
[3,4]The applicant adopts this method for screening active ingredients, successfully separates to obtain a plurality ofly having a sea star egg parent cell cell cycle and suppressing active new diterpene-kind compound from the sponge (Phyllospongia dendyi) that West Pacific Ocean's Palau (Palau) archipelagic sea is gathered.
Reference:
[1]Faulkner DJ，marine pharmacology.Antonie van leeuwenhoek 77：135-145[2]Faulkner DJ，marine natural products.Nat Prod Rep 19：1-48
[3]Morinaga，C.，Izumi，K.，Sawada，H.，Sawada，M.T.，Activation of maturation promoting factorand 26S proteasome assembly accelerated by a high concentration of 1-methyladenine instarfish oocytes.，Biosci.Biotechnol.Biochem，2000，64，268-274.
[4]Toraya，T.；Maoka，T.；Tsuji，H.；Kobayashi，M.Purification and structural determination of aninhibitor of starfish oocyte maturation from a Bacilus speciese.，Applied and Environ.Micro.，1995，61，1799-1804
Summary of the invention: the present invention relates to have the provide protection that the sea star egg parent cell cycle suppresses active new diterpene-kind compound and be used to prevent and treat the infringement that ocean fry aquaculture etc. is caused because of a large amount of breedings of starfish, and as the application of cell division cycle inhibitor.
Embodiment embodiment 1: the separation method of new diterpene-kind compound:
The raw materials used sponge of the present invention (Strongyphora strongylata) is picked up from table island, Japan west, and is frozen in-20 ° refrigerator.Take out sponge during application, at room temperature thaw, chopping, with 3 times of weight dehydrated alcohol extraction 3 times, united extraction liquid, drying under reduced pressure.Residue is scattered in isopyknic water, with isopyknic chloroform extraction 2 times, combined chloroform layer, vacuum decompression drying, chloroform extract.With carrying out chromatographic separation, the methanol-water gradient elution with the open post of anti-phase ODS filler.60% methanol-water wash-out part obtains compound 1,2 through reversed phase high efficiency liquid phase separation (65% methanol-water); 70% methanol-water wash-out part obtains compound 5 through reversed phase high efficiency liquid phase separation (73% methanol-water); The active stream part of 80% methanol-water wash-out part obtains compound 3,4,6 through reversed phase high efficiency liquid phase separation (78% methanol-water) again.
Compound 1 and 2: white powder, UV (MeOH) λ
Maxnm(ε): 203 (8450), 293 (3264); HRFABMS, m/z430.2706[M]
+(calcd for C
26H
38O
5, 430.2719);
13C and
1H NMR data see Table 2.
Compound 3 and 4: white powder, UV (MeOH) λ
Maxnm(ε): 204 (12882), 220 (s, 4097), 230 (s, 3074), 296 (2085); HRFABMS, m/z 412.2595[M]
+(calcd for C
26H
36O
4, 412.2614);
13C and
1H NMR data see Table 2.
Compound 5: white powder, UV (MeOH) λ
Maxnm(ε): 208 (10865), 220 (s, 6580), 228 (s, 5752), 250 (1592), 257 (1558), 263 (s, 1340), 296 (3396); HRFABMS, m/z 414.2774[M]
+(calcd for C
26H
38O
4, 414.2770);
13C and
1H NMR data sees Table 2.
Compound 6: white powder, white powder, UV (MeOH) λ
Maxnm(ε): 206 (9257), 220 (s, 4696), 229 (s, 4015), 295 (2089); HRFABMS, m/z 398.2792[M]
+(calcd for C
26H
38O
3, 398.2821);
13C and
1The HNMR data see Table 2.
Compound 7: white powder, UV (MeOH) λ
Maxnm(ε): 207 (21645), 229 (s, 5434), 257 (2492), 297 (1624); HRFABMS, m/z 427.2465[M+H]
+(calcd for C
26H
35O
5, 427.5609);
13C and
1H NMR data data see Table 2.
The 2 sea star egg parent cell cycles of embodiment are suppressed active testing method:
The sea star egg parent cell is the spontaneous early stage that is synchronized with initial meiosis before the ripening stage, i.e. the G2/M phase, in this stage, can observe complete nucleus.Ovum enters the M phase with maturation under the effect of hormone (1-methyladenines) but induce in maturation, and nucleus breaks and carries out reduction division.
It is littoral that female starfish (Asterina pectinifera) individuality picks up from Japan, gathers in annual 4-5 month and 8-10 month, cultures that (ASW, 10mM EPPS-NaOH (pH8.2) contains 0.46M NaCl, 10mM KCl, 35.9mMMgCl in artificial seawater
2, 1.75mM MgSO
4, and 9.18mM CaCl
2) in.Get one of female starfish Asterina pectinifera, cut off, take out red ovary, put into artificial seawater washing 2-3 time of calcium ions not, be suspended in the not calcareous artificial seawater of 30mL along each tentacle center.Ovary is shredded, remove floating follicular cell, three layers of filtered through gauze.Low-speed centrifugal is suspended in the precipitation that obtains in the 200ml artificial seawater then, and microscopic count transfers to 100/ml with cell count, promptly gets required starfish immature egg parent cell.
