CN102558143A - Derivant III of natural product Bostrycin and preparation method and purpose thereof - Google Patents
Derivant III of natural product Bostrycin and preparation method and purpose thereof Download PDFInfo
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- CN102558143A CN102558143A CN2012100125101A CN201210012510A CN102558143A CN 102558143 A CN102558143 A CN 102558143A CN 2012100125101 A CN2012100125101 A CN 2012100125101A CN 201210012510 A CN201210012510 A CN 201210012510A CN 102558143 A CN102558143 A CN 102558143A
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- bostrycin
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Abstract
The invention discloses a derivant III of a natural product Bostrycin and a preparation method and a purpose thereof. The derivant III of the natural product Bostrycin is provided with a structure of a formula (I), is linear alkyl and substitutional or non-substitutional phenyl with the formula that R12=H, OH; R13=H, Cl-C5 and is linear alkyl and substitutional or non-substitutional phenyl with the formula that R14=H, Cl-C5. The derivant of the natural product Bostrycin has good anti-tumor cell viability and can be further developed to be novel anti-tumor medicine as shown in the results of preliminary pharmacological researches (external anti-tumor cell tests).
Description
Technical field
The present invention relates to the discovery field of pharmaceutical chemistry, lead compound, be specifically related to one type of new natural product bostrycin verivate, its preparation method and purposes in the preparation antitumor drug through modifying.
Background technology
Bostrycin is a kind of pigment of redness, at first from Bostryconema alpespre cesati (Tetrahedron Lett. 58:6087,1968; Tetrahedron Lett. 58:6091,1968; Tetrahedron. separate obtaining 26:1339,1968), can suppress gram positive bacterium.Report (Sankyo Kenkyusho Nenpo. 21:165 subsequently again from Nigrospora oryzae; 1969), Fungus Arthrinium phaeospermum (Experientia. 31:783; 1975), Alternaria eichhorniae (Appl Environ Microbiol. 43:846; 1982) separate obtaining in, and find that it has weeding activity.2000; Jiang Guangce, Lin Yongcheng, Zhou Shining (Zhongshan University's journal (natural science edition); 39:68; 2000) separation obtains Bos trycin from South China Sea mangrove endogenetic fungus #1403 secondary metabolite, and cell in vitro poison test-results shows: Bostrycin all can effectively suppress growth of various tumor cell strains (CN1347865A; CN1850765A; CN1762961A; CN101544556A).
For a long time, human health and life in malignant tumour serious threat always.The sickness rate and the lethality rate of tumor disease rise year by year; Yet the specifics of treatment tumor disease especially at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, thereby limited the general applicability of such medicine.Therefore, seek and find that the new antitumor drug with high-efficiency low-toxicity is worldwide research focus.
Yet ball surface-area 70% is taken up an area of in the ocean, and abundant Biological resources are also being contained in the ocean when containing the abundant mineral and the energy.Marine microorganism in quantity or the variety aspect is all quite abundant.Because the living environment of marine microorganism is special, the compound of energy metabolism novel structure, and have good pharmacologically active has been found the compound of antitumor in a large number, treatment cardiovascular disorder, antibiotic, antiviral isoreactivity at present.According to the report of John professor at 2010 " Natural Product Reports ", found that the marine natural product new compound surpassed 1000 kinds first in 2008, marine microorganism is one of main source (accounting for 23%).In addition, marine microorganism is easy to gather and cultivate, and the meta-bolites that the artificial fermentation produces is purified easily, and cost is low, meets the resources development and utilization principle of Sustainable development, so the active compound that therefrom screens is more conducive to suitability for industrialized production.
Make full use of oceanic resources; With its effective constituent is that lead compound carries out structure of modification and composition optimizes; Design is synthetic to have the more compound of strong biological activity, is an effective way seeking new type antineoplastic medicine, and the present invention is a lead compound with South China Sea ocean mangrove endophytic fungus #1403 secondary metabolite Bos trycin; It is carried out structure of modification, and purpose is to seek the natural antitumor drug candidate of high-efficiency low-toxicity.
Summary of the invention
The contriver obtains the structure that compound Bostrycin has following IV by extraction separation in the South China Sea thalassiomycetes #1403 secondary metabolite.
（Ⅳ）
The used fungi 1403 of the present invention has been preserved in Chinese typical culture collection center (CCTCC, Chinese Wuhan University are in the school),
Preserving number is CCTCC NO:M201018, and preservation day is April 23 calendar year 2001.
The purpose of this invention is to provide a kind of novel natural product Bostrycin verivate.
Another object of the present invention provides the preparation method of above-mentioned novel natural product Bostrycin verivate.
A purpose more of the present invention provides the purposes of novel natural product Bostrycin verivate in the preparation antitumor drug.
The novel natural product Bostrycin verivate of the present invention has the structure of formula (I):
R
12=?H、OH；
R
13The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl;
R
14The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl.
