CN1629173A - Novel antibiotic preparing process - Google Patents
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- CN1629173A CN1629173A CN 200310122330 CN200310122330A CN1629173A CN 1629173 A CN1629173 A CN 1629173A CN 200310122330 CN200310122330 CN 200310122330 CN 200310122330 A CN200310122330 A CN 200310122330A CN 1629173 A CN1629173 A CN 1629173A
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Abstract
The invention discloses a plurality of novel corner anthracene nucleus polyketone antibiotics, which is generated by culturing Streptomyces venezuelae ISP5230 (ATCC no.10712) in culture medium of cerebrose-amino acid at 27-30 deg. C and under the condition of extraneous stimulation, extracting the compounds with acetic ester, and conducting silica gel chromatography. These compounds can repress the growth of G+ bacterium and tumor cells.
Description
Technical field
The invention belongs to the microbiotic technical field, concretely, the invention relates to the method for making a series of new angles anthracycline compound with streptomyces venezuelae (Streptomyces venezuelae) ISP5230 (ATCC NO.10712).New angle anthracycline compound is the streptomyces venezuelae meta-bolites, and its cultured products is obtained through silica gel column chromatography with ethyl acetate extraction.Product behind the purifying is similar with the Jetta mycin B that reports for work (being called for short JB) through the nuclear magnetic resonance spectroscopy certification structure, but compound disclosed by the invention structurally has new feature, and biological activity test shows that these compounds can suppress G
+The growth of bacterium and tumour cell.
Technical background
Microbiotic is the compound of inhibition or kill microorganisms or tumour cell optionally under lower concentration.At present, all adopting chemistry or biosynthetic method production both at home and abroad, is the main medicine of diseases such as human treatment microorganism, virus infection and tumour.
People such as Ayer in 1991 find that streptomyces venezuelae is cultivated for 37 ℃ and produced a kind of new coloured microbiotic in semi-lactosi-Isoleucine substratum, name that structural formula as shown in Figure 1a into Jetta mycin (Jadomycin is called for short JA).People such as Doull in 1993 find that the primary product of biological metabolism exists with the glycosylation form of angle anthracene nucleus polyketide under above-mentioned culture condition, are referred to as Jetta mycin B (being called for short JB), and its structural formula is shown in Fig. 1 b.
Studies show that JB is derived and next angle anthracycline compound by fragrant polyketone, on second ring, form a nitrogenous five-membered ring because an Isoleucine molecule inserts.Biological activity test proves that JB can suppress the Gram-positive bacteria growing.
At present, on the basis of clone's synthetic gene bunch, finished the part Study of JB pathways metabolism.In the JB synthetic gene bunch (jad gene cluster), polyketide synthase gene (jadABC) and jadJMN etc. are responsible for the synthetic of polyketone carbochain; Cyclase gene (jadDI) the coding carbochain of ketoreductase gene (jadE) and two suppositions is modified and the cyclisation associated protein; Three oxidase genes (jadFGH) may be relevant with modification after open loop and the cyclisation; Synthetic and the metastasis related protein of JadOPQSTUVX encoding glycosyl; In addition, also have six genes may participate in the regulation and control of JB synthetic, jadR
1Be a specific regulatory factor of replying of approach, promote the synthetic of JB, jadR
2, jadR* and jadW1 are negative regulator genes.The grown cell of streptomyces venezuelae can be considered a multienzyme catalyst system, coordinates mutually, the synthetic mould chlorins compound of Jetta.
Patent WO/94/20061 has reported JB compound and antimicrobial acivity thereof, at present, has only reported that above-mentioned angle anthracene nucleus polyketone antibiotic be JB one kind both at home and abroad, and do not suppress the report of growth of tumour cell.
