CN108623607A - Polycyclic compounds of macrolactams containing tetramic acid of 5,5,6- and its preparation method and application - Google Patents
Polycyclic compounds of macrolactams containing tetramic acid of 5,5,6- and its preparation method and application Download PDFInfo
- Publication number
- CN108623607A CN108623607A CN201710181976.7A CN201710181976A CN108623607A CN 108623607 A CN108623607 A CN 108623607A CN 201710181976 A CN201710181976 A CN 201710181976A CN 108623607 A CN108623607 A CN 108623607A
- Authority
- CN
- China
- Prior art keywords
- optionally
- compound
- acid
- formula
- methanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
5,5,6 polycyclic compounds of Macrocyclic lactams containing tetramic acid and its preparation method and application.The 5,5,6 polycyclic compound of macrolactams containing tetramic acid can be used as tumor cell proliferation inhibitor or tumor cytotoxicity agent or aspergillus fumigatus growth inhibitor.
Description
Technical field
The present invention relates to polycyclic compounds of macrolactams containing tetramic acid of 5,5,6- and its preparation method and application.
Background technology
《Chinese residents nourishment and chronic disease status report (2015)》It points out, it is dead in national residents chronic disease in 2012
Rate is 5,33/,100,000, accounts for the 86.6% of total death toll.Based on cardiovascular and cerebrovascular diseases, cancer and chronic respiratory disease extremely
Cause, accounts for the 79.4% of total death, and wherein cancer mortality is that 144.3/10 ten thousand (first five position is lung cancer, liver cancer, gastric cancer, food respectively
Road cancer, colorectal cancer).And be published within 2016 mono- report of Cancer Journal for Clinicians point out (2016,
66:115-132), in China, cancer has become first of many disease causes of the death, and morbidity and mortality persistently rise, in 2015 years
State in advance in respect of 429.2 ten thousand new hair tumor cases and 281.4 ten thousand deaths, the whole world almost 22% new cancer cases and
27% cancer mortality case is in China.Cancer has become very important public health problem, and Chinese population radix is numerous
So that the data of compatriots are of great significance to global cancer prevention and control.
With the continuous development of science and technology and medical level, the method that the mankind explore a variety for the treatment of tumours, main point
Multidisciplinary synthesis treatment etc. is intervened for operation, chemotherapy, radiotherapy, traditional Chinese medicine.Wherein, chemotherapy is the important means for the treatment of cancer patient
One of.Chemotherapy is to kill tumour cell using chemicals, inhibit the growth and breeding of tumour cell and promote point of tumour cell
A kind of therapeutic modality changed, almost all of chemotherapeutics can cause hepatic disorder, less serious case to may occur in which dysfunction of liver, suffer from
Person may occur in which uncomfortable liver area, can notably lead to toxic hepatitis；Some chemotherapeutic large dosages can cause kidney function damage and occur
Pain in the back, kidney area discomfort etc., and due to the poor selectivity of chemotherapeutics, chemotherapeutic is normal thin while killing tumour cell
Born of the same parents and immunocyte are also largely killed, and side effect and toxic action are very big.Therefore, a kind of safe and efficient there is an urgent need to research and develop
Antitumor drug will not injure the normal cell to sustain life, significantly when effectively killing the specific tumors cell of patient's body
Improve the survival rate and life quality of patient.
The polycyclic compound of macrolactams containing tetramic acid (the Polycyclic Tetramate of 5,5,6-
Macrolactams, PTMs) most Streptomyces phaeochromogenes were isolated from earlier than 1972
var.ikaruganensis Sakai(Jomon K,Kuroda Y,Ajisaka M,Sakai H.A new antibiotic,
ikarugamycin.J.Antibiot.1972,25:271-280), such compound has novel design feature comprising：
1 uncommon four amino acids residue, more than one and cyclic structure and a Macrocyclic lactams parent nucleus.It not only has been assigned and has much
Challenge structure, PTMs also show many potential effective actives, especially antifungal activity (Sugawara T, Chiao
YF,Kaneda Y,Ando T,Adachi T.AFA0520from Streptomyces species,and
pharmaceuticals and fungicides containing it.Jpn.Kokai Tokkyo Koho,JP
10310584A 19981124.Hashidoko Y,Tahara S,Nakayama T.Xanthobaccin
antibiotics.PCT Int.Appl.(2000),WO 2000020418A1 20000413).In addition to this, PTMs classes chemical combination
Object also has antitumor activity to report (Bae MA, Yamada K, Uemura D, Seu JH, Kim YH.Aburatubolactam
C,a novel apoptosis-inducing substance produced by marine Streptomyces
sp.SCRC A-20.J.Microbiol.Biotechnol.1998,8(5):455-460).In this regard, chemist, biologist,
Drug scholar never stops the exploration to such compound.
Invention content
The drug that the present inventor is dedicated to the polycyclic compounds of macrolactams containing tetramic acid of 5,5,6- is opened
On the one hand hair finds that such compound has antitumor activity and preferable selectivity.On the other hand, such compound is found
There is good inhibitory activity to aspergillus fumigatus growth.
A kind of compound of formula I of present invention offer, its pharmaceutically acceptable salt or prodrug,
Preferably, the compound of formula I is Formulas I ' compound,
Formulas I and Formulas I ' in,
R1Selected from-H ,-OH ,=O or R1' O-, wherein R1' it is alkyl；R2Selected from-H ,-OH or R2' O-, wherein R2' it is alkane
Base；
R3、R4Composition-O- together；Alternatively, R4For H, R3Selected from-H ,-OH, R'O- or R " COO-, wherein R', R " are respectively only
It is on the spot alkyl；
R5、R6Composition-O- or singly-bound together；Alternatively, R5、R6It is each independently selected from-H or-OH；
R7、R8Composition-O- or singly-bound together；Alternatively, R7For H, R8Selected from alkyl or alkenyl；
R9For alkyl；
R10、R11Composition-O- or singly-bound together；Alternatively, R10、R11It is each independently selected from-H or-OH；
R12、R13It is each independently selected from-H or alkyl；
Optionally, the alkyl is C1~C20Branched-chain or straight-chain alkyl, or be C1~C16Branched-chain or straight-chain alkyl, or
For C1~C8Branched-chain or straight-chain alkyl, or be C1~C4Branched-chain or straight-chain alkyl；The alkenyl is C2~C20Branch or straight chain alkene
Base, or be C2~C16Branch or straight-chain alkenyl, or be C2~C8Branch or straight-chain alkenyl, or be C2~C4Branch is straight
Alkenyl.