Natural product Bostrycin verivate of the present invention prepares through following method: employing Bostrycin is a raw material, under the catalysis of alkali, obtains compound with the reaction of dithiols compound
25-27
Above-claimed cpd of the present invention is through preliminary pharmaceutical research, and through anticancer experiment in vitro, wherein majority of compounds has shown good activity, has good antineoplastic activity, can develop to be novel natural antitumor medicine.
Preferred compound of the present invention has following compound
25,26,27Structure:
The compounds of this invention
25With
26The preparation process following:
Compound
25With
26Preparation technology comprise:
Bostrycin is under triethylamine catalysis, and the dithioglycol reaction obtains 6,7,8,9,11-pentahydroxy-9-methyl-2,3,7,8,9,10
-hexahydroanthra [2,3-b] [1,4] dithiine-5,12-dione (compound
25) and 6,8,9,11-tetrahydroxy-8-methyl-
2,3,7,8,9,10-hexahydroanthra [2,3-b] [1,4] dithiine-5,12-dione (compound
26).
The compounds of this invention
27The preparation process following:
Compound
27Preparation technology comprise:
Bostrycin under triethylamine catalysis, 2,3-succinimide mercaptans reaction obtains 6,7,8,9,11-pentahydroxy-2,3,9-trimethyl
-2,3,7,8,9,10-hexahydroanthra [2,3-b] [1,4] dithiine-5,12-dione (compound
27).
Natural product Bostrycin verivate involved in the present invention, preliminary pharmaceutical research (extracorporeal anti-tumor cell tests), the result shows that this compounds has good antitumor cell activity, can further develop to be novel antitumor drug.
Embodiment:
Further specify the present invention through embodiment below.Embodiment has provided synthetic, the dependency structure appraising datum and the compound activity data of representative new compound.Mandatory declaration, following embodiment is used to explain the present invention rather than limitation of the present invention.The simple modifications that essence according to the present invention is carried out the present invention all belongs to the present invention and requires the scope protected.
Beijing X is used in fusing point test
4Type micro melting point apparatus (TM is not proofreaied and correct).
1HNMR,
13C NMR is with U.S. Varian Inova-500 NB and Switzerland Bruker AVANCE AV-400NB,
TMS does interior mark.
Mass spectrum is measured with Thremo LCQ DECA XP LC-MS appearance and Thremo DSQ mass spectrograph.
Embodiment 1: compound
25With
26Preparation
The reaction of Bostrycin and dithioglycol, building-up process is with embodiment 20.Compound
25: yield: 31.4%.mp：>300℃；
1H?NMR（δ
H,?DMSO，400MHz）：12.84(1H，s)，12.67(1H，s)，5.26(1H，s)，4.94(1H，d，
J=4.4?Hz)，4.75(1H，d，
J=4.4?Hz)，4.49(1H，s)，3.53(1H，t，
J=4.4?Hz)，3.35(4H，s)，2.71(2H，q，
J=18.4?Hz)，1.23(4H，s)；EI(m/z)：396(M
+)，376，360(100%)，344，332，307，294，279。Compound
26: yield: 24.8%.mp：>300℃；
1H?NMR（δ
H,?DMSO，400MHz）：12.64(2H，s)，4.79(1H，d，
J=5.2?Hz)，4.45(1H，s)，3.64(1H，dt，
J=7.5，5.2?Hz)，3.34(4H，s)，2.89–2.76(1H，m)，2.71–2.54(1H，m)，1.21(3H，s)；EI(m/z)：380(M
+)，362，344(100%)，319，307，291，279，251。
Embodiment 2: compound
27Preparation
Bostrycin and dithioglycol 2, the reaction of 3-succinimide mercaptans, building-up process is with embodiment 20.Yield: 63.5%.mp：146-147℃；
1H?NMR（δ
H,?DMSO，400MHz）：12.85(1H，s)，12.69(1H，s)，5.22(1H，s)，4.91(1H，d，
J=4.5?Hz)，4.75(1H，d，
J=3.6?Hz)，4.45(1H，s)，3.67(1H，q，
J=6.2?Hz)，3.54(1H，t，
J=4.5?Hz)，3.48(1H，d，
J=?5.7?Hz)，2.72(2H，q，
J=18.3?Hz)，1.34–1.29(6H，m)，1.23(3H，s)；EI(m/z)：424(M
+)，406，388，351，335，322，307，295，71(100%)。
Embodiment 3: the test of extracorporeal anti-tumor cytoactive
1. material:
1.1 tetrazolium bromide (MTT): (3-(4 with the phosphate buffered saline buffer (PBS) of 0.01mol/L dissolving MTT; 5-dimethythiazol-z-yl) 2,5-diphenyl-tetrazolium bromide, SIGMA) final concentration 5mg/mL; Filtration sterilization, 4 ℃ keep in Dark Place after the packing.
1.2 the preparation of target cell: recovery and the cultivation of MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116.