Summary of the invention
The object of the present invention is to provide a kind of manufacture method of new angle anthracene nucleus polyketone antibiotic, and provide the one group of new angle anthracene nucleus polyketone analogue that obtains by this method, they are called after new angle anthracene nucleus polyketone JF respectively, new angle anthracene nucleus polyketone JT, new angle anthracene nucleus polyketone JS etc.Their structural formulas respectively as shown in Figure 2.Should be pointed out that from structural formula second ring inserts different amino acid moleculars respectively as can be seen, can obtain to have the active analogue of antibiosis of different structure, can correspondingly have the side-chain radical of different aminoacids on the formed five-membered ring.New through looking into, one group of above-mentioned new angle anthracene nucleus polyketone antibiotic is a new compound.Biological activity test shows that the anti-microbial activity of these compounds is similar to JB or stronger, has the effect that suppresses tumor growth in addition, there is no relevant report at home and abroad so far.
The invention provides a kind of new angle of biosynthetic series anthracene nucleus polyketide that utilizes at the clinical anti-G of preparation
+Application in the medicine of the growth of bacterium medicine and tumour cell.
The step that the preparation method of new angle anthracene nucleus polyketide relates to:
1. serve as to produce bacterium with streptomyces venezuelae ISP5230 (ATCC NO.10712), in semi-lactosi-amino acid whose minimal medium, cultivate that it is matrix (100ml) that substratum is formed with water: semi-lactosi 1.8g, amino acid 30mM, MgSO
47H
2O 0.02g, KH
2PO
40.102g, K
2HPO
40.044g, NaCl 0.088g, CaCl
20.0065g, ZnSO
47H
2O 0.4mg, CuSO
45H
2O0.018mg, MnSO
4H
2O 2.7mg, boric acid 2.6mg, four water ammonium molybdate 1.7mg, pH 7.0--7.5.At the amino acid described in the above-mentioned substratum can be that Phe, Ser, Thr and other aromatic series and the heterocycle same clan are amino acid whose a kind of, adds dissimilar amino acid, forms different products.Foregoing new angle anthracene nucleus polyketone analogue is to add afterwards that at English first letter of Jetta mycin (Jadomycin) " J " the amino acid whose one-letter symbol of substrate names, for example, phenylalanine tunning called after JF, Threonine tunning called after JT, Serine tunning called after JS.
2. collect the supernatant liquor of mentioned microorganism fermented liquid, by the conventional method of extracting of organic compound, ordinary method comprises utilizes compound microbiotic and impurity to extract the new angle of preparation anthracene nucleus polyketone analogue in the difference of aspects such as solubleness, ion avidity, adsorptive power, molecular weight.These methods can be used separately, also can cooperate centrifugation, membrane sepn, and organic solvent extraction, ion-exchange or absorption are used etc. method.Another one characteristics of the present invention are except that above-mentioned general preparation process, the purification step of product can be reduced to: collect the fermented liquid culture, centrifugal back ethyl acetate extraction, extract purifying, organic solvent dissolution, rotary evaporation on silica-gel plate concentrate and obtain product.
3. the product behind the purifying is defined as angle anthracene nucleus polyketide through mass spectrum and nuclear magnetic resonance measuring analysis, is the analogue of JB, but the side chain of before having on the five-ring, not reporting.
4. the new compound that obtains is through antibiotic, antitumor cell growth activity experiment.Similar to the JB activity of report, tangible resisting gram-positive bacteria activity is arranged, the antitumor cell activity of this compounds of this patent reported first.
Characteristics of the present invention:
1. utilize the secondary metabolism synthetic antibiotic of microorganism, its technology is easy, and the cycle is short, and cost is low.
2. biological process synthetic antibiotic environmentally safe of the present invention.
3. the compound that relates to of invention is the analogue of disclosed JB, but molecular structure is different from and reports JB, and the antimicrobial spectrum of these compounds is similar to JB, yet there are no identical report so far.The present invention discloses the anti-G of these compounds first
+Bacterium and anti-tumor activity.
4. the angle anthracene nucleus skeleton and the JB of the compound that the present invention relates to are similar, but the feature of its side chain do not appear in the newspapers, and therefore, antibiotic structure of the present invention is different from the structure of disclosed compound among the existing patent WO 94/20061.