Optionally, above-mentioned compound of formula I, its pharmaceutically acceptable salt or prodrug are Formula II compound, it pharmaceutically may be used
The salt or prodrug of receiving,
Preferably, the Formula II compound is Formula II ' compound,
Formula II and Formula II ' in,
R1Selected from-OH or=O；R2Selected from-H or-OH；R3Selected from-H ,-OH or R " COO-, wherein R " is alkyl, the alkane
Base is C1~C20Branched-chain or straight-chain alkyl, or be C1~C16Branched-chain or straight-chain alkyl, or be C1~C8Branch or straight chain alkane
Base.
Optionally, above-mentioned compound of formula I, its pharmaceutically acceptable salt or prodrug, selected from following compounds, its pharmacy
Upper acceptable salt or prodrug,
Optionally, above-mentioned compound of formula I, its pharmaceutically acceptable salt or prodrug, wherein described pharmaceutically acceptable
Salt is the salt that the compound of formula I is formed with following compound：Hydrochloric acid；Sulfuric acid；Phosphoric acid；Formic acid；Acetic acid；Propionic acid；Lactic acid；Lemon
Acid；Tartaric acid；Succinic acid；Fumaric acid；Maleic acid；Tussol；Malic acid；Camphorsulfonic acid；The pharmaceutically acceptable prodrug
The prodrug being combined into including the compound of formula I and pharmaceutically acceptable carrier；Optionally, described pharmaceutically acceptable
Carrier includes：Three ester of phosphoglycerol, macrogol ester, polyethylene glycol amide, polyglycol ether.
The present invention also provides a kind of above-mentioned compound of formula I, the preparation method of its pharmaceutically acceptable salt or prodrug,
In, this method includes：
The different wall actinomyces A.cyanogriseus WH1-2216-6 of fermented and cultured, the fermentation that the fermented and cultured is obtained
Liquid carries out isolating and purifying obtained product；Optionally, it using the product isolated and purified as raw material, carries out semi-synthetic reaction and is made,
Optionally, the fermented and cultured includes：Different wall actinomyces A.cyanogriseus WH1-2216-6 are trained in seed
It supports and is cultivated in base, is inoculated into fermentation medium, cultivated, tunning is made in fermentation；
Optionally, the seed culture medium includes：Carbon source, nitrogen source, sodium chloride-containing aqueous solution；Optionally, the seed training
Foster base includes：Peptone, glycerine, analysis for soybean powder, soluble starch, calcium carbonate, seawater；Optionally, the seed culture medium is egg
White 15 parts by weight of peptone, 15 parts by weight of glycerine, 5 parts by weight of analysis for soybean powder, 15 parts by weight of soluble starch, 2 parts by weight of calcium carbonate and old
1000 parts by weight of seawater, pH=7.8；
Optionally, the fermentation medium includes：Soluble starch, glycerine, peptone, calcium carbonate, macroporous absorbent resin
And Chen Haishui；Optionally, the fermentation medium is 20 parts by weight of soluble starch, 20 parts by weight of glycerine, 20 weight of peptone
Part, 1000 parts by weight of 2 parts by weight of calcium carbonate, 50 parts by weight of XAD-16 macroporous absorbent resins and Chen Haishui, pH=7.5；
Optionally, it is described isolate and purify including：The zymotic fluid is extracted with organic solvent, after organic phase concentration, is added
Acid solution, organic solvent extraction remove organic phase, and water phase adds alkali to adjust pH, then is extracted with organic solvent, concentrates organic phase,
Obtain alkaloid moiety, the decompression silica gel column chromatography gradient elution separation of gained alkaloid moiety, the inverted silicagel column of elution fraction
Chromatography, gel column chromatography, half preparative separation of efficient liquid phase；Optionally, each extraction is each independently selected from second with organic solvent
Acetoacetic ester, dichloromethane, chloroform, petroleum ether；Optionally, the acid solution is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid；Optionally
The alkali is selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate；Optionally, described to depressurize washing for silica gel chromatographic column
De- agent is selected from petroleum ether, dichloromethane, methanol, methylene chloride-methanol mixed liquor, water；Optionally, the gel column chromatography is washed
De- agent is selected from methanol, methylene chloride-methanol mixed liquor；Optionally, the semipreparative eluant, eluent of the efficient liquid phase is methanol-trifluoro
Acetic acid mixture；
Optionally, carrying out semi-synthetic reaction step as raw material using the product isolated and purified includes：Product knot will be isolated and purified
The epoxidation reaction of double bond, dihydroxylation reaction, hydration reaction in structure, the methylation reaction of NH-, OH-, OH- acylation reactions, oxidation
Reaction, carbonyl O=reduction reactions or their composite reaction；
Optionally, the compound of formula I is compound 1-6；
Optionally, the compound 1-6 preparation methods include：By different wall actinomyces A.cyanogriseus WH1-2216-
6 cultivate in seed culture medium, are inoculated into fermentation medium, and shaking table culture fermentation obtains fermentate, fermentate acetic acid second
Ester extracts, and organic phase is concentrated to give crude extract, HCl solution is added into crude extract, extracted with dichloromethane, and water phase is adjusted with ammonium hydroxide
It is extracted to pH=8.0, then with dichloromethane, concentration organic phase obtains alkaloid moiety, gained alkaloid moiety decompression silicagel column
Chromatographic isolation, successively with petroleum ether, dichloromethane, methylene chloride-methanol (v/v, 100:1,50:1,25:1,15:1,10:1,5:
Isosorbide-5-Nitrae:1,2:1,1:1,0:1) it is that solvent carries out gradient elution：Wherein dichloromethane in methylene chloride-methanol eluant, eluent:Methanol=
5:The inverted silica gel column chromatography of 1 (v/v) elution fraction detaches, with ‰ trifluoroacetic acid aqueous solution=70 of methanol -1.5:30 (v/v) are washed
It is de-, obtain compound 6；Dichloromethane in methylene chloride-methanol eluant, eluent:Methanol=4:1 (v/v) elution fraction is through Sephadex
The separation of LH20 gel column chromatographies is eluted with methanol, and obtained component is again through half preparative separation of efficient liquid phase, with ‰ trifluoro of methanol -1.5
Acetic acid aqueous solution=75:25 (v/v) are eluted, and obtain compound 1-5.