A. from liquid nitrogen container, take out the cold pipe of depositing of MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116; Insert rapidly in 37 ℃ of water baths; Do not stop to shake and make it to dissolve rapidly, aseptic technique moves in the centrifuge tube;
B. add DMEM complete culture solution to 10 mL, the centrifugal 5min of 1000rmp abandons supernatant;
C. repeat above operation once;
D. move in the culturing bottle 5%CO after making the cell mixing with the piping and druming of DMEM complete culture solution
2, 37 ℃ of cultivations;
E. the observation of cell growing state is in time changed nutrient solution, divides bottle.
1.3 cell counting:
A. choose the logarithmic phase cell, trysinization, the DMEM perfect medium stops, and moves in the centrifuge tube, adds the DMEM perfect medium to 10mL;
B. get 10 μ L cell suspensions and splash in the tally one side groove, the TCS of microscopically counting four big lattice, divided by 4 takes advantage of 10
4, be every milliliter of contained cell count of nutrient solution;
C. adjust cell count to 1 * 10
5/ mL.
1.4 natural product Bostrycin derivative solution configuration:
Get natural product Bostrycin verivate and join in the DMEM perfect medium, adjustment concentration is 500 μ g/mL, ultrasonic emulsification, filtration sterilization, 4 ℃ of preservations.
2. TP
A. each hole of 96 orifice plates adds MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116 100 μ L (1 * 10
5/ mL), cultivate 4h for 37 ℃.
B. the study subject 100 μ L that add different concns, contrast adds DMEM perfect medium 100 μ L, continues to cultivate 48h..
C. add each 10 μ L of MTT (5mg/mL), continue to cultivate 4h.
D. remove nutrient solution, every hole adds DMSO 100 μ L, and the 5-10min that vibrates gently makes the particle dissolving.
E. enzyme linked immunological appearance 570nm measures every hole OD value down.
F. calculate inhibiting rate:
Tumor cell destruction %=[the average OD value that (the average OD value of average OD value-dosing group mensuration that control group is measured)/control group is measured] * 100%.
G. with the logarithm mapping of inhibiting rate, try to achieve IC to drug level
50Value:
With lgc is X-coordinate, and inhibiting rate is an ordinate zou, tries to achieve IC
50Value.
Table
1Be the extracorporeal anti-tumor cytoactive result of The compounds of this invention.
Table
1
EPI (Pharmorubicin
) be U.S. Pharmacia Company products
Claims (8)
1. natural product Bostrycin verivate
III, it is characterized in that having the structure of logical formula I,
R
12=?H、OH；
R
13The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl;
R
14The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl.
2. according to the described natural product Bostrycin of claim 1 verivate, the compound 2 that it is characterized in that having following structure
5,
3. according to the described natural product Bostrycin of claim 1 verivate, the compound that it is characterized in that having following structure
26,
。
4. according to the described natural product Bostrycin of claim 1 verivate, the compound that it is characterized in that having following structure
27,
5. according to the preparation method of each described natural product Bostrycin verivate of claim 1 ~ 4, it is characterized in that adopting Bostrycin is raw material, under the catalysis of alkali, obtains corresponding compounds with the sulfur alcohol compound reaction.
6. preparation method according to claim 5 is characterized in that said alkali is triethylamine.
7. the application of the said natural product Bostrycin of claim 1 verivate in the preparation antitumor drug.
8. application as claimed in claim 7 is characterized in that said antitumor be anti-breast cancer, lung cancer, liver cancer or colorectal carcinoma.
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|---|---|---|---|
| CN201210012510.1A CN102558143B (en) | 2012-01-16 | 2012-01-16 | Derivant III of natural product Bostrycin and preparation method and purpose thereof |
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|---|---|---|---|
| CN201210012510.1A CN102558143B (en) | 2012-01-16 | 2012-01-16 | Derivant III of natural product Bostrycin and preparation method and purpose thereof |
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| CN102558143B CN102558143B (en) | 2014-04-23 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796017A (en) * | 2012-08-24 | 2012-11-28 | 中山大学 | Natural product deoxybostrycin derivatives and preparation method and application thereof |
| CN111329848A (en) * | 2020-04-01 | 2020-06-26 | 武汉轻工大学 | Application of spinosad |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850765A (en) * | 2006-05-26 | 2006-10-25 | 中山大学 | Quinone compounds, and their preparing method and antitumour use |
| CN101544556A (en) * | 2008-06-06 | 2009-09-30 | 中山大学 | Quinone compound Bostrycin, preparation method thereof and anti-tumor application thereof |
-
2012
- 2012-01-16 CN CN201210012510.1A patent/CN102558143B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850765A (en) * | 2006-05-26 | 2006-10-25 | 中山大学 | Quinone compounds, and their preparing method and antitumour use |
| CN101544556A (en) * | 2008-06-06 | 2009-09-30 | 中山大学 | Quinone compound Bostrycin, preparation method thereof and anti-tumor application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796017A (en) * | 2012-08-24 | 2012-11-28 | 中山大学 | Natural product deoxybostrycin derivatives and preparation method and application thereof |
| CN111329848A (en) * | 2020-04-01 | 2020-06-26 | 武汉轻工大学 | Application of spinosad |
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|---|---|
| CN102558143B (en) | 2014-04-23 |
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