5. set up in the substratum that contains semi-lactosi and different aminoacids, with the method for the synthetic a series of angles of streptomyces venezuelae ISP5230 (ATCC NO.10712) anthracycline compound, for screening new antibiotic medicine provides new resources.
Description of drawings
The molecular structural formula of Fig. 1 .JB
Fig. 2. the molecular structural formula of new angle anthracene nucleus polyketide: new angle anthracene nucleus polyketone JF, new angle anthracene nucleus polyketone JT, the new new angle of anthracene nucleus polyketone, angle anthracene nucleus polyketone JS.
Fig. 3. new angle anthracene nucleus polyketide high-pressure liquid phase collection of illustrative plates (313nm): new angle anthracene nucleus polyketone JF, new angle anthracene nucleus polyketone JT, the new new angle of anthracene nucleus polyketone, angle anthracene nucleus polyketone JS
Embodiment
Following example will the invention will be further described, and protection scope of the present invention is not subjected to the restriction of these examples.
The preparation of embodiment 1 new angle anthracene nucleus polyketone antibiotic JF
50 μ l streptomyces venezuelae spore suspensions are inoculated in 100ml contain in the substratum (MYM) of yeast extract paste, maltose and wort, 27 ℃, 200 ~ 250rpm concussion cultivate 24 hours standby as seed.In the triangular flask of 250mL, add 100mL substratum, its composition (100ml): semi-lactosi 1.8g, phenylalanine-3,4-quinone 0mM, MgSO
47H
2O 0.02g, KH
2PO
40.102g, K
2HPO
40.044g, NaCl 0.088g, CaCl
20.0065g, ZnSO
47H
2O 0.4mg, CuSO
45H
2O0.018mg, MnSO
4H
2O 2.7mg, boric acid 2.6mg, four water ammonium molybdate 1.7mg, pH 7.0--7.5,8 pounds/30min sterilization.With cultured fresh seeds, under aseptic condition, be inoculated in the above-mentioned triangular flask, inoculum size is 10%.27 ℃ of concussions were cultivated 6-9 hour, and adding 6% ethanol stimulates the amount that improves product, continued to cultivate 40-48 hour, and nutrient solution becomes garnet by little yellow and stops to cultivate, and collects culture.
Centrifugal (4000rpm) collects supernatant, regulates pH to 3.0--4.0 with 1M hydrochloric acid, adds the ethyl acetate of 1/3 fermentating liquid volume in separating funnel, and fully mixing is placed 20min under the room temperature, treat the solution layering after, collect the top ethyl acetate.Fermented liquid is so extracted three times repeatedly, merges the acetic acid ethyl acetate extract of collecting, and puts into matrass, and rotary evaporation concentrates in 37-40 ℃ water-bath, obtains wine-colored product.
Product is dissolved in the ethanol, and concentration is 50-100 μ g/mL.Get 10-20 μ L point sample in silica-gel plate (GF
254) on, make object of reference with the fermented product extract and the JB that do not add the ethanol stimulation, dry back: methyl alcohol: ascending development in the mixing solutions of acetate (95: 10: 0.2) at chloroform, when developping agent goes upward to isolated edge 1cm place, from chromatography cylinder, take out silica-gel plate, dry back is observed, because the compound of preparation has color, chromatography spot or band are at silica-gel plate (GF
254) on can see.Desired product is scraped from silica-gel plate, be immersed in the dehydrated alcohol, place 30min under the room temperature, centrifugal (5000 commentaries on classics/min), collect supernatant, extract repeatedly three times, merge the ethanolic soln of collecting, rotary evaporation concentrates and is under the condition that nitrogen exists that ethanolic soln is air-dry, obtains the wine-colored angle anthracene nucleus polyketide JF of purifying.
Angle anthracene nucleus polyketide JF to the purifying that obtains among the embodiment 1, carry out following analysis:
1. under the 313nm wavelength, the residence time that high pressure liquid chromatography detects this compound is 12.7min, about 15.4min of the residence time of JB (Fig. 3).