The present invention also provides a kind of pharmaceutical compositions comprising above-mentioned compound of formula I, its pharmaceutically acceptable salt or preceding
At least one of medicine and pharmaceutically acceptable auxiliary material.The pharmaceutically acceptable auxiliary material can be the auxiliary of this field routine
Material, optionally, the auxiliary material are selected from diluent, filler, adhesive, wetting agent, sorbefacient, surfactant, absorption
Carrier or lubricant.
Optionally, the dosage form of described pharmaceutical composition includes solid formulation and liquid formulation；Optionally, the pharmaceutical composition
The dosage form of object includes oral preparation, ejection preparation, percutaneous preparation；Optionally, the dosage form of described pharmaceutical composition includes tablet, glue
Wafer, pulvis, granule, pastille, suppository, oral solution, sterile parenteral suspension, injection；Optionally, the injection includes freeze-drying
Powder-injection.The drug of above-mentioned dosage form can be prepared according to the conventional method of pharmaceutical field.
The present invention also provides above-mentioned compound of formula I, its pharmaceutically acceptable salt or prodrug or aforementioned pharmaceutical compositions
Purposes in the preparation of antitumor drugs；Optionally, the antitumor drug is tumor cell proliferation inhibitor or tumour cell
Kill agent；Optionally, the antitumor drug does not include anti-human human umbilical vein endothelial cell drug, anti-human liver cancer cell HepG2 medicines
Object, anti-human breast cancer cell line Bcap-37 drug and anti-human leukaemia cell P-388 drugs；Optionally, the antitumor drug is anti-
Human colon cancer cell HCT-116 drugs, anti-human peripheral blood leukemia T cell Jurkat drugs, anti-human pancreatic cancer cell PANC-1
Drug, anti-human pancreatic cancer cell BXPC-3 drugs or anti-human chronic marrow original K562 Leukaemia drug.
The present invention also provides above-mentioned compound of formula I, its pharmaceutically acceptable salt or prodrug or aforementioned pharmaceutical compositions
Purposes in preparing aspergillus fumigatus growth inhibitor or anti-aspergillus fumigatus drug.
The present invention also provides above-mentioned compound of formula I, its pharmaceutically acceptable salt or prodrug as inhibit cell Proliferation or
Inhibit the purposes in the low molecule bioprobe of aspergillus fumigatus growth.Optionally, the low molecule bioprobe can also include medicine
Acceptable carrier, excipient or auxiliary material on；The carrier, excipient or auxiliary material, which can be low molecule bioprobe, routinely to be made
Carrier, excipient or auxiliary material.
The present invention also provides a kind of low molecule bioprobe kits comprising above-mentioned low molecule bioprobe, Yi Jiren
The biocompatible media of choosing；Optionally, one kind in methanol, water, dimethyl sulfoxide (DMSO) of the biocompatible media or
It is a variety of.
It is Actinoalloteichus cyanogriseus WH1- to prepare the bacterial strain used in formula Compound I
2216-6, culture presevation number：CCTCC M 209277, preservation date：On November 28th, 2009, preservation place：It is Chinese military
The Chinese, Wuhan University, China typical culture collection center preservation.The details of actinomycetes strain WH1-2216-6 have been reported
In (Fu P, Wang S, Hong K, Li X, Liu P, Wang Y, Zhu W.Cytotoxic bipyridines from the
marine-derived actinomycete Actinoalloteichus cyanogriseus WH1-2216-
6.J.Nat.Prod.2011,74,1751-1756) in document.The application is not related to biological deposits.
The method that fermented microorganism prepares the compounds of this invention, which can be used, other any can produce the compounds of this invention
Microorganism, as long as the microorganism that can produce the compounds of this invention can be used as production, bacterium is used to prepare the compounds of this invention.
The compounds of this invention has preferable antitumor activity, has significant inhibiting effect to tumor cell proliferation, together
When it is weaker to normal cell growth inhibiting effect, there is preferable selectivity.
On the other hand, the compounds of this invention has good inhibiting effect to aspergillus fumigatus growth, to aspergillus fumigatus growth inhibition
The exploitation of agent has important directive significance.
Specific implementation mode
The present invention is illustrated by the following examples, but the scope of the present invention is not limited to following implementations
Example.
【Preparation example】
(1) prepared by compound 1-6
Fermented and cultured：By different wall actinomyces A.cyanogriseus WH1-2216-6 in seed culture medium culture 5 days, connect
In kind to 150mL fermentation mediums, shaking table culture is fermented 12 days, and zymotic fluid is obtained；Wherein, seed culture medium：Peptone 15g,
Glycerine 15g, analysis for soybean powder 5g, soluble starch 15g, calcium carbonate 2g, pH=7.8, Chen Haishui 1L；Fermentation medium：Solubility is formed sediment
Powder 20g, glycerine 20g, peptone 20g, calcium carbonate 2g, XAD-16 macroporous absorbent resin 50g, Chen Haishui 1L, pH=7.5.
It isolates and purifies：The isometric ethyl acetate of above-mentioned zymotic fluid is extracted three times, it is dense after combined ethyl acetate extract liquor
Contract to obtain crude extract, and 3% HCl solution of 50mL is added into every gram of crude extract, stirs, and stands, and is extracted with isometric dichloromethane
It taking three times, water phase is adjusted to pH=8.0 with ammonium hydroxide, then is extracted with dichloromethane, and concentration organic phase obtains 35.0g alkaloid moieties,
Alkaloid moiety decompression silica gel column chromatography separation, successively with petroleum ether, dichloromethane, methylene chloride-methanol (v/v,
100:1,50:1,25:1,15:1,10:1,5:Isosorbide-5-Nitrae:1,2:1,1:1,0:1) it is that solvent carries out gradient elution：Wherein dichloromethane
Dichloromethane in alkane-methanol eluant, eluent:Methanol=5:The inverted silica gel column chromatography of 1 (v/v) elution fraction detaches, with methanol-
1.5 ‰ trifluoroacetic acid aqueous solution=70:30 (v/v) are eluted, and obtain compound 6 (9.5mg)；In methylene chloride-methanol eluant, eluent
Dichloromethane:Methanol=4:1 (v/v) elution fraction is detached through Sephadex LH20 gel column chromatographies, is eluted with methanol, gained
Component is again through half preparative separation of efficient liquid phase, with ‰ trifluoroacetic acid aqueous solution=75 of methanol -1.5:25 (v/v) are eluted, and are changed
Close object 1 (15.0mg, retention time tR9.7min), 2 (24.0mg, retention time tR14.4min), 3 (8.2mg, retention time
tR16.2min), 4 (25.0mg, retention time tR19.2min), 5 (5.0mg, retention time tR 26.4min)。
Compound 1, the unformed powder of light red, HRESIMS：527.2747[M+H]+(calcd for C29H39N2O7,
527.2752)；[α]D 21+20(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)210(3.99),326(3.55)nm；CD(c
0.05,CH3OH)λmax(Δε)221(+3.2),249(-3.8),328(+1.7)nm；IR(KBr)νmax 3589,3570,3535,
3483,3402,3205,2915,2846,1655,1637,1509,1474,1024,889cm-1；1H and13C NMR datas are shown in Table 1.