Laboratory sample is dissolved in DMSO, and concentration is 2mg/ml, as test liquid.The starfish immature egg parent cell of getting 1ml adds in 24 orifice plates, the test liquid 10ul that adds different concns simultaneously, cultivate after 10 minutes on the ice bath, add 1.25uM1-methyladenines 100ul, act on after 50 minutes, the form of observation of cell nuclear under inverted microscope, if compare with negative blank group, nucleus is kept perfectly and shows that promptly the sea star egg cell mature process is had the activity of inhibition.Starfish oocyte maturation inhibiting rate is calculated as follows.
Table 1: compound 1-7 is active to the sophisticated inhibition of sea star egg parent cell
| Compound | Active (IC 50) |
| 1 | 35.0μM |
| 2 | 35.0μM |
| 3 | 36.4μM |
| 4 | 36.4μM |
| 5 | 1.2μM |
| 6 | 35.2μM |
| 7 | 36.4μM |
Table 2: compound 1-7's
13C-NMR spectrum data (pyridine-d
5, 500MHz)
| C# | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 1 | 40.4 | 40.4 | 40.5 | 40.5 | 35.6 | 35.0 | 39.9 |
| 2 | 22.8 | 22.9 | 22.9 | 22.7 | 19.2 | 19.0 | 20.1 |
| 3 | 35.3 | 40.9 | 35.1 | 40.7 | 36.4 | 42.1 | 40.3 |
| 4 | 37.3 | 37.1 | 37.4 | 37.1 | 39.1 | 33.2 | 43.2 |
| 5 | 51.1 | 48.7 | 51.5 | 49.1 | 57.3 | 57.0 | 49.7 |
| 6 | 19.8 | 20.0 | 21.0 | 20.4 | 18.9 | 18.4 | 21.2 |
| 7 | 40.1 | 40.6 | 38.9 | 39.3 | 42.9 | 41.9 | 31.9 |
| 8 | 39.4 | 39.7 | 36.4 | 36.6 | 37.5 | 37.5 | 43.5 |
| 9 | 56.9 | 57.5 | 56.9 | 57.6 | 62.4 | 62.1 | 46.3 |
| 10 | 37.8 | 37.6 | 37.9 | 37.7 | 42.4 | 42.8 | 36.7 |
| 11 | 17.6 | 17.6 | 19.0 | 18.0 | 22.1 | 22.5 | 19.1 |
| 12 | 44.7 | 44.7 | 42.1 | 42.1 | 43.0 | 43.1 | 39.9 |
| 13 | 73.8 | 73.8 | 76.3 | 76.3 | 76.7 | 76.7 | 74.0 |
| 14 | 63.0 | 63.0 | 53.0 | 53.0 | 53.4 | 53.4 | 99.6 |
| 15 | 27.6 | 27.6 | 22.9 | 22.9 | 23.1 | 23.0 | 31.9 |
| 16 | 131.9 | 131.9 | 123.5 | 123.5 | 123.5 | 123.5 | 130.1 |
| 17 | 149.9 | 149.9 | 146.8 | 146.8 | 146.9 | 146.8 | 154.0 |
| 18 | 117.7 | 117.7 | 118.0 | 118.0 | 118.0 | 118.0 | 108.7 |
| 19 | 114.6 | 114.6 | 115.3 | 115.3 | 115.3 | 115.3 | 114.4 |
| 20 | 151.3 | 151.3 | 152.2 | 152.2 | 152.0 | 152.0 | 152.6 |
| 21 | 119.4 | 119.4 | 116.9 | 116.9 | 116.9 | 116.8 | 112.4 |
| 22 | 24.7 | 24.7 | 21.0 | 21.0 | 20.5 | 20.5 | 24.9 |
| 23 | 16.4 | 16.5 | 15.7 | 15.7 | 15.5 | 15.6 | 17.5 |
| 24 | 67.9 | 62.0 | 67.9 | 62.0 | 62.2 | 61.5 | 73.8 |
| 25 | 24.3 | 24.1 | 24.0 | 24.2 | 28.6 | 34.2 | 23.5 |
| 26 | 98.9 | 99.1 | 98.9 | 99.1 | 64.9 | 22.0 | 176.1 |
Table 3: compound 1-6,8
1H-NMR spectrum data (pyridine-d
5, 500MHz)
| C# | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 1 | 1.00，m 2.17，m | 1.00，m 2.17，m | 1.00，m 2.17，m | 1.00，m 2.17，m | 0.77，m 2.51，m | 0.67，m 2.53，m | 0.86，m 1.95，m |
| 2 | 1.55，m 2.84，m | 1.56，m 2.50，m | 1.56，m 2.83，m | 1.56，m 2.56，m | 1.45，m 1.88，m | 1.43，m 1.74，m | 1.15，m 1.50，m |
| 3 | 1.22，m 2.50，m | 1.34，m 1.56，m | 1.20，m 2.52，m | 1.34，m 1.56，m | 1.09，m 2.14，m | 1.16，m 1.37，m | 1.30，m 1.74，m |
| 5 | 0.88，m | 0.80，m | 1.12，m | 1.04，m | 1.13，m | 0.90，m | 1.15，m |
| 6 | 1.25，m 1.60，m | 1.50，m 2.50，m | 1.06，m 1.65，m | 1.72，m 2.60，m | 1.73，2H，m | 1.44，2H，m | 1.15，m 1.50，m |