2. electron spray ionisation source (ESI) high resolution mass spectrum determines that molecular formula is C
33H
30NO
9, molecular weight is 583.Positive pulse atmospheric pressure chemical ionization source (APCI) spectrum is shown: 584[M+H]
+, 540[M+H-CO
2]
+, 454[M+H-digitoxose]
+, 410[M+H-digitoxose-CO
2], 306[M+H-digitoxose-C
9H
8O
2].
3. INFRARED SPECTRUM is shown, IR (KBr): v=3468 (br, m), 2928 (br, w), 1804,1684 (sh, s), 1777,1516 (sh, w), 1454 (sh, m), 1381 (sh, w), 1273 (sh, w), 1211 (sh, s), 1136 (sh, s), 970 (sh, and m) 843 (sh, m), 804 (sh, m), 726 (sh, m) cm
-1
4. UV spectrum shows, UV/Vis (Methanol): λ max (ε)=497 (1000), 393 (1400), 310 (9300), 289 (sh), 239 (9100), 211 (13000) nm.
5.
1H-NMR composes (400MHz, d
6-acetone, TMS) and
13C-NMR composes (100MHz, d
6-acetone, TMS) analysis revealed, this compound have two kinds of interconvertible configurations, as shown in Figure 2, are respectively structure I (1S, 3aS; 60%), structure I I (1S, 3aR; 40%), the results are shown in Table 1.
The new angle of table 1. anthracene nucleus polyketide JF nucleus magnetic resonance
Structure I (1S, 3aS; 60%)
| The position | Chemical shift δ 1H ????[ppm] | Even summation (J[Hz]) | Chemical shift δ 13C [ppm] | Long-range coupling spectrum HMBC | Close spectrum COSY with nuclear phase |
| ????1 | ????5.65 | ????dd(5，3) | ????61.8 | ???1’α，1’β | |
| ????2 | ????171.9 |
| ????3a | ????6.08 | ????s | ????88.0 | ???3b，7a | |
| ????3b | ????119.6 e | ||||
| ????4 | ????6.06 | ????s(br) | ????113.8 | ???3a，3b，5- ???CH 3，7a | ????6 |
| ????5 | ????142.9 | ||||
| ????5-CH 3 | ????2.22 | ????s | ????21.1 | ???4，5，6 | |
| ????6 | ????6.69 | ????s(br) | ????119.9 | ???4，5- ???CH 3，7，7a | ????4 |
| ????7 | ????154.9 | ||||
| ????7-OH | ????10.19 | ????s(br) | |||
| ????7a | ????112.1 | ||||
| ????7b | ????135.4 e | ||||
| ????8 | ????184.2 | ||||
| ????8a | ????135.9 | ||||
| ????9 | ????7.95 | ????dd(7.5，1) | ????121.4 | ???8，12a | ????10 |
| ????10 | ????7.89 | ????dd(8.5，7.5) | ????137.3 | ???8a，9，11，12 | ????9，11 |
| ????11 | ????7.70 | ????dd(8.5，1) | ????120.9 | ???9，12a | ????10 |
| ????12 | ????157.2 | ||||
| ????12a | ????118.6 | ||||
| ????13 | ????181.7 | ||||
| ????13a | ????131.5 | ||||
| ????1’α | ????3.26- ????3.36 | ????m* | ????39.2 | ???3’，7’ | ????1 |
| ????β | ????3.26- ????3.36 | ????m* | ???3’，7’ | ????1 | |
| ????2’ | ????136.6 | ||||
| ????3’ | ????7.36 | ????m* | ????130.8 | ???5’，7’ | ????4’ |
| ????4’ | ????7.21- ????7.31 | ????m* | ????129.8 | ???6’ | ????3’，5’ |
| ????5’ | ????6.90 | ????m* | ????127.9 | ????4’，6’，7’ |
| ???6’ | ????7.21- ????7.31 | ????m* | ????129.8 | ????4’ | ????5’ |
| ???7’ | ????6.79 | ????m* | ????130.6 | ????5’ | |
| ???1” | ????6.16 | ????d(3.5) | ????95.8 | ????3” | ????2” ax |
| ???2” ax | ????2.29 | ????ddd ????(15.5，3.5，3 ????) | ????36.0 | ????3” | ????1”，2” eq |
| ??? eq | ????2.44 | ????ddd ????(15.5，3.5，1 ????) | ????3”，4” | ????2” ax | |