Compound 2, the unformed powder of light red, ESIMS：513.3554[M+H]+(calcd for C29H41N2O6,
513.29)；[α]D 21+21(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)212(4.29),314(3.99)nm；CD(c
0.05,CH3OH)λmax(Δε)221(+10.7),249(-15.0),328(+5.2)nm；IR(KBr)νmax 3676,3650,
3630,3621,3569,3402,1655,1638,1596,1561,1509,1459,1033,845cm-1；1H and13C NMR datas
It is shown in Table 1.
Compound 3, the unformed powder of light red, ESIMS：497.3828[M+H]+(calcd for C29H41N2O5,
497.29)；[α]D 21+26(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)212(4.04),320(3.73)nm；CD(c
0.05,CH3OH)λmax(Δε)221(+9.6),249(-12.7),328(+4.6)nm；IR(KBr)νmax 3753,3713,
3692,3589,3402,2366,1701,1654,1596,1509,1459,1022,799cm-1；1H and13C NMR datas are shown in Table 1.
Compound 4, the unformed powder of light red, ESIMS：511.3254[M+H]+(calcd for C29H39N2O6,
511.27)；[α]D 21+15(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)206(4.05),316(3.63)nm；CD(c
0.05,CH3OH)λmax(Δε)221(+14.4),249(-12.7),328(+3.3)nm；IR(KBr)νmax 3752,3736,
3713,3670,3630,3621,3589,3569,3401,1655,1638,1544,1509,1459,1022,792cm-1；1H and13C NMR datas are shown in Table 2.
Compound 5, the unformed powder of light red, ESIMS：495.3551[M+H]+(calcd for C29H39N2O5,
495.28)；[α]D 21+13(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)206(3.81),320(3.29)nm；CD(c
0.05,CH3OH)λmax(Δε)221(+4.4),249(-4.8),328(+1.4)nm；IR(KBr)νmax 3735,3651,3649,
3630,3621,3589,3446,3402,2953,2360,1647,1558,1541,1508,1457,1385,1207,1033,
806cm-1；1H and13C NMR datas are shown in Table 2.
Compound 6, the unformed powder of light red, ESIMS:533.3[M+Na]+(calcd for C29H38N2O6Na,
533.27), 509.2 [M-H]-(calcd for C29H37N2O6,509.2)；[α]D 21+14(c 0.15,CH3OH)；UV(CH3OH)
λmax(logε)219(3.9),322(3.7)nm；IR(KBr)νmax 3667,3645,3629,3618,3588,3572,3403,
1651,1644,1600,1561,1509,1459,1103,921cm-1；1H and13C NMR datas are shown in Table 2.
1. compound 1,2,3 of table1H and13C NMR datas
Note：Compound nuclear magnetic resonance spectroscopy (1H NMR) and carbon spectrum (13C NMR) respectively in the magnetic fields 500MHz and 125MHz frequency
With deuterated dimethyl sulfoxide (DMSO-d under rate6) solvent, tetramethylsilane (TMS) is used as to be scanned record as internal standard compound.
【Test example 1】Antitumor activity is tested
1, laboratory sample and experimental method
The preparation of sample solution：Test sample is that the compound 1-5 of preparation is detached in above-described embodiment 1.It is accurate to claim
Appropriate amount of sample is taken, the solution of required concentration is configured to methanol, for active testing.
The squamous subculture of cell line and cell：Active testing uses 5 plants of tumor cell lines, specially human colon cancer cell line
HCT-116 cells, human peripheral leukemia T cell Jurkat cell, human pancreatic cancer cell PANC-1, BXPC-3 cell, people
Chronic marrow original Leukemia Cell Lines K562 cells and 1 plant of Human normal hepatocyte system L-02 cell.Wherein human peripheral leukaemia
T cell Jurkat cell, human pancreatic cancer cell BXPC-3, Human normal hepatocyte system L-02 are thin
2. compound 4,5,6 of table1H and13C NMR datas
Note：Compound nuclear magnetic resonance spectroscopy (1H NMR) and carbon spectrum (13C NMR) respectively in the magnetic fields 500MHz and 125MHz frequency
With deuterated dimethyl sulfoxide (DMSO-d under rate6) solvent, tetramethylsilane (TMS) is used as to be scanned record as internal standard compound.
Born of the same parents system uses MTT model measurements；Human colon cancer cell line HCT-116, human pancreatic cancer cell PANC-1 cell lines,
The chronic marrow original Leukemia Cell Lines K562 of people uses SRB model measurements；Various cells are trained with the RPMI-1640 containing 10%FBS
Support base, the squamous subculture in the incubator that 37 DEG C are passed through 5% carbon dioxide.