| 7 | 0.88，m 2.06，m | 0.88，m 2.06，m | 0.88，m 1.65，m | 0.88，m 1.65，m | 0.95，m 1.76，m | 1.00，m 1.72，m | 1.25，m 1.58，m |
| 9 | 0.85，m | 0.85，m | 0.94，m | 0.94，m | 1.10，m | 1.03，d(11.0)b | 2.05，d(12.5) |
| 11 | 1.28，m 1.55，m | 1.28，m 1.55，m | 1.12，m 1.74，m | 1.55，m 1.72，m | 2.03，m 2.16，m | 2.05，m 2.20，m | 1.17，m 1.70，m |
| 12 | 1.75，m 2.03，m | 1.75，m 2.03，m | 1.74，m 2.08，m | 1.74，m 2.08，m | 1.76，m 2.14，m | 1.74，m 2.12，m | 1.93，m 2.22，m |
| 14 | 1.95，m | 1.95，m | 1.65，m | 1.65，m | 1.74，m | 1.72，m | |
| 15 | 2.65，m 3.24，m | 2.65，m 3.24，m | 2.60，2H，m | 2.60，2H，m | 2.66，2H，d，(9.0) | 2.68，2H，m | 3.02，d(15.0) 3.51，d(15.0) |
| 18 | 7.18，m | 7.18，m | 6.98，m | 6.98，m | 6.99，d(9.0) | 6.99，d(9.0) | 6.80，d(9.0) |
| 19 | 7.10，m | 7.10，m | 7.04，m | 7.04，m | 7.04，dd(3.0，9.0) | 7.04，dd(3.0，9.0) | 6.94，d(9.0) |
| 21 | 7.34，m | 7.34，m | 7.05，m | 7.05，m | 7.09，d(3.0) | 7.09，d(3.0) | 7.12，br.s |
| 22 | 1.36，3H，s | 1.36，3H，s | 1.17，3H，s | 1.16，3H，s | 1.25，3H，s | 1.25，3H，s | 1.38，3H，s |
| 23 | 0.87，3H，s | 0.96，3H，s | 0.75，3H，s | 0.86，3H，s | 1.15，3H，s | 1.17，3H，s | 0.96，3H，s |
| 24 | 3.65，d(12.5) 4.17，d(12.5) | 3.40，d(12.5) 4.57，d(12.5) | 3.67，d(11.0) 4.20，d(11.0) | 3.42，d(11.0) 4.61，d(11.0) | 4.09，dd(5.5，12.0) 4.23，dd(5.5，12.0) | 4.03，dd(5.5，12.0) 4.20，dd(5.5，12.0) | 4.01，d(12.5) 4.76，d(12.5) |
| 25 | 1.01，3H，s | 1.08，3H，s | 1.03，3H，s | 1.11，3H，s | 1.25，3H，s | 0.87，3H，s | 1.18，3H，s |
| 26 | 5.18，br.s | 5.06，d(3.3) | 5.20，br.s | 5.08，d(3.3) | 3.75，d(10.0) 3.99，d(10.0) | 0.80，3H，s | |
| OH | 8.02，br.s | 7.56，d(3.3) | 8.10，br.s | 7.65，d(3.3) |
Claims (3)
1. the diterpene-kind compound that has following array structure:
2, the described diterpene-kind compound of claim 1 is used to prevent and treat the infringement that ocean fry aquaculture etc. is caused because of a large amount of breedings of starfish.
3, the described diterpene-kind compound of claim 1 is as the application of cell division cycle inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410026676 CN1268622C (en) | 2004-03-31 | 2004-03-31 | New ramification of diterpenes possessing periodic inhibitory action like matricyte of sea star egg |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410026676 CN1268622C (en) | 2004-03-31 | 2004-03-31 | New ramification of diterpenes possessing periodic inhibitory action like matricyte of sea star egg |
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| CN1268622C true CN1268622C (en) | 2006-08-09 |
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| CN101445499B (en) * | 2008-12-25 | 2011-12-21 | 中国人民解放军第二军医大学 | Diterpenoid antitumor compound and preparation method thereof |
| JP5429706B2 (en) * | 2009-02-05 | 2014-02-26 | 国立大学法人名古屋大学 | Novel acetylene alcohol derivative, NGF-related active substance and process for producing the same |
| CN102417509B (en) * | 2011-12-28 | 2013-12-11 | 大连美罗中药厂有限公司 | Application of three compounds extracted from starfish to promotion of bone fracture healing, and preparation method for three compounds |
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