| ???3” | ????4.15 | ????m | ????67.0 | ????1” | ????4” |
| ???4” | ????3.23 | ????dd(10，3.5) | ????73.3 | ????5”-CH 3 | ????3”，5” |
| ???5” | ????3.77 | ????dq(10，6) | ????66.7 | ????5”-CH 3 | ????4”，5”-CH 3 |
| ???5”-CH 3 | ????1.17 | ????d(6) | ????18.3 | ????4”，5” | ????5” |
Structure I I(1S, 3aR) 40%
| The position | Chemical shift δ 1H[ppm]δ | Even summation (J[Hz]) | Chemical shift δ 13C ????[ppm] | Long-range coupling spectrum HMBC | Close spectrum COSY with nuclear phase |
| ????1 | ????5.68 | ????dd(7，3.5) | ????61.0 | ????3a，2’ | ??1’α，1’β |
| ????2 | ????171.0 | ||||
| ????3a | ????5.93 | ????s | ????87.9 | ||
| ????3b | ????121.3 e1 | ||||
| ????4 | ????6.67 | ????s(br) | ????116.1 | ????5-CH 3，7a | ??6 |
| ????5 | ????142.5 | ||||
| ????5-CH 3 | ????2.31 | ????s | ????21.1 | ????4，5，6 | |
| ????6 | ????6.80 | ????s(br) | ????121.5 | ????4，5-CH 3，7a | ??4 |
| ????7 | ????155.2 |
| ????7-OH | ????10.86 | ????s | |||
| ????7a | ????112.0 | ||||
| ????7b | ????136.3 e1 | ||||
| ????8 | ????182.5 | ||||
| ????8a | ????136.3 | ||||
| ????9 | ????7.88 | ????m* | ????121.9 | ???8，8a | ????10 |
| ????10 | ????7.87 | ????m* | ????137.5 | ???8a，9，11，12 | ????9，11 |
| ????11 | ????7.67 | ????m* | ????121.2 | ???9，10 | ????10 |
| ????12 | ????156.5 | ||||
| ????12a | ????120.0 | ||||
| ????13 | ????182.8 | ||||
| ????13a | ????128.6 | ||||
| ????1’α | ????3.41 | ????m* | ????36.6 | ????1 | |
| ????β | ????3.47 | ????m* | ???3’，7’ | ????1 | |
| ????2’ | ????134.8 | ||||
| ????3’ | ????7.36 | ????m* | ????130.8 | ???5’，7’ | ????？ |
| ????4’ | ????7.21-7.31 | ????m* | ????129.6 e2 | ???6’ | ????？ |
| ????5’ | ????6.83 | ????m* | ????128.5 | ???2’ | ????？ |
| ????6’ | ????7.21-7.31 | ????m* | ????129.7 e2 | ???4’ | ????？ |
| ????7’ | ????6.82 | ????m* | ????128.6 | ???2’ | ????？ |
| ????1” | ????6.07 | ????d(3.5) | ????96.4 | ???2”，3” | ????2” ax |
| ????2” ax | ????2.31 | ????ddd(15.5， ????3.5，3) | ????36.2 | ????1”，2” ex | |
| ???? eq | ????2.47 | ????ddd(15.5， ????3.5，1.5) | ???3”，4” | ????2” ax | |
| ????3” | ????4.15 | ????m | ????67.3 | ????4” | |
| ????4” | ????3.28 | ????dd ????(10，3.5) | ????73.4 | ???5”-CH 3 | ????3”，5” |
| ????5” | ????3.88 | ????dq(10，6) | ????66.7 | ???5”-CH 3 | ????4”，5”- ????CH 3 |
| ?5”-CH 3 | ????1.20 | ????d(6) | ????18.4 | ????4”，5” | ????5” |
E is variable,
*High order effect
Embodiment 3_ antibacterial activity test
Fixed new polyketone angle anthracycline compound carries out antibacterial activity test in the example 2.The spore suspension 1ml (10 of bacterial strain to be measured
5CFU), add the soft agar of 19ml 0.6%, mixing is paved into flat board, and the scraps of paper that will contain 100ug JB analogue are flattened on the flat board, cultivates the back and surveys antibacterial circle diameter.By under tabulate 2 as seen, new angle anthracycline compound has stronger restraining effect to gram-positive bacteria.
The anti-microbial activity of the new angle of table 2. part anthracene nucleus polyketide
Tested of the influence of new angle anthracycline compound with mtt assay, the results are shown in down tabulation 3 growth of tumour cell.By seeing Table 3 as seen, these angle anthracycline compounds can suppress the growth of oncocyte, and wherein JF has better antitumor activity, and the microbiotic volumetric molar concentration (IC50) that suppresses the growth of 50% lung carcinoma cell is 12.4 μ m, and anti-tumor activity is higher than JB, and JB is 21.8 μ m.
The anti-tumor activity of the new angle of table 3. part anthracene nucleus polyketide
Annotate: IC50[μ m]: the microbiotic volumetric molar concentration that suppresses 50% growth of tumour cell.
In with the substratum of embodiment 1, add a kind of amino acid and carry out microbial fermentation, as: add Threonine, one of Serine or other aromatic series and heterocycle family amino acid substituted benzene L-Ala.Carry out microbial fermentation cultivation and extraction, purifying of antibiotics according to the method among the embodiment 1 respectively; Carry out product analysis according to the method among the embodiment 2, prove JT, JS has structure as shown in Figure 2; Detect anti-microbial activity according to the method among the embodiment 3; According to the influence of the detection of the method among the embodiment 4 to growth of tumour cell.Because add dissimilar amino acid in substratum, the result obtains the meta-bolites difference of streptomyces venezuelae, obtains the new angle anthracene nucleus polyketide of different molecular structures: new angle anthracene nucleus polyketone JT, the new new angle of anthracene nucleus polyketone, angle anthracene nucleus polyketone JS.The residence time difference (Fig. 3) that their high pressure liquid chromatography detects.The new angle of above-mentioned different aminoacids synthetic its structure of anthracene nucleus polyketide as shown in Figure 2.
Claims (8)
1, the manufacture method of the new angle of a kind of new antibiotic anthracene nucleus polyketone analogue, this new angle anthracene nucleus polyketide has the structural formula that is shown below:
Wherein R represents Phe, Ser, the amino acid whose side chain of Thr and other aromatic series and the heterocycle same clan, this method is included in and cultivates streptomyces venezuelae (Streptomyces venezuelae) ISP5230 ATCC NO.10712 in semi-lactosi-amino acid minimal medium earlier, from the supernatant liquor of its culture, pass through the conventional method of extracting of organic compound again, utilize compound microbiotic and impurity in solubleness, ion avidity, adsorptive power, the difference of molecular weight, centrifugation, membrane sepn, organic solvent extraction, ion-exchange or absorption are extracted and are made new angle anthracene nucleus polyketone analogue.
2. method according to claim 1 is collected culture supernatants, centrifugal back ethyl acetate extraction, and extract purifying, organic solvent dissolution, rotary evaporation on silica-gel plate concentrate and make new angle anthracene nucleus polyketone analogue.
3. method according to claim 1, its composition of semi-lactosi-amino acid minimal medium is matrix 100ml with water: semi-lactosi 1.8g, amino acid 30mM, MgSO
47H
2O0.02g, KH
2PO
40.102g, K
2HPO
40.044g, NaCl 0.088g, CaCl
20.0065g, ZnSO
47H
2O0.4mg, CuSO
45H
2O 0.018mg, MnSO
4H
2O 2.7mg, boric acid 2.6mg, four water ammonium molybdate 1.7mg, pH7.0-7.5, above-mentioned amino acid are that Phe, Thr, Ser and other aromatic series and heterocycle family are amino acid whose a kind of.
4. method according to claim 1, the R in the new angle anthracene nucleus polyketide structural formula shown in it is that Serine, Threonine, phenylalanine replace or one of them side-chain radical of other aromatic series and heterocycle family amino acid replaces.
5. method according to claim 4, the R in the new angle anthracene nucleus polyketide structural formula shown in it is the new angle anthracene nucleus polyketone JS that is of Serine replacement; That Threonine replaces is new angle anthracene nucleus polyketone JT; That phenylalanine replaces is new angle anthracene nucleus polyketone JF..
6. its new angle anthracene nucleus polyketone JF according to claim 5, new angle anthracene nucleus polyketone JT, new angle anthracene nucleus polyketone JS have structure as shown in Figure 2 respectively.
7. method according to claim 1, R in the new angle anthracene nucleus polyketide structural formula shown in it is the new angle anthracene nucleus polyketide that one of them side-chain radical of other aromatic series and heterocycle family amino acid replaces, and removes them and has same structure shown in claim 1 outward respectively according to separately aminoacid replacement R.
8. method according to claim 1 is at the clinical anti-G of preparation
+Application in the new angle anthracene nucleus polyketone medicine of the growth of bacterium medicine and tumour cell.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100465277C (en) * | 2005-07-01 | 2009-03-04 | 中国科学院上海有机化学研究所 | Chlorothricin biological synthesis gene cluster and its uses |
| CN102558122A (en) * | 2011-12-22 | 2012-07-11 | 中国科学院微生物研究所 | Compound resisting multiple drug-resistant bacteria, and preparation method and application thereof |
| CN104177609A (en) * | 2012-12-28 | 2014-12-03 | 张雅珍 | New compound containing anthracycline antibiotic structure, and preparation method and use thereof |
| CN110885281A (en) * | 2019-11-05 | 2020-03-17 | 山东大学 | Tetracyclic diterpenoid compounds and preparation method and application thereof |
| CN116199564A (en) * | 2023-03-02 | 2023-06-02 | 山东大学 | Novel diterpenoid compound and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2091389A1 (en) * | 1993-03-05 | 1994-09-06 | Stephen W. Ayer | Polyketide antibiotics from streptomyces venezuelae |
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2003
- 2003-12-16 CN CNB200310122330XA patent/CN100387609C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100465277C (en) * | 2005-07-01 | 2009-03-04 | 中国科学院上海有机化学研究所 | Chlorothricin biological synthesis gene cluster and its uses |
| CN102558122A (en) * | 2011-12-22 | 2012-07-11 | 中国科学院微生物研究所 | Compound resisting multiple drug-resistant bacteria, and preparation method and application thereof |
| CN104177609A (en) * | 2012-12-28 | 2014-12-03 | 张雅珍 | New compound containing anthracycline antibiotic structure, and preparation method and use thereof |
| CN104177609B (en) * | 2012-12-28 | 2018-08-17 | 张雅珍 | Compound and preparation method containing anthracycline antibiotic structure and purposes |
| CN110885281A (en) * | 2019-11-05 | 2020-03-17 | 山东大学 | Tetracyclic diterpenoid compounds and preparation method and application thereof |
| CN116199564A (en) * | 2023-03-02 | 2023-06-02 | 山东大学 | Novel diterpenoid compound and preparation method and application thereof |
| CN116199564B (en) * | 2023-03-02 | 2024-03-29 | 山东大学 | Novel diterpenoid compound and preparation method and application thereof |
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| CN100387609C (en) | 2008-05-14 |
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