Mtt assay：Dehydrogenase can be metabolized the bromination 3- (4,5- dimethylthiazoles) -2 of reduction yellow in living cells mitochondria,
5- diphenyltetrazolium bromides are the first a ceremonial jade-ladle, used in libation not soluble in water of bluish violet, first a ceremonial jade-ladle, used in libation number can measure its trap by microplate reader and ask
.Since the amount of first a ceremonial jade-ladle, used in libation is directly proportional to viable count, so the number of living cells can be found out according to trap, to understand drug
The ability of inhibition or killing tumor cell.When active testing, the test cell system of logarithmic growth phase, with fresh RPMI-
It is every milliliter 3 × 10 that 1640 culture mediums, which are configured to density,4The cell suspension of a cell is inoculated in by 100 μ L of every hole in 96 orifice plates,
After being cultivated 24 hours at 37 DEG C, the sample solution of 100 μ L various concentrations is added per hole, continues culture 72 hours.Then it is added
Culture solution is slowly poured out after continuing culture 4 hours and adds 150 μ L by IPMI-1640 solution (5mg/L) of the 20 μ L containing MTT
DMSO dissolves first a ceremonial jade-ladle, used in libation, its trap is measured at 540nm.The cell proliferation inhibition rate under each concentration is calculated according to the following formula
(IR%)：IR%=(ODBlank control-ODSample)/ODBlank control× 100%.Find out IC50。
Srb assay：According to cell growth rate, by the tumour cell (culture medium in exponential phase：Containing 10% new green tire
The RPMI-1640 culture mediums of cow's serum (FBS)；Cell density 3 × 104Cell/mL) with 180 holes μ L/ be inoculated in 96 holes culture
Plate, in 37 DEG C, 5%CO2Under the conditions of adherent growth 24 hours again plus 20 holes μ L/ of test sample, each concentration set four multiple holes.(sample
Product primary dcreening operation final concentration is set as 10 μM, tests IC50When with doubling dilution set 5~7 concentration gradients；Positive drug is 1 μ of adriamycin
M；Blank control is the culture medium for the respective concentration that equivalent is added).Tumour cell after dosing is in 37 DEG C, 5%CO2Under the conditions of after
Continuous culture 72 hours, then incline culture solution, and cell is fixed with 10% cold trichloroacetic acid (TCA), 4 DEG C place 1 hour after with steaming
Distilled water is washed 5 times, is spontaneously dried in air.Then the sulphonyl rhodamine B (SRB, Sigma) prepared by 1% glacial acetic acid is added
100 holes μ L/ of 4mg/ml solution are dyed 15 minutes in room temperature, remove supernatant, washed 5 times, be air-dried with 1% acetic acid.Finally plus
The Tris solution for entering 150 holes μ L/ measures trap OD values with microplate reader under 540nm wavelength.According to IR%=(ODBlank control-
ODSample)/ODBlank control× 100% formula calculates the cell proliferation inhibition rate (IR%) under each concentration.Find out IC50。
Selection index (Selection Index, SI) is test sample to normal cell strain growth inhibition CC50It is worth and to swollen
Tumor cell proliferation inhibits IC50The ratio of value can reflect selectivity, the safety of sample indirectly to a certain extent.
Calculation formula：SI=CC50(L-02 plants of normal cell)/IC50(tumor cell line)
2, experimental result
3 compound 1 of table is to each tumor cell line and normal cell strain cytotoxic activity IC50(μM) and selection index SI
| Cell line | 1 (IC of compound50/SIb) |
| HCT-116 | 5.7/41.4 |
| Jurkat | 7.5/31.5 |
| PANC-1 | 7.9/29.9 |
| BXPC-3 | 4.5/52.4 |
| L-02a | 235.9/- |
Note：a CC50；bSI：Select index=CC50(L-02 plants of normal cell)/IC50(tumor cell line).
Compound 1 is to HCT-116, Jurkat, BXPC-1, BXPC-3 it can be seen from the active testing result of table 3
IC50Respectively 5.7 μM, 7.5 μM, 7.9 μM and 4.5 μM, the antitumor activity having had, and to the CC of human normal cell line L-0250
Up to 235.9 μM, small to normal human cell's toxic side effect, safety coefficient is high.
4 compound 4 of table is to each tumor cell line and normal cell strain cytotoxic activity IC50(μM) and selection index SI
| Cell line | 4 (IC of compound50/SIb) |
| HCT-116 | 4.4/3.7 |
| Jurkat | 1.9/8.5 |
| PANC-1 | 5.4/3 |
| BXPC-3 | 4.1/3.9 |
| L-02a | 16.1/- |
Note：aCC50；bSI：Select index=CC50(L-02 plants of normal cell)/IC50(tumor cell line).
Compound 4 is to HCT-116, Jurkat, BXPC-1, BXPC-3 it can be seen from the active testing result of table 4
IC50Respectively 4.4 μM, 1.9 μM, 5.4 μM and 4.1 μM, the antitumor activity having had；Compound 4 is to human normal cell line L-02
CC50It it is 16.1 μM, small to normal human cell's toxic side effect, safety coefficient is high.
5 compound 5 of table is to each tumor cell line and normal cell strain cytotoxic activity IC50(μM) and selection index SI
| Cell line | 5 (IC of compound50/SIb) |
| HCT-116 | 4.6/3.2 |
| Jurkat | 6.7/2.2 |
| PANC-1 | 7.0/2.1 |
| BXPC-3 | 4.0/3.6 |
| L-02a | 14.5/- |
Note：aCC50；bSI：Select index=CC50(L-02 plants of normal cell)/IC50(tumor cell line).
Compound 5 is to HCT-116, Jurkat, BXPC-1, BXPC-3 it can be seen from the active testing result of table 5
IC50Respectively 4.6 μM, 6.7 μM, 7.0 μM and 4.0 μM, the antitumor activity having had；Compound 5 is to human normal cell line L-02
CC50It it is 14.5 μM, small to normal human cell's toxic side effect, safety coefficient is high.
6 compound 2 of table is to each tumor cell line IC50(μM)
| Cell line | 2 (IC of compound50) |
| K562 | 4.9 |
| HCT-116 | 2.9 |
| Jurkat | 1.7 |
| PANC-1 | 2.1 |
| BXPC-3 | 4.3 |
Compound 2 is to K562, HCT-116, Jurkat, BXPC-1, BXPC- it can be seen from the active testing result of table 6
3 IC50Respectively 4.9 μM, 2.9 μM, 1.7 μM, 2.1 and 4.3 μM, there is preferable antitumor activity.
7 compound 3 of table is to each tumor cell line IC50(μM)
| Cell line | 3 (IC of compound50) |
| K562 | 5.7 |
| HCT-116 | 2.9 |
| Jurkat | 1.4 |
| PANC-1 | 2.3 |
| BXPC-3 | 2.9 |
It can be seen from the active testing result of table 7 compound 3 to HCT-116, Jurkat, BXPC-1, BXPC-3 have compared with
Good anti tumor activity in vitro.
In summary, there is higher selection while the compounds of this invention can effectively inhibit tumor cell proliferation
Property, toxicity is smaller, and safety coefficient is higher.
【Test example 2】Anti-aspergillus fumigatus active testing
1, laboratory sample and experimental method
The preparation of sample solution：Positive drug Itraconazole is made into 1mg/mL DMSO solutions, and compound of formula I 1-5 is made into
10mg/mL takes 10 μ L that 990 μ L sterile waters are added and releases 100 times of liquid respectively, and it is respectively 10 μ g/mL and 100 μ g/ that initial concentration, which is made,
ML working solutions, for use.
Aspergillus fumigatus is prepared with RPMI-1640 culture mediums：The 3- N-morpholinyls (MOPS) of 6.906g are taken to be dissolved in 70ml70
In DEG C distilled water, the glucose of 4g is continuously added, after cooling to be dissolved, adds 2.08g solid RPMI1640 culture mediums, supplemented
Distilled water is to 90mL；The NaOH of 0.5g is dissolved in 10ml distilled water, is slowly added into culture medium, pH to 7.0 is adjusted；It prepares
Good culture medium passes through 0.2mm filtering with microporous membrane degermings, and 4 DEG C save backup.
The preparation of bacterium solution：Well-grown aspergillus fumigatus maturation spore is in the physiological saline of 4mL on scraping PDA plate culture medium
In, mortar pours into after grinding well in test tube, stands 10min, takes the liquid at 1/2-2/3 below liquid level, passes through blood counting chamber meter
Number, bacterium solution final concentration of 2.0 × 10 is diluted to sterile RPMI-1640 culture mediums4CFU/ml。
Using 96 orifice plate turbidimetrys test anti-aspergillus fumigatus activity：
It is separately added into 96 orifice plates：
(1) control group：The sterile no medicine RPMI-1640 culture mediums of blank are added per hole for negative control group and sterile distilled water is each
100μL；Bacterium solution and each 100 μ L of sterile distilled water are added per hole for growth control group；Bacterium solution and the positive are added per hole for positive controls
Each 100 μ l of medicine working solution.
(2) measurement group：Bacterium solution is added per hole and each 100 μ L of compound working solutions (are tested per hole positive drug with drug in this way
The 1/2 of working solution concentration before final concentration of sample-adding).3 parallel laboratory tests are done per hole.As a result interpretation：Add the culture plate of sample
Level shakes 3min or so, is subsequently placed in wet box, is observed after being cultivated 3~5 days in 28 DEG C of incubators；
It visually observes, using growth control as reference standard.If active at this concentration, with sterile steaming before dosing
Distilled water is tested after being diluted working solution successively using doubling dilution, until the MIC value of compound is measured, with aspergillus fumigatus
The apparent break of growth change is as MIC terminals (culture solution is by limpid change muddiness).
2, experimental result
8 positive drug Itraconazole anti-aspergillus fumigatus active testing result of table
Note：+ indicate there is obvious inhibiting effect to strain growth under the test concentrations (culture solution is limpid, similarly hereinafter)；- indicate
Without obvious inhibiting effect under test concentrations (culture solution is muddy, similarly hereinafter).
9 compound 1-5 anti-aspergillus fumigatus active testing results of table
Note：+ indicate there is obvious inhibiting effect to strain growth under the test concentrations；- indicate under test concentrations without apparent suppression
It makes and uses；/ indicate not tested.
The minimum inhibitory concentration MIC of positive drug Itraconazole known to the test result of table 8 is 1.25 μ g/mL；By table 9
The minimum inhibitory concentration MIC that test result can be seen that compound 2 is 1.5625 μ g/mL, suitable with positive drug；3 He of compound
5 minimum inhibitory concentration MIC are 25 μ g/mL；The minimum inhibitory concentration MIC of compound 4 is 3.125 μ g/mL.
In summary, formula Compound I has good inhibitory activity to aspergillus fumigatus growth.
Claims (10)
1. a kind of compound of formula I, its pharmaceutically acceptable salt or prodrug,
Preferably, the compound of formula I is Formulas I ' compound,
Formulas I and Formulas I ' in,
R1Selected from-H ,-OH ,=O or R1' O-, wherein R1' it is alkyl；R2Selected from-H ,-OH or R2' O-, wherein R2' it is alkyl；
R3、R4Composition-O- together；Alternatively, R4For H, R3Selected from-H ,-OH, R'O- or R " COO-, wherein R', R " are each independently
For alkyl；
R5、R6Composition-O- or singly-bound together；Alternatively, R5、R6It is each independently selected from-H or-OH；
R7、R8Composition-O- or singly-bound together；Alternatively, R7For H, R8Selected from alkyl or alkenyl；
R9For alkyl；
R10、R11Composition-O- or singly-bound together；Alternatively, R10、R11It is each independently selected from-H or-OH；
R12、R13It is each independently selected from-H or alkyl；
Optionally, the alkyl is C1~C20Branched-chain or straight-chain alkyl, or be C1~C16Branched-chain or straight-chain alkyl, or be C1
~C8Branched-chain or straight-chain alkyl, or be C1~C4Branched-chain or straight-chain alkyl；The alkenyl is C2~C20Branch or straight-chain alkenyl,
Or it is C2~C16Branch or straight-chain alkenyl, or be C2~C8Branch or straight-chain alkenyl, or be C2~C4Branch or straight chain alkene
Base.
2. compound of formula I according to claim 1, its pharmaceutically acceptable salt or prodrug, compounds of formula I is formula
II compounds,
Preferably, the Formula II compound is Formula II ' compound,
Formula II and Formula II ' in,
R1Selected from-OH or=O；R2Selected from-H or-OH；R3Selected from-H ,-OH or R " COO-, wherein R " is alkyl, and the alkyl is
C1~C20Branched-chain or straight-chain alkyl, or be C1~C16Branched-chain or straight-chain alkyl, or be C1~C8Branched-chain or straight-chain alkyl.
3. compound of formula I according to claim 1 or 2, its pharmaceutically acceptable salt or prodrug are selected from following chemical combination
Object, its pharmaceutically acceptable salt or prodrug,
4. compound of formula I according to any one of claim 1-3, its pharmaceutically acceptable salt or prodrug, wherein institute
It is the salt that the compound of formula I is formed with following compound to state pharmaceutically acceptable salt：Hydrochloric acid；Sulfuric acid；Phosphoric acid；Formic acid；Second
Acid；Propionic acid；Lactic acid；Citric acid；Tartaric acid；Succinic acid；Fumaric acid；Maleic acid；Tussol；Malic acid；Camphorsulfonic acid；The medicine
Acceptable prodrug includes the prodrug that the compound of formula I is combined into pharmaceutically acceptable carrier on；Optionally, institute
Stating pharmaceutically acceptable carrier includes：Three ester of phosphoglycerol, macrogol ester, polyethylene glycol amide, polyglycol ether.
5. the side of a kind of compound of formula I prepared described in any one of claim 1-4, its pharmaceutically acceptable salt or prodrug
Method, which is characterized in that including：
The different wall actinomyces A.cyanogriseus WH1-2216-6 of fermented and cultured, the zymotic fluid that the fermented and cultured is obtained into
Row isolates and purifies obtained product；Optionally, it using the product isolated and purified as raw material, carries out semi-synthetic reaction and is made,
Optionally, the fermented and cultured includes：By different wall actinomyces A.cyanogriseus WH1-2216-6 in seed culture medium
Middle culture, is inoculated into fermentation medium, cultivates, and tunning is made in fermentation；
Optionally, the seed culture medium includes：Carbon source, nitrogen source, sodium chloride-containing aqueous solution；Optionally, the seed culture medium
Including：Peptone, glycerine, analysis for soybean powder, soluble starch, calcium carbonate, seawater；Optionally, the seed culture medium is peptone
15 parts by weight, 15 parts by weight of glycerine, 5 parts by weight of analysis for soybean powder, 15 parts by weight of soluble starch, 2 parts by weight of calcium carbonate and Chen Haishui
1000 parts by weight, pH=7.8；
Optionally, the fermentation medium includes：Soluble starch, glycerine, peptone, calcium carbonate, macroporous absorbent resin and old
Seawater；Optionally, the fermentation medium is 20 parts by weight of soluble starch, 20 parts by weight of glycerine, 20 parts by weight of peptone, carbon
1000 parts by weight of 2 parts by weight of sour calcium, 50 parts by weight of XAD-16 macroporous absorbent resins and Chen Haishui, pH=7.5；
Optionally, it is described isolate and purify including：The zymotic fluid is extracted with organic solvent, after organic phase concentration, is added acid
Solution, organic solvent extraction remove organic phase, and water phase adds alkali to adjust pH, then is extracted with organic solvent, concentrates organic phase, obtains life
Alkaloids part, the decompression silica gel column chromatography gradient elution separation of gained alkaloid moiety, elution fraction and then inverted silicagel column
Chromatography, gel column chromatography, half preparative separation of efficient liquid phase；Optionally, each extraction is each independently selected from second with organic solvent
Acetoacetic ester, dichloromethane, chloroform, petroleum ether；Optionally, the acid solution is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid；Optionally
The alkali is selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate；Optionally, described to depressurize washing for silica gel chromatographic column
De- agent is selected from petroleum ether, dichloromethane, methanol, methylene chloride-methanol mixed liquor, water；Optionally, the gel column chromatography is washed
De- agent is selected from methanol, methylene chloride-methanol mixed liquor；Optionally, the semipreparative eluant, eluent of the efficient liquid phase is methanol-trifluoro
Acetic acid mixture；
Optionally, carrying out semi-synthetic reaction as raw material using the product isolated and purified includes：It isolates and purifies in product chemistry structure
Epoxidation reaction, dihydroxylation reaction, the hydration reaction of double bond, the methylation reaction of NH-, OH-, the acylation reaction of OH-, oxidation are anti-
It answers, the reduction reaction of carbonyl O=or their composite reaction；
Optionally, the compound of formula I is compound 1-6；
Optionally, the preparation method of the compound 1-6 includes：By different wall actinomyces A.cyanogriseus WH1-2216-6
It cultivates, is inoculated into fermentation medium in seed culture medium, shaking table culture fermentation obtains fermentate, fermentate acetic acid second
Ester extracts, and organic phase is concentrated to give crude extract, HCl solution is added into crude extract, extracted with dichloromethane, and water phase is adjusted with ammonium hydroxide
It is extracted to pH=8.0, then with dichloromethane, concentration organic phase obtains alkaloid moiety, gained alkaloid moiety decompression silicagel column
Chromatographic isolation, successively with petroleum ether, dichloromethane, methylene chloride-methanol (v/v, 100:1,50:1,25:1,15:1,10:1,5:
Isosorbide-5-Nitrae:1,2:1,1:1,0:1) it is that solvent carries out gradient elution：Wherein dichloromethane in methylene chloride-methanol eluant, eluent:Methanol=
5:The inverted silica gel column chromatography of 1 (v/v) elution fraction detaches, with ‰ trifluoroacetic acid aqueous solution=70 of methanol -1.5:30 (v/v) are washed
It is de-, obtain compound 6；Dichloromethane in methylene chloride-methanol eluant, eluent:Methanol=4:1 (v/v) elution fraction is through Sephadex
The separation of LH20 gel column chromatographies is eluted with methanol, and obtained component is again through half preparative separation of efficient liquid phase, with ‰ trifluoro of methanol -1.5
Acetic acid aqueous solution=75:25 (v/v) are eluted, and obtain compound 1-5.
6. a kind of pharmaceutical composition, which is characterized in that including compound of formula I, its pharmacy described in any one of claim 1-4
Upper at least one of acceptable salt or prodrug and pharmaceutically acceptable auxiliary material；
Optionally, the dosage form of described pharmaceutical composition includes solid formulation and liquid formulation；Optionally, described pharmaceutical composition
Dosage form includes oral preparation, ejection preparation, percutaneous preparation；Optionally, the dosage form of described pharmaceutical composition includes tablet, capsule
Agent, pulvis, granule, pastille, suppository, oral solution, sterile parenteral suspension, injection；Optionally, the injection includes freeze-dried powder
Injection.
7. the compound of formula I, its pharmaceutically acceptable salt or prodrug or right described in any one of claim 1-4 are wanted
Seek the purposes of pharmaceutical composition in the preparation of antitumor drugs described in 6；Optionally, the antitumor drug increases for tumour cell
Grow inhibitor or tumor cytotoxicity agent；Optionally, the antitumor drug does not include anti-human human umbilical vein endothelial cell drug, resists
Human liver cancer cell HepG2 drugs, anti-human breast cancer cell line Bcap-37 drug or anti-human leukaemia cell P-388 drugs；Optionally,
The antitumor drug is anti-human colon cancer cell HCT-116 drugs, anti-human peripheral blood leukemia T cell Jurkat drugs, resists
Human pancreatic cancer cell PANC-1 drugs, anti-human pancreatic cancer cell BXPC-3 drugs or anti-human chronic marrow original K562 Leukaemia medicine
Object.
8. the compound of formula I, its pharmaceutically acceptable salt or prodrug or right described in any one of claim 1-4 are wanted
Seek purposes of the pharmaceutical composition in preparing aspergillus fumigatus growth inhibitor or anti-aspergillus fumigatus drug described in 6.
9. a kind of low molecule bioprobe for inhibiting cell Proliferation or inhibiting aspergillus fumigatus growth, which is characterized in that wanted including right
Seek the drug described in compound of formula I, its pharmaceutically acceptable salt or prodrug or the claim 6 described in any one of 1-4
Composition.
10. a kind of low molecule bioprobe kit, which is characterized in that including the low molecule bioprobe described in claim 9,
And optional biocompatible media；Optionally, the biocompatible media is in methanol, water, dimethyl sulfoxide (DMSO)
It is one or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710181976.7A CN108623607B (en) | 2017-03-24 | 2017-03-24 | 5,5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710181976.7A CN108623607B (en) | 2017-03-24 | 2017-03-24 | 5,5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108623607A true CN108623607A (en) | 2018-10-09 |
| CN108623607B CN108623607B (en) | 2021-04-27 |
Family
ID=63707573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710181976.7A Active CN108623607B (en) | 2017-03-24 | 2017-03-24 | 5,5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108623607B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642863A (en) * | 2019-09-23 | 2020-01-03 | 中国科学院南海海洋研究所 | 5,5,6 type PTM compound and preparation method and application thereof |
| CN111253408A (en) * | 2020-02-11 | 2020-06-09 | 中国科学院南海海洋研究所 | Antibiotic pactamide G, preparation method thereof and application thereof in preparation of antibacterial drugs |
| CN113121545A (en) * | 2021-04-25 | 2021-07-16 | 山东大学 | Polycyclic macrocyclic lactam compound and preparation method and application thereof |
| CN113308407A (en) * | 2021-06-16 | 2021-08-27 | 中国科学院深海科学与工程研究所 | Streptomyces abyssocyanensis and Tianyamycin series compounds and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000020418A1 (en) * | 1998-10-06 | 2000-04-13 | Japan Science And Technology Corporation | Xanthobaccin antibiotics |
| CN104592239A (en) * | 2014-12-25 | 2015-05-06 | 南京农业大学 | Metabolite with anti-fungus and anti-oomycetes activity in lysobacter enzymogenes OH11 and separation method thereof |
| CN106434702A (en) * | 2016-09-06 | 2017-02-22 | 中国科学院南海海洋研究所 | Biosynthetic gene cluster of paquete amide and application thereof |
-
2017
- 2017-03-24 CN CN201710181976.7A patent/CN108623607B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000020418A1 (en) * | 1998-10-06 | 2000-04-13 | Japan Science And Technology Corporation | Xanthobaccin antibiotics |
| CN104592239A (en) * | 2014-12-25 | 2015-05-06 | 南京农业大学 | Metabolite with anti-fungus and anti-oomycetes activity in lysobacter enzymogenes OH11 and separation method thereof |
| CN106434702A (en) * | 2016-09-06 | 2017-02-22 | 中国科学院南海海洋研究所 | Biosynthetic gene cluster of paquete amide and application thereof |
Non-Patent Citations (7)
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642863A (en) * | 2019-09-23 | 2020-01-03 | 中国科学院南海海洋研究所 | 5,5,6 type PTM compound and preparation method and application thereof |
| CN111253408A (en) * | 2020-02-11 | 2020-06-09 | 中国科学院南海海洋研究所 | Antibiotic pactamide G, preparation method thereof and application thereof in preparation of antibacterial drugs |
| CN113121545A (en) * | 2021-04-25 | 2021-07-16 | 山东大学 | Polycyclic macrocyclic lactam compound and preparation method and application thereof |
| CN113308407A (en) * | 2021-06-16 | 2021-08-27 | 中国科学院深海科学与工程研究所 | Streptomyces abyssocyanensis and Tianyamycin series compounds and application thereof |
| CN113308407B (en) * | 2021-06-16 | 2023-08-18 | 中国科学院深海科学与工程研究所 | Deep sea streptomycete, tianyamycin series compound and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108623607B (en) | 2021-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108623607A (en) | Polycyclic compounds of macrolactams containing tetramic acid of 5,5,6- and its preparation method and application | |
| CN108484699A (en) | Bipyridyliums alkaloid, preparation method and use | |
| CN103865809B (en) | A kind of anticancer usage of the penicillium sp enol B1 coming from Aspergillus citrimum | |
| CN101560198A (en) | New isoandrographolidume sulfonate, pharmaceutical composition containing sulfonate, preparation method and applications thereof | |
| CN107986951A (en) | New Topological isomerase I inhibitor and its pharmaceutical composition and its preparation method and application | |
| CN110041375A (en) | Compound, preparation method and its application in preparation of anti-tumor drugs with asymmetric monosubstituted naphthalimide tetravalence platinum structure | |
| JP3639973B2 (en) | Spongistatin 6 | |
| CN101812079B (en) | Piprazine compound containing polysulfide bond and preparation method and application thereof | |
| CN111499649B (en) | Benzodifuranone compound with anti-tumor activity, preparation method and application thereof | |
| US11098052B2 (en) | 4-azapodophylotoxins compounds | |
| CN103275106B (en) | A kind of indole alkaloid adduct and preparation method thereof and preparing the application in antitumor drug | |
| CN102399221B (en) | The application of two indole quinazoline Alkaloids in antitumor, the antifungal drug of preparation | |
| CN112513000A (en) | Novel biphenyl derivative compound and use thereof | |
| CN111732579B (en) | Polyether polyketone compound polydecaminmycin and preparation method and application thereof | |
| CN109384823B (en) | Two piericins glucoside and application thereof in anti-renal cancer drugs | |
| CN107224432B (en) | Application of compound Stemphol in preparation of antitumor drugs | |
| CN102399215B (en) | Indole alkaloids (phidianidine A and phidianidine B) and preparation method and application thereof | |
| CN101277942A (en) | Cytotoxin compounds and methods of isolation | |
| CN101304991A (en) | Indole derivatives as antitumoural compounds | |
| CN103275139A (en) | C16:1DLSL and application thereof | |
| CN108947790B (en) | Diterpenoid compounds and application thereof in preparation of antitumor drugs | |
| CN103275138A (en) | Carbon 16 zero double bond diacetylation lactone sophorolipid and application thereof | |
| CN109384710B (en) | Three piericins natural products and application thereof in preparing anti-renal cancer drugs | |
| CN114732813B (en) | Application of citrinin dimer P4 in preparation of anti-tumor and anti-tumor angiogenesis medicines | |
| CN112961170B (en) | Sponge source actinomycetes and preparation method and application of sulfur-containing alkaloid produced by sponge source actinomycetes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |