CN101277942A - Cytotoxin compounds and methods of isolation - Google Patents
Cytotoxin compounds and methods of isolation Download PDFInfo
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- CN101277942A CN101277942A CNA2006800366454A CN200680036645A CN101277942A CN 101277942 A CN101277942 A CN 101277942A CN A2006800366454 A CNA2006800366454 A CN A2006800366454A CN 200680036645 A CN200680036645 A CN 200680036645A CN 101277942 A CN101277942 A CN 101277942A
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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- KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pyrane Compounds (AREA)
Abstract
The present invention concerns groups of compounds derived from tunicates of the Synoicum species, as well as to pharmaceutical compositions comprising these compounds, and uses thereof. Extracts from tunicates show selective toxicity against several different cancer cell lines in the NCI 60 cell line panel. These compounds are useful in the effective treatment of cancers, particularly malignant melanomas, colon cancer, and renal cancer cell lines.
Description
The cross reference of related application
The application's requirement is filed in the rights and interests of the U.S. Provisional Application sequence number 60/717,598 on September 16th, 2005, at this full content that it comprises chart is introduced the application as a reference.
The present invention obtains the subsidy of National Science Foundation (National Science Foundation) with OPP-9901076 and OPP-0125152, so United States Government enjoys certain right for the present invention.
Background technology
One of greatest objective of the struggle of modern medicine is exactly control and alleviates cell hyperplastic disease, for example cancer.Considerable research is being devoted to seek always particular cancers is had useful active new biologically active cpds and the biology that can produce these compounds.For example, some ocean software alcyonarian is exactly the cytotoxic source with biologic activity.Equally, can effectively resist the human diseases (referring to United States Patent (USP) the 6th, 750, No. 247) of lipoxygenase mediation from poriferous compound.
It is the important source of biologically active native product that urochordates (tunicates) also is proved to be.In the marine natural product that is used for the treatment of cancer of exploitation, ecteinascidin class (ecteinascidins) and film ecteinascidin class (didemnins) all derive from urochordates, and gill fungus shape ecteinascidin class (eudistomins) has good antiviral activity.As the part of the bioactivity research of ongoing South Pole marine invertebrate, the present inventor has an opportunity to have studied urochordates Synoicum adareanum.
S.adareanum is the polar region urochordates, is usually located at Anvers island, the South Pole (64 ° of 46 ' S, 64 ° 03 ' W) 15-796 rice shoaling water.The S.adareanum colony is formed by big circle or clavate head and by end handle like gauffer and the leather, and end handle is only slightly narrow than head.The S.adareanum colony can have 18 centimetres high at the most, and diameter is 12 centimetres.The S.adareanum colony can comprise single head or six at the most, and bull can grow on single handle.
The present invention's summary
The present invention relates to S.adareanum extract and uses thereof, described extract comprises that the handkerchief Monot founds moral (Palmerolide) A, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and/or the upright moral K of handkerchief Monot.Field-based feeding-deterrent assays shows the The compounds of this invention biologically active.New isolating polyketides, it is the main natural product that derives from the S.adareanum extract that the handkerchief Monot founds moral A, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.These polyketides (NCI) have optionally cytotoxicity in 60 clones in state-run cancer research institute (National Cancer Institute), can suppress melanoma (UACC-64, LC
500.018 μ M), compare with other test cell system, its susceptibility exceeds three orders of magnitude.
The present invention also relates to treat cancer patients's method, this method comprises at least a isolated compound that gives the patient treatment significant quantity, and this compound is available from the extract of Synoicum kind.In one embodiment, the Synoicum kind is S.adareanum, and isolated compound is the upright moral of handkerchief Monot.In specific embodiment, the upright moral of handkerchief Monot is selected from the upright moral A1 of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.
Description of drawings
Fig. 1 is the skeleton view of the chemical structural formula of the upright moral A of handkerchief Monot.
Fig. 2 is the NMR data form of the upright moral A of handkerchief Monot.
Fig. 3 shows the ROE dependency of selection, relates to the relative stereochemical structure between C-11 and the C-19.
Fig. 4 A is the in vitro tests result of the upright moral A of the exploitation treatment project handkerchief Monot of state-run cancer research institute (NCI).
Fig. 4 B is continuous table, shows the in vitro tests result of the upright moral A of the exploitation treatment project handkerchief Monot of state-run cancer research institute (NCI).
Fig. 5 is the dose response curve of the upright moral A of handkerchief Monot of state-run cancer research institute (NCI) exploitation treatment project testing to all clone.
Fig. 6 is the dose response curve of the upright moral A of handkerchief Monot of state-run cancer research institute (NCI) exploitation treatment project testing to melanoma cell series.
Fig. 7 is the dose response curve of the upright moral A of handkerchief Monot of state-run cancer research institute (NCI) exploitation treatment project testing to colon carcinoma cell line.
Fig. 8 is the dose response curve of the upright moral A of handkerchief Monot of state-run cancer research institute (NCI) exploitation treatment project testing to renal carcinoma cell line.
Fig. 9 is the skeleton view of the chemical structural formula of the upright moral C of handkerchief Monot.
Figure 10 is the NMR data form of the upright moral C of handkerchief Monot.
Figure 11 A is the in vitro tests result of the upright moral C of the exploitation treatment project handkerchief Monot of state-run cancer research institute (NCI).
Figure 11 B is continuous table, shows the in vitro tests result of the upright moral C of the exploitation treatment project handkerchief Monot of state-run cancer research institute (NCI).
Figure 12 is the dose response curve of the upright moral C of handkerchief Monot of state-run cancer research institute (NCI) exploitation treatment project testing to all clone.
Figure 13 is the skeleton view of the chemical structural formula of the upright moral D of handkerchief Monot.
Figure 14 is the NMR data form of the upright moral D of handkerchief Monot.
Figure 15 is the skeleton view of the chemical structural formula of the upright moral E of handkerchief Monot.
Figure 16 is the NMR data form of the upright moral E of handkerchief Monot.
Figure 17 A is the in vitro tests result of the upright moral E of the exploitation treatment project handkerchief Monot of state-run cancer research institute (NCI).
Figure 17 B is continuous table, shows the in vitro tests result of the upright moral E of the exploitation treatment project handkerchief Monot of state-run cancer research institute (NCI).
Figure 18 is the dose response curve of the upright moral E of handkerchief Monot of state-run cancer research institute (NCI) exploitation treatment project testing to all clone.
Figure 19 is for separating the purification step of the upright moral A-G of handkerchief Monot.
Figure 20 is the skeleton view of the chemical structural formula of the upright moral B of handkerchief Monot.
Figure 21 is the skeleton view of the chemical structural formula of the upright moral F of handkerchief Monot.
Figure 22 is the skeleton view of the chemical structural formula of the upright moral G of handkerchief Monot.
Figure 23 is the skeleton view of the chemical structural formula of the upright moral H of handkerchief Monot.
Figure 24 is the skeleton view of the chemical structural formula of the upright moral K of handkerchief Monot.
The present invention describes in detail
The present invention relates to extract of S.adareanum and uses thereof, described extract claims in this article Make the vertical moral of handkerchief Monot. The vertical moral of the handkerchief Monot of concrete example comprises that the handkerchief Monot founds moral A, Pa Monuo herein Vertical moral B, the vertical moral C of handkerchief Monot, the vertical moral D of handkerchief Monot, the vertical moral E of handkerchief Monot, the vertical moral F of handkerchief Monot, The handkerchief Monot founds moral G, the vertical moral H of handkerchief Monot and the vertical moral K of handkerchief Monot. Field-based Feeding-deterrent assays shows that The compounds of this invention has biologically active. These compounds exist Have selective active in state-run cancer research institute (NCI) 60 clones, particularly can suppress melanocyte Oncocyte system.
The compounds of this invention comprises compound and isomers, racemic modification or its racemic mixture or its pharmaceutically acceptable salt or the crystal form that those have following formula (I) chemical structural formula:
Wherein:
R
1Be formaldehyde,-CHCHNHC (O)-alkyl,-OC-alkyl,-OC-aryl,-OC-amino, aryl, amino,-vinyl amido, the aryl amido, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, the heteroaryl carbonyl, the Heterocyclylalkyl carbonyl, aryloxycarbonyl, the heteroaryloxy carbonyl, the heterocycle alkoxy carbonyl, halogen or-CHO, they each all can choose wantonly and replace by following groups: H, alkyl, alkoxyl group,-OH,-NO
2,-NH
2,-COOH, halogen or-CH
3
R
2Independent be OH, O-acyl group, carbamate, H, O-alkyl, amino ,-OSO
3H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen and/or oxo;
R
3Be H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
R
4Independent is H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl; Alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
In one embodiment, at least one R
2For-OC (NH
2) O.
In one embodiment, R
3Be methyl.
In one embodiment, at least one R
4Be methyl.In another embodiment, two R
4Equal methyl.
In one embodiment, R
1For-CHCHNHC (O) CHC (CH
3)
2
In one embodiment, R
1For-CHCHNHC (O) CHC (CH
3) CH
2C (CH
3) CH
2
In one embodiment, R
1For-CHCH-NHC (O) CH
2C (CH
3) CH
2
In one embodiment, R
1For-CH=O.
In one embodiment, at least one R
2For-OH.
In one embodiment, at least one R
2For-OSO
3H.
In one embodiment, at least two R
2For-OH, and at least one R
2For-OC (NH
2) O, and optional R
3And R
4For-CH
3
The compounds of this invention comprise those compounds with following formula (I) chemical structural formula with and isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form:
Wherein:
R
1Be formaldehyde,-CHCHNHC (O)-alkyl,-OC-alkyl,-OC-aryl,-OC-amino, aryl, amino,-vinyl amido, the aryl amido, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, the heteroaryl carbonyl, the Heterocyclylalkyl carbonyl, aryloxycarbonyl, the heteroaryloxy carbonyl, the heterocycle alkoxy carbonyl, halogen or-CHO, they each all can choose wantonly and replace by following groups: H, alkyl, alkoxyl group,-OH,-NO
2,-NH
2,-COOH, halogen or-CH
3
R
2Independent be OH, O-acyl group, carbamate, H, O-alkyl, amino ,-OSO
3H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen and/or oxo;
R
3Be H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
R independently is H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
In one embodiment, at least one R
2For-OC (NH
2) O.
In one embodiment, R
3Be methyl.
In one embodiment, at least one R
4Be methyl.In another embodiment, two R
4Be methyl.
In one embodiment, R
1For-CHCHNHC (O) CHC (CH
3)
2
In one embodiment, R
1For-CHCHNHC (O) CHC (CH
3) CH
2C (CH
3) CH
2
In one embodiment, R
1For-CHCH-NHC (O) CH
2C (CH
3) CH
2
In one embodiment, R
1For-CH=O.
In one embodiment, at least one R
2For-OH.
In one embodiment, at least one R
2For-OSO
3H.
In one embodiment, at least two R
2For-OH, and at least one R
2For-OC (NH
2) O, optional R
3And R
4For-CH
3
In one embodiment, provide the handkerchief Monot who contains separative formula (III) upright moral A compound compositions (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form):
In another embodiment, the invention provides the composition of the upright moral C compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (IV):
In another embodiment, the invention provides the composition of the upright moral D compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula V:
The present invention also provides the composition of the upright moral E compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (VI):
The present invention also provides the composition of the upright moral B compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (VII):
The present invention also provides the composition of the upright moral F compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (VIII):
The present invention also provides the composition of the upright moral G compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (IX):
The present invention also provides the composition of the upright moral H compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (X):
The present invention also provides the composition of the upright moral K compound (or isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form) of handkerchief Monot that contains separative formula (XI):
In the preferred embodiment of the invention, new compound is pure basically; Ideal should contain at least 95% compound (measuring according to the analytical procedure of having set up), and the acceptable compound that should contain at least 90% needs permissiblely should contain at least 75% compound.
The present invention also provides new medicinal compositions, the mixture of new compound wherein of the present invention or two or more these compounds accounts for the 0.01%-60% (weight ratio) of composition total weight, preferred 0.1%-50% (weight ratio), more preferably 1%-35% (weight ratio), said composition also contains one or more pharmaceutically acceptable carrier or thinner.
It will be understood by those skilled in the art that there is multiple tautomeric form in the upright Dehua of handkerchief Monot disclosed herein compound.This type of all tautomeric forms also is an integral part of the present invention.
Alkyl used herein is meant have 1-20 carbon atom straight or branched, saturated or single-or polyunsaturated alkyl, C
1-XAlkyl is meant the straight or branched alkyl with 1 to as many as X carbon atom, comprises alkyl, alkenyl and alkynyl.For example, C
1-6Alkyl refers to have the straight or branched alkyl of 1-6 carbon atom.Alkoxyl group is meant alkyl-O-group, and wherein alkyl as mentioned above.Cycloalkyl comprises non-aromatic monocyclic or polycyclic system, comprises having about 3 fused rings and volutions to about 10 carbon atoms.It is that part is unsaturated that cycloalkyl can be chosen wantonly.Cycloalkyloxy is meant cycloalkyl-O-group, and wherein cycloalkyl as defined herein.Aryl is meant aromatic monocyclic or encircles the carbocyclic ring system more, comprises having about 6 fused rings and volutions to about 14 carbon atoms.Aryloxy is meant aryl-O-group, and wherein aryl as defined herein.Alkyl-carbonyl is meant RC (O)-group, and wherein R is an alkyl defined herein.Alkoxy carbonyl is meant ROC (O)-group, and wherein R is an alkyl defined herein.Naphthene base carbonyl is meant RC (O)-group, and wherein R is a cycloalkyl defined herein.Cyclo alkoxy carbonyl is meant ROC (O)-group, and wherein R is a cycloalkyl defined herein.
Assorted alkyl is meant to have 1-20 carbon atom and one or more is selected from the heteroatomic straight or branched of nitrogen, oxygen or sulphur, and wherein nitrogen and sulphur atom can be chosen wantonly oxidizedly, and promptly they can be the forms of N-oxide compound or S-oxide compound.Heterocyclylalkyl is meant monocycle or polycyclic system (they can be saturated or part is undersaturated), comprise and have about 5 fused rings and volutions to about 10 ring memberses, wherein one or more ring members in this ring system can be selected from nitrogen, oxygen, silicon or sulphur atom for being not the member of carbon.Heteroaryl is meant 5 to about 14-unit's aromatic monocyclic or polynuclear hydrocarbon member ring systems, comprise fused rings and volution, wherein one or more ring members in this ring system can be selected from nitrogen, oxygen, silicon or sulphur atom, and wherein the N atom can be the form of N-oxide compound for being not the member of carbon.Aryl carbonyl is meant aryl-CO-group, and wherein aryl as defined herein.The heteroaryl carbonyl is meant heteroaryl-CO-group, wherein heteroaryl as defined herein, the Heterocyclylalkyl carbonyl is meant Heterocyclylalkyl-CO-group, wherein Heterocyclylalkyl as defined herein.Aryloxycarbonyl is meant ROC (O)-group, and wherein R is aryl as defined above.The heteroaryloxy carbonyl is meant ROC (O)-group, and wherein R is heteroaryl as defined above.The heterocycle alkoxyl group is meant Heterocyclylalkyl-O-group, and wherein Heterocyclylalkyl as defined above.The heterocycle alkoxy carbonyl is meant ROC (O)-group, and wherein R is Heterocyclylalkyl as defined above.
The example of saturated alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, tert-butyl, isobutyl-, the second month in a season-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.Undersaturated alkyl is for having one or more pair key or triple-linked alkyl.Undersaturated alkyl comprises, for example vinyl, propenyl, butenyl, hexenyl, vinyl, 2-propynyl, 2-isopentene group, 2-butadienyl, ethynyl, 1-proyl, 3-proyl and 3-butynyl.Cycloalkyl comprises, for example cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl and suberyl.Heterocyclylalkyl comprises, for example piperidino, 2-piperidyl, 3-piperidyl, morpholinyl, 4-morpholinyl, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, tetramethylene sulfide-2-base, tetramethylene sulfide-3-base, 1-piperazinyl, 2-piperazinyl and 1,4-diazabicyclo octane.Aryl comprises, for example phenyl, indenyl, xenyl, 1-naphthyl, 2-naphthyl, anthryl and phenanthracenyl.Heteroaryl comprises, for example 1-pyrryl, 2-pyrryl, 3-pyrryl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, indyl, quinolyl, isoquinolyl, benzoquinoline base, carbazyl and diaza phenanthryl.
Halogen used herein is meant element fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
Oxo used herein be meant contain with carbon or other element with doubly linked Sauerstoffatom, promptly=compound of O.This term comprises aldehyde, carboxylic acid, ketone, sulfonic acid, acid amides and ester.
The present invention also relates to test kit, in one or more packing, contain compound of the present invention or composition.In specific embodiment, test kit of the present invention contains the upright moral A of one or more handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.In one embodiment, test kit contains pharmaceutically acceptable carrier, for example thinner in addition.In another embodiment, test kit contains antitumor or anticancer compound in addition.
The present invention also relates to suppress the method for vacuole (vacuolar) apysase (V-ATPase), this method comprises The compounds of this invention or the composition that makes the V-ATPase contact or be exposed to significant quantity, and described significant quantity should be enough to suppress the active of V-ATPase or block its function.In one embodiment, described compound or composition comprise that one or more handkerchief Monot founds moral, are selected from the upright moral A of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.
The invention still further relates to and suppress or the method for kill cancer cell, comprise making the The compounds of this invention or the composition of described cells contacting significant quantity.In one embodiment, described compound or composition contain the upright moral of one or more handkerchief Monot, are selected from the upright moral A of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.The kind of the cancer cells that can suppress according to the present invention or kill includes but not limited to the cancer cells and/or the tumour cell of following tissue or organ: bone, breast, kidney, oral cavity, larynx, esophagus, stomach, testis, uterine neck, head, neck, colon, ovary, lung, bladder, skin (for example, melanoma), liver, muscle, pancreas, prostate gland, hemocyte (comprising lymphocyte) and brain.
The present invention also relates to treat the method with V-ATPase enzyme unconventionality expression or overexpression diseases associated, it comprises The compounds of this invention or the composition of suffering from human or animal's significant quantity that disease and needs treat.The disease that can treat according to the present invention includes but not limited to: cell proliferative diseases, for example cancer; Diabetes; Pancreatitis; And osteoporosis.In one embodiment, described compound or composition contain the upright moral of one or more handkerchief Monot, are selected from the upright moral A of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.
The present invention also provides treatment to suffer from the human or animal's of cancer or tumor disease method.In one embodiment, this method comprises at least a isolated compound available from Synoicum kind extract of administration of human or treatment of animals significant quantity.Described animal can be (but being not limited to) Mammals, for example primates (monkey, chimpanzee, ape etc.), dog, cat, ox, pig or horse, or suffer from other animal of tumor disease.Method of the present invention can be chosen wantonly and comprise that diagnosis human or animal needs maybe may need to carry out the treatment of cancer or tumor disease.In one embodiment, the Synoicum kind is S.adareanum, and isolated compound is the upright moral of handkerchief Monot.In a specific embodiment, the upright moral of handkerchief Monot is selected from the upright moral A of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot and the upright moral K of handkerchief Monot.The kind of the cancer that can treat according to the present invention includes but not limited to the cancer and/or the tumor disease of following tissue or organ: bone, breast, kidney, oral cavity, larynx, esophagus, stomach, testis, uterine neck, head, neck, colon, ovary, lung, bladder, skin (for example, melanoma), liver, muscle, pancreas, prostate gland, hemocyte (comprising lymphocyte) and brain.When carrying out the treatment of tumor disease, can be with The compounds of this invention and composition and other antitumor or cancer therapy drug Combined Preparation in the patient of needs treatment, perhaps with radiotherapy and/or photodynamic therapy or with the surgical operation therapy combined utilization to remove tumour.These other medicines or radiotherapy can give in identical time or different time with The compounds of this invention or composition.For example, The compounds of this invention or composition can with following medication combined application: mitotic inhibitor, for example taxol or vinealeucoblastine(VLB); Alkylating agent, for example endoxan or ifosfamide; Metabolic antagonist, for example 5 FU 5 fluorouracil or hydroxyurea; DNA intercalator, for example Zorubicin or bleomycin; Topoisomerase enzyme inhibitor, for example etoposide or camptothecine; Angiogenesis inhibitors, for example angiostatin (angiostatin); Estrogen antagonist medicine, for example tamoxifen; And/or other cancer therapy drug or antibody, for example, and GLEEVEC (Novartis PharmaceuticalsCorporation) and HERCEPTIN (Genentech, Inc.).
The present invention also relates to separate method with the purifying The compounds of this invention.In one embodiment, described method comprises solvent extraction Synoicum urochordates; Remove described solvent and obtain extract; Described extract fractionation is found moral to separate described handkerchief Monot.
The present invention also relates to the method for synthetic The compounds of this invention.
" pharmaceutically acceptable carrier " is meant any carrier, thinner, vehicle, wetting agent, buffer reagent, suspensoid, lubricant, auxiliary, solvent, transfer system, emulsifying agent, disintegrating agent, absorption agent, sanitas, tensio-active agent, tinting material, correctives or sweeting agent, and be preferred nontoxic and be suitable for the carrier of medicinal compositions.
" pharmaceutically acceptable Equivalent (equivalent) " includes but not limited to pharmacy acceptable salt or crystallized form, hydrate, metabolite, prodrug and isostere.Many pharmaceutically acceptable Equivalents all should have in external or body and the same or analogous activity of The compounds of this invention.
" pharmacy acceptable salt or crystallized form " is meant the salt of the The compounds of this invention with the pharmacological activity that needs, and both the also non-others of abiology institute was unwanted for they.Can include but not limited to acetate with the salt that acid forms, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, glucoheptose salt (glucoheptanoate), glycerophosphate, Hemisulphate (hemisulfate), enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, the 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate-, tosylate and undecane hydrochlorate.The example of basic salt comprises ammonium salt; An alkali metal salt, for example sodium and sylvite; Alkaline earth salt, for example calcium and magnesium salts; Form with organic bases, for example dicyclohexyl amine salt, N-methyl D-glycosamine; With the amino acid salt that forms of arginine and Methionin for example.The group that contains basic nitrogen can be quaternized with some reagent, and described reagent comprises elementary alkyl halide, for example methyl, ethyl, propyl group and butyl muriate, bromide and iodide; Dialkylsulfates, for example dimethyl, diethyl, dibutyl and diamyl sulfuric ester; Long-chain halogenide, for example decyl, dodecyl, tetradecyl and stearyl-halogenide and iodide; Aralkyl halide, for example benzyl and styroyl bromination thing.
" prodrug " is meant the derivative of The compounds of this invention, and it is through bio-transformation (for example passing through metabolism) back performance pharmacotoxicological effect.Acceptance level and the compliance that the purpose of preparation prodrug is to improve chemical stability, improve the patient, improve bioavailability, prolong action time, improve the organ selectivity, (for example improve the preparation performance, increase water-soluble) and/or reduce side effect (for example, toxicity).Adopt methods known in the art, for example according to the method for describing in the document (Burger ' s Medicinal Chemistryand Drug Chemistry, the 5th edition, the 1st volume, the 172-178 page or leaf, 949-982 page or leaf (1995)) can easily prepare prodrug from The compounds of this invention.
" the handkerchief Monot founds moral " used herein is meant the polynary big ring polyketide that carries carbonic ether and amide functional group.In one embodiment, the upright moral of handkerchief Monot is separated and is obtained from gathering near South Pole Palmer station urochordates Synoicwn adareanum.
" polyketide " used herein is meant any natural compounds (β-polyketone) that contains alternative carbonyl and methylene radical, and the repetition condensation by acetyl-CoA obtains.
" big ring " used herein is meant the be formed by connecting macromole of circular permutation of various half-compounds (semi-compounds) on each site.The site that connects and the character of Asia-molecule have determined to contain the character and the physiologic function of their compound.
" macrolide " used herein is meant a class microbiotic, it is characterized in that molecule is made of macrolide.
" alkene " used herein has same meaning with " alkene ", is meant the acyclic hydrocarbous that contains one or more pair key.
" clinical response " used herein is the response of cell hyperplastic disease (for example melanoma, colorectal carcinoma and kidney) to adopting new compound disclosed herein to treat.Evaluation is widely accepted to the standard of the response of treatment, the curative effect that can compare different treatments is (referring to Slapak and Kufe, Principles ofCancer Therapy, in Harrison ' s Principles of Internal Medicine, the 13rd edition, editors such as Isselbacher, McGraw-Hill, Inc.1994).Response fully (or alleviating fully) is that detectable malignant disease disappears.Partial response is that the maximum perpendicular diameter of one or more pathology reduces about 50%.The size of any pathology no longer increases or does not have new pathology to occur.PD means that the maximum perpendicular diameter of a kind of pathology or tumour has increased at least about 25% or has new pathology or tumour to occur.The evaluation of response to treatment is carried out after the patient finishes treatment.
" medicinal compositions " of the present invention should be consistent with the route of administration of estimating.The example of route of administration comprises parenteral (for example, intravenously), intradermal, subcutaneous, oral or nasal cavity (for example, sucking), transdermal (part), saturating mucous membrane and rectal administration.The solution or the suspension that are used for parenteral, intradermal or subcutaneous administration can comprise following ingredients: sterile diluent, for example water for injection, physiological saline, expressed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic; Antiseptic-germicide, for example benzylalcohol or methyl p-hydroxybenzoate; Oxidation inhibitor, for example xitix or sodium bisulfite; Sequestrant, for example ethylenediamine tetraacetic acid (EDTA); Buffer reagent, for example acetate, Citrate trianion or phosphoric acid salt; Be used to regulate the composition of osmotic pressure, for example sodium-chlor or glucose.Can adopt acid or alkali (for example hydrochloric acid or sodium hydroxide) to regulate pH.Parenteral administration can be encapsulated in ampoule, disposable syringe or the multiple dose vials that glass or plastics make.
The medicinal compositions that is applicable to drug administration by injection comprises sterile aqueous solution (water miscible) or dispersion liquid and sterilized powder, and this powder can be formulated as aseptic injectable solution or dispersion liquid temporarily.For intravenously administrable, appropriate carriers comprises the salt solution (PBS) of physiological saline, bacteriostatic water or phosphate buffered.Under any circumstance, said composition must be aseptic, and should be can mobile to satisfy the requirement that is easy to inject.It must be stable under the condition of producing and storing, and it must carry out anticorrosion pollution with combating microorganisms (for example bacterium and fungi).Described carrier can be solvent or dispersion medium, comprises for example water, ethanol, polyvalent alcohol (for example, glycerine, propylene glycol and polyoxyethylene glycol etc.) and suitable mixture thereof.By for example adopt dressing (for example Yelkin TTS dressing), under the situation of dispersion liquid by keeping essential size of particles and by adopting tensio-active agent to keep suitable flowability.The effect of prophylaxis of microbial can be undertaken by adding various antibiotic and anti-fungal compositions (for example, parabens, butylene-chlorohydrin, phenol, xitix, Thiomersalate etc.).In many cases, preferably comprise in the composition etc. and to ooze composition, for example carbohydrate, polyalcohols (for example N.F,USP MANNITOL or sorbyl alcohol) and/or sodium-chlor.The delay of composition for injection absorbs and can assign to produce by add the one-tenth that postpones to absorb in composition, and described composition is aluminum monostearate and gelatin for example.
Aseptic injectable solution can be prepared by the active compound of adding necessary amounts and a kind of or its combination of composition listed above in appropriate solvent, if desired, and the subsequent filtration degerming.Usually, by active compound being added preparation dispersion liquid in the sterile carrier (containing alkaline dispersion medium and essential other composition listed above).For the sterilized powder that is used to prepare aseptic injectable solution, preferred manufacturing procedure is vacuum-drying and lyophilize, is produced the powder of activeconstituents and any composition that other needs by the solution of filtration sterilization in advance.
Oral compositions comprises inert diluent or edible carrier usually.They can be encapsulated in the gelatine capsule or be pressed into tablet.Be oral therapeutic administration, active compound can be mixed with vehicle, can use with tablet, lozenge or capsular form.Oral compositions also can adopt the liquid vehicle preparation, and as mouth-washes, wherein the compound in the liquid vehicle can use by per os, gargles and spues or swallow.Pharmaceutically compatible tackiness agent and/or auxiliary material also can be used as the integral part of composition.Tablet, pill, capsule, lozenge etc. can contain the compound of following any composition or similar quality: tackiness agent, for example Microcrystalline Cellulose, tragacanth or gelatin; Vehicle, for example starch or lactose; Disintegrating agent, for example alginic acid, sodium starch glycolate (Primogel) or W-Gum; Lubricant, for example Magnesium Stearate or Sterotes; Glidant; Colloid silica for example; Sweeting agent, for example sucrose or asccharin; Or correctives, for example peppermint, wintergreen oil or the agent of orange flavor.For inhalation, compound with the form of aerosol in pressurized vessel that contains suitable propellent (for example gas, as carbonic acid gas) or delivery device or administration in atomizer.
The general administration also can be undertaken by saturating mucous membrane or transdermal methods.For saturating mucous membrane or transdermal administration, in preparation, can use the suitable permeate agent of barrier that needs are permeated.This type of permeate agent is well known in the art usually, for transmucosal administration, comprises for example sanitising agent, cholate and fusidic acid derivatives.Transmucosal administration can be undertaken by adopting nasal mist or suppository.For transdermal administration, active compound can be made ointment as known in the art, ointment, gel or creme.Compound also can be prepared as the form (for example adopting conventional suppository bases, for example theobroma oil and other glyceride type) of suppository or be used for the enema,retention of rectal administration.
In one embodiment, active compound can be prepared as for example controlled release preparation with carrier, comprises implanting and the micro-capsule transfer system, and described carrier can protect compound to avoid its quick elimination in vivo.Can adopt biodegradable, biocompatible polymkeric substance, for example ethylene vinyl acetate copolymer, poly-acid anhydrides, polyglycolic acid, collagen, poe and poly(lactic acid).The method for preparing this type of preparation is known to those skilled in the art.This material also can be available from AlzaCorporation and Nova Pharmaceuticals, Inc..Liposome suspension (liposome that comprises the cell-targeting that monoclonal antibody (antibody of virus antigen) is infected) also can be used as pharmaceutically acceptable carrier.These can prepare according to method known to those skilled in the art.
By directly and cells contacting or the method by carrier, The compounds of this invention and composition can be delivered to cell.The carrier method that composition is delivered to cell is well known in the art, and for example comprises compound or composition are encapsulated in the liposome.The another kind of method that The compounds of this invention is delivered to cell comprise with compound be attached to can targeted delivery on the protein or nucleic acid of target cell.U.S. Patent number 6,960,648 and laid-open U.S. Patents application number 20030032594 disclose can with other compound link coupled aminoacid sequence, it can make compound change the position to pass through microbial film.Laid-open U.S. Patents application number 20020035243 has also been described and the composition of biology composition transhipment by cytolemma can be used for transmitting in the cell.Compound and composition also can be incorporated in the polymkeric substance, and the example of polymkeric substance comprises poly-(D-L lactide-co-glycolide) polymkeric substance that is used for intracranial tumors; Mol ratio is 20: 80 poly-[two (to the carboxyl phenoxy group) propane: sebacic acid] (as employed among the GLIADEL); Chrondroitin; Chitin; And chitosan.
It will be understood by those skilled in the art that The compounds of this invention can contain the carbon atom of one or more asymmetric replacement, therefore, can produce steric isomer.All these type of steric isomers (comprise enantiomer and diastereomer and mixture, comprise its racemic mixture) are included in the scope of the present invention.
" treatment significant quantity " is the necessary amount of corresponding compounds that the treatment significant quantity can be provided in vivo for the amount of the upright moral (comprising that the handkerchief Monot founds moral A, B, C, D, E, F, G, H and K) of handkerchief Monot of the present invention or its any combination, this amount.The amount of this compound must be to obtain response effectively, include but not limited to prevent fully (for example, prevention and cure fully) and raising survival rate or faster recovery from illness or elimination symptom relevant or other those skilled in the art indication by the appropriate means selection with cell hyperplastic disease.According to the present invention, the size of suitable single dose can be prevented or alleviate the amount of (reducing or eliminating) patient symptom for administration one in reasonable time or repeatedly.Those skilled in the art can be identified for the suitable single dose size of whole body administration easily according to mammiferous volume and route of administration.
Embodiment 1-is used for the tubular fibre analysis (HOLLOW FIBERASSAY FOR PRELIMINARY IN VIVO TESTING) of tentative experiment in the body
The biological experiment department of exploitation treatment project has adopted the interior preliminary screening instrument of body to be used to estimate the potential antitumour activity that extensive cell in vitro screens the compound of being differentiated.This tubular fibre analysis from June nineteen ninety-five just bring into use (
Http:// dtp.nci.nih.gov/branches/btb/hfa.html).
On the same day that implantation is carried out, the sample of each tumor cell line analyzes by stable terminal point MTT all that to carry out viable cell quantitative, the cell concentration of (0) when knowing zero.So, can suppress cell and the ability of killing cell by the determination experiment compound.The the 3rd or 4 day after tubular fibre is implanted begins with experiment material treatment mouse, once a day, and totally 4 dosage.Each material is estimated by 2 dosage levels of peritoneal injection, and scheme is 3 mouse/dosage/experiments.Vehicle Control comprises 6 mouse, only accepts the diluted chemical compound agent.Carried out stable terminal point MTT and analyze from the mouse recycled fiber same day behind the 4th compounds for treating.In the optical density(OD) of 540nm place each sample of spectrphotometric method for measuring, calculate the average of each treatment group.Calculate in each treatment group the percentage of clean cell growth, compare with the percentage of clean cell growth in the control group of vehicle treated.Estimating each compound in totally 4 experiments (3 clone/experiments * 4 experiments=12 clones).
The data of analyzing according to a plurality of tubular fibres are screened compound and to be carried out other experiment (for example, time/dosage expose the preliminary pharmaceutical research of research, subcutaneous xenotransplantation effectiveness study).Standard comprises: have 10 clean cell growths to reduce by 50% or more in (1) 48 possible experiment combination (site, 12 clones * 2 * 2 compound dosage); The rarest 4 clean cell growths reduce by 50% or more in (2) 24 amphi position point combinations (intraperitoneal administration/subcutaneous culture); And/or (3) cell of one or more clone in any implantation site is killed (amount of viable cell is reduced to the level when being lower than the experiment beginning).
In order to simplify evaluation, to adopt and divide valve system (point system) to estimate, it can investigate the activity of appointed compound fast.For this reason, to making the reduction by 50% of viable cell quantity or each above compound be appointed as 2 fens.Intraperitoneal and subcutaneous sample are scored respectively so that with standard (1) and (2) definite value.IP+SC is 20 minutes in conjunction with the compound score of administration, and the compound score of SC administration is 8 minutes, and the compound that perhaps clean cell is killed one or more clone can consider to carry out other experiment.A kind of score value of maximum possible of medicine is 96 minutes (site, 12 clones * 2 * 2 dosage level * 2[score values]).In tubular fibre analysis and heteroplastic transplantation experiment, these standards have been confirmed from statistics by the active result who compares>80 compounds of selecting at random.This relatively shows: if the tubular fibre analysis is used as first screening method in the body, the possibility of omitting the xenotransplantation active compound so is very little.Because the reason in the tubular fibre analysis design, can not report the result of single clone, because the statistical power of this analysis is based on the influence of compound to whole clone group.Except the tubular fibre analytical results, other factors (for example, particular structure, the mechanism of action etc.) also may cause compound is carried out other research (if compound can not satisfy the standard that these tubular fibres are analyzed).
The separation of the upright moral of example II-Pa Monot
Extract (the handkerchief Monot founds moral A, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot and the upright moral E of handkerchief Monot) available from S.adareanum shows activity in field-based feeding-deterrent assays, make the present inventor study these active chemical property.New isolating polyketide is provided, and the handkerchief Monot founds moral A, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot and the upright moral E of handkerchief Monot, and they are the main natural products available from the S.adareanum extract.These polyketides show cytotoxicity in National Cancer Institute (NCI) 60 clone groups (panel), particularly can suppress wherein melanoma (UACC-64, LC
500.018 μ M), the susceptibility than the clone of other experiment exceeds 3 orders of magnitude.
According to similar methods, adopt contriver's the standard scheme that is used for fractionation lipotropy natural product to separate upright moral A-H of handkerchief Monot and K.Freeze dried biomass (biomass) are used methylene chloride 1: 1 (3 *) extraction fully as far as possible, are concentrated into the extract that merges dried.With sample on the extract to the silicagel column of filling with 100% hexane.The hexane of twice column volume divides two portions wash-out, adopt 1: 9,2: 8,4: 6,8: 2 ethyl acetate/hexane, 100% ethyl acetate and 5%, 10% last and the 20%MeOH/ ethyl acetate gradient elution of twice column volume subsequently, collect each column volume as a flow point.Repeat high performance liquid chromatography (HPLC; Waters YMC 5 μ, ODS 10mm * 30mm adopts the different water MeCN wash-outs of measuring, and depends on separation requirement), 5 kinds of handkerchief Monots that obtain purifying found moral.(referring to Figure 19).The upright moral metabolite of other handkerchief Monot can separate by bigger flow point from the polarity of this lipophilic extract.For example, from other fraction products of the ethyl acetate/methanol wash-out flow point of the flash chromatography of lipophilic extract obtain the bigger upright moral of handkerchief Monots of three kinds of polarity (by
1The HNMR chromatogram detects, and the upright moral of these handkerchiefs Monot is the height hydroxylation more).Bioanalysis as herein described and other analysis known in the art can confirm the biological activity of these separated products.
The upright moral of handkerchief Monot or other melanoma-bioactive compounds that the polarity that exists in hydrophilic extract is bigger can carry out fractionation by anti-phase vacuum chromatogram.Water is filled C-18 improvement silica gel by the vacuum funnel, then with sample on the extract, adopts the methanol of the water of two bed volumes and 1: 9,2: 8,4: 6,8: 2, is 100% methyl alcohol vacuum wash-out then, collects the flow point of each column volume.Perhaps, polar component can be adsorbed on the polystyrene resin (HP-20 or XAD), adopt similar methyl alcohol or acetone gradient elution scheme.The chromatogram flow point that will so obtain then concentrates and carries out bioanalysis.Subsequently or can select to carry out chromatographic step known in the art, adopt above-mentioned identical stationary phase, adopt narrower solvent gradient, perhaps if necessary, adopt other stationary phase example gel infiltration (LH-20 or G-IO) to obtain purifying.
By HPLC the biological activity separated product is carried out last purifying.Chromatographic behavior according to separated product adopts various fixed to separate on HPLC.Usually, anti-phase (C-18, phenyl) post is applicable to non-polar compound, and normal phase column is applicable to the compound of middle polarity, and other multiple bonding phase (amino, cyano group, glycol) post is applicable to the compound that has similar quality with weighting material.Yet it is not rare adopting the organic compound of reversed-phase HPLC separating polar maximum.It should be noted that the contriver has successfully adopted polymerization stationary phase C-18 (YMC and/or Waters) (being applicable to pure water and/or buffer solvent) so that can be by the metabolite (amino acid, nucleosides) of reversed-phase HPLC separating polar maximum.Contriver's HPLC equipment is equipped with series mass susceptibility (differential refractive index (RI) and/or evaporat light scattering (ELSD)) detector and UV-detector.Double check is important, although because RI or ELSD detector relative insensitivity have proportional response to quality.UV-detector is extremely sensitive, but its optical extinction coefficient that responds according to chromophore changes.This HPLC device comprises analysis, half preparation and processability (four kinds of equipment, 0.1mL/min to 300mL/min), when needs, contriver's LC/MS can integrate to add MS (total chromatography of ions with any equipment, TIC) detect, have the advantage of mass spectral characteristic to guarantee separated product.
Although the contriver has the HPLC equipment that is used to the upright moral of preparation property separation handkerchief Monot, this method also has some shortcoming, and these shortcomings can overcome by adopting high-speed countercurrent chromatography known in the art (CCC) or high speed partition chromatography (CPC).CCC and CPC to two kinds not the separation of the assay of mixing between mutually have advantage, compare with absorbing chromatogram, physical properties makes it have the higher rate of recovery.At present available equipment comprises and is used for the isolating many volumes rotor of preparation amount (two kinds of gravity gradient that technology all adopt rotation to bring out).Employings such as Foucault water/DMSO/THF system has finished the successful purifying of polyketone macrolide (amphotericin B), and this is the good beginning of the upright moral purifying of handkerchief Monot.(Foucault, A.P. etc., 1993).
EXAMPLE III-Pa Monot founds moral A
Separating the upright moral A of the handkerchief Monot who obtains in 1: 1 methanol/ethyl acetate flow point of the silica gel chromatography wash-out of crude product lipotropy (1: 1 ethanol/methylene) extract is white solid.Learn that by mass spectroscopy molecular formula is C
33H
48N
2O
7(HRFABMS m/z 585.3539, Δ 0.1mmu, [M
++ 1]).C-1 to the C-24 carbon skeleton of the upright moral A of handkerchief Monot can basis
1H-
13The C connectivity is arranged and is clearly belonged to by gHMBC spectrum.Can finish being connected of big ring by observing C-19 (δ 73.69) methyne with the dependency between the C-1 ester carbonyl group.The hydroxyl methyne that can clearly belong to C-7 and C-10 place according to the coupling of hydroxyl proton in gHMBC and the COSY wave spectrum: in the gHMBC wave spectrum, hydroxyl proton and α-relevant respectively with β-carbon, and in the COSY wave spectrum, it is relevant with the hydroxyl methine protons to observe hydroxyl proton.Senecioyl acid amides (determining by 2D NMR analysis) has been finished general structure, except CO in the molecular formula
2NH
2Outside failing to belong to.This remaining carbon is relevant with proton on the C-11 that carries oxygen (δ 75.25), but other connectivity is not obvious.Last remaining valency must be by-NH
2Occupy, thereby obtain formamyl on C-11, finished the two dimensional structure of the upright moral A of handkerchief Monot.
Stereoassay finds that all disubstituted alkene are the E configuration, this be according to them bigger coupling constant (>14Hz) definite.According to observed H-16 and H in the ROESY wave spectrum
2-18 and H-15 and H
3-25 dependency also is appointed as the E configuration with the trisubstituted alkene of C-16 position.Equally, according to H-24 and H
3-27, H-23 and H
3-27 and H-21 and H
3-27 with H-20 and H
3-26 ROESY dependency also is appointed as the E configuration with C-21 alkene.(R) of the upright moral A of handkerchief Monot-and (S)-the MTPA ester
41Proof C-7 and C-10 are the R configuration.Little between the ortho position proton that arrives according to the observation
3J
H-10/H-11And big related of H-10/C-12 with H-11/C-9
3J
CH, the segmental conformational analysis of C-10/C-11
42Determined gauche form (gauche) relation of H-10 and H-11.
2J
C-11/H-10With
2J
C-10/H-11In also found other evidence of structure picture, they both be big and negative, thereby the absolute stereo chemistry of determining C-11 is R.Equally, according to greatly
3J
H-19/H-20, little
3J
C-21/H-19,
3J
C-26/H-19With
3J
C-18/H-20And it is big
2J
C-19/H-20, the conformational analysis of C-19/C-20 system shows trans (anti) relation of each proton.The relative position of C-18 is determined by following in this fragment: observed H
2-18 and H-20 and H
2-18 and H
3ROESY dependency between-26, and at H
2-18 and H-21 between do not observe the ROESY dependency, need 19R
*, 20S
*Relative configuration.The NMR data of the upright moral A of handkerchief Monot can be referring to table 2.
Four alkene in big ring have limited flexibility common in the macrolide, make to be easy to NOE research carrying out stereoassay.The further analysis of ROESY wave spectrum shows that macrolide has two bigger planar side of the ring of tear-drop shape, and a side is made of C-1 to C-6, and opposite side is made of C-11 to C-19, and C-7 to C-10 provides crooked connection.Specifically, H-19, H
3-27, H-15 and H
2-13 (referring to Fig. 3) order in ROESY spectrum is relevant, H
3-26, H
2-18, H-16, H-14 and H-12 are like this equally, thereby have defined the top in the western hemisphere and the border of bottom.H-11 is only relevant with a series of protons at top, and it is consistent that result and C-19 and C-11 are the R configuration.
Urochordates is not the product survivor of known I type polyketide, although patellazoles and iejimalides are the representatives of important biologically active.The upright moral A of handkerchief Monot carries little big ring unusually, and it is 20 yuan of rings (and patellazoles and iejimalides are 24 yuan of rings), and carries vinylamide, and for example tolytoxin is more relevant with Macrolide derived from blue-green algae for this feature.The upright moral A of handkerchief Monot has the cytotoxicity (see figure 2) to multiple other melanoma cell series, [M14 (LC
500.076 μ M), SK-MEL-5 (6.8 μ M) and LOX IMVI (9.8 μ M)], aforementioned UACC-62 is also had cytotoxicity.Outside melanoma (Fig. 3), a kind of colon carcinoma cell line (HCC-2998,6.5 μ M) (Fig. 4 A) and a kind of renal carcinoma cell line (PvXF 393,6.5 μ M) (Fig. 4 B), the upright moral A of handkerchief Monot lacks cytotoxicity (LC to other
50>10 μ M), this is illustrated in that the selectivity index to most of sensitive cellss is 10 in the test cell system
3Importantly, in the NCI database, handkerchief Monot upright moral A is retrieved as the COMPARE.-feminine gender, shows that its mechanism of action do not appear in the newspapers.
Fig. 4 A and 4B have shown the experiment in vitro result that National Cancer Institute's exploitation treatment project is carried out the upright moral A of handkerchief Monot.Fig. 5 has shown that the handkerchief Monot that National Cancer Institute (NCI) exploitation treatment project provides founds the dose response curve of moral A to all experimental cells systems.As a comparison, melanoma (Fig. 6), colorectal carcinoma (Fig. 7) and kidney (Fig. 8) have been provided independent test-results respectively.
The cytotoxicity of the upright moral C of EXAMPLE IV-Pa Monot
The chemical formula that the handkerchief Monot founds moral C (listing below with among Fig. 9) is C
33H
49N
2O
7(the NMR data are seen Figure 10).The NCI cytotoxicity provides in Figure 11 A and Figure 11 B.The dose response curve to all cells system that NCI provides is shown in Figure 12.
The cytotoxicity of the upright moral D of EXAMPLE V-Pa Monot
The chemical formula that the handkerchief Monot founds moral D (listing below with among Figure 13) is C
36H
53N
2O
7The upright moral D NMR data rows of handkerchief Monot is shown in Figure 14.
The cytotoxicity of the upright moral E of example VI-Pa Monot
The chemical formula that the handkerchief Monot founds moral E (listing below with among Figure 15) is C
27H
39NO
7(the NMR data are seen Figure 16).The NCI cytotoxicity provides in Figure 17 A and Figure 17 B.The dose response curve to all cells system that NCI provides is shown in Figure 18.
Example VII A-bioanalysis
The clone of determining (UACC-62, SK-MEL-5 and MK14, they are all to the upright moral A sensitivity of handkerchief Monot) is available from the NCI standard scheme that is used for cell cultures.Be 95% in atmospheric moisture, in 5%CO
2, make UACC-62 (Amundson etc. in 37 ℃ the environment, 2000) and MEL14 (Lin etc., 2003) cell is grown in RPMI 1640 substratum, and this culture medium supplemented has 10% foetal calf serum and glutamine and adopts microbiotic (100 units/mL penicillin, 100mg/mL Streptomycin sulphate) to handle.
SK-MEL-5 (Miracco etc., 2003).Be 95% in atmospheric moisture, in 5%CO
2, in 37 ℃ the environment, cell is grown in containing the EagleShi minimum essential medium of EarleShi BSS, regulate this substratum and make and wherein contain 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acid and 1.0mM Sodium.alpha.-ketopropionate.
Bioanalysis adopts 96-hole lattice MTT-based (Vogt etc., 2004) method that cell growth-inhibiting and the cell lethality that the upright moral of handkerchief Monot and derivative thereof cause carried out quantitatively.In this was analyzed, metabolic activity lysis MTT (MTT) (it is an xanchromatic) formed the purple first
Dyestuff, simultaneously with the ultraviolet displacement, can adopt read the plate instrument measure in 540nm place absorb carry out quantitative.
The structure of example VII A I-bioactive metabolites is set forth
When separating metabolite, the discriminating of isolate (going redundancy) is important.
1H NMR chromatogram detects (being used in combination with the mass spectrum information of LC/MS and/or ESIMS) can be used to differentiate aforesaid compound usually.The database search of marine natural product data helps redundancy with reviewing very much; Drs.J.Blunt and M.Munro (Blunt, J.W.; Munro, M.H.G.MarinLit.University ofCanterbury, Christchurch, New Zealand, 12.4 editions, 2004) the marine natural product database of producing and the mass spectral database of NIST and Wiley be useful in this respect.As described in the initial stage data division of the upright moral A of handkerchief Monot, new compound is carried out Spectrum Analysis completely.
The structure that the present age, chromatographic process can be used for new isolate is determined (people such as Crews, 1998; People such as Silverstein, 1998).One dimension proton and carbon NMR wave spectrum are used in combination with mass spectroscopy (deriving from LC/MS or electro-spray ionization (ESI) or substance assistant laser desorpted ionized (MALDI) mass spectrograph), can guarantee the accurate ownership of new compound molecular formula.Be used in combination for example COSY people such as (, 1976) Aue or have spin system people such as (, 1983) Braunschweiler of the expansion of TOCSY of two dimensional NMR techniques, can establish being connected of two keys and triple bond proton-proton.Adopt HMQC or HSQC (people such as Bax, 1986a; People such as Bodenhausen, 1980) (people such as Bax, 1986b) (two keys or triple bond) can establish the connection of proton-carbon for (key) and HMBC.These NMR experiment is the most common with the gradient that is used to obtain maximum susceptibility (people such as Maudsley, 1978; People such as Ruiz-Cabello, 1992) the pattern acquisition, if necessary, can adopt the solvent peak pressing.If there are enough materials to use, then can be by adopting to such an extent that 2D-INADEQUATE wave spectrogram people such as (, 1980) Bax is established carbon-to-carbon and connected;
13C-
13The direct mensuration of C coupling makes the integral part of structure determine easily.If possible, according to result or NOESY (people such as Crews, 1998 of coupling constant data and nucleus overhauser effect (nuclear Overhauserenhancement); People such as Silverstein, 1998) technology or the stereochemistry in the configuration qualification system is determined by derivatize or degraded.Analyze to adopt
3J
HHWith
2,3J
CH(respectively derived from decoupling and/or ECOSY (people such as Griesinger, 1985) (
3J
HH) or the HMBC (Furihata etc., 1999) that decomposes of J-(
2,3J
CH)) Murata method (Murata etc., 1999) stereochemistry of flexible system (linear or big ring) is analyzed.Under the unascertainable situation of spectral method, then can adopt chemical derivatization and/or degradation technique progress one to illustrate structure, perhaps can growing crystal so that x-ray crystal analysis (people such as Yoshida, 1995; Ankisetty etc., 2004).
Example I X-Study on degradation
The upright moral of handkerchief Monot provides abundant functionalization (functionalization) for Study on degradation.The reduction ozone of handkerchief Monot upright moral A, D and/or E decomposes generation three kinds of hexane polyvalent alcohols (11-13, flow process 1).By with 11 optically-active and conclusive (R ,+)-1,2, the optically-active of 6-trihydroxy-hexane people such as (, 2000) Wu relatively can obtain the stereochemistry conformation of the upright German-Chinese C-7 position of these handkerchiefs Monot.
By comparing the position that can prove C-10 and C-11 with four-alcohol 12, described alcohol does not appear in the newspapers in chemical literature.According to flow process people such as (, 2001) Zhu of preparation analogue compounds, can be easily from D-semi-lactosi preparation four-alcohol 12 (flow processs 2).By adopting periodate cleavage D-semi-lactosi 1,3-acetal (16) people such as (, 1990) Dolder can provide 12 of needs by Wittig reaction homologization, hydrogenation people such as (, 2001) Zhu and hydrolysis then, is used for comparison.
Flow process 1: the handkerchief Monot founds the Study on degradation (ozone decomposition) of moral A (1), D (8) and E (9).
Flow process 2: preparation (2R, 3R)-1,2,3, the synthetic method of 6-tetrahydroxy hexane (12)
Flow process 3.i) Ti (O-í-Pr)
4(0.2eq), D-DET (0.3eq), t-BuOOH.ii)CuCN,MeLi,Et
2O。iii)11,TsOH。Iv) Swern oxidation (Mancuso etc., 1981).v)Ph
3PCH
3,BuLi。vi)TsOH
3,H
2O。
The Study on degradation of upright moral B (6) of handkerchief Monot and C (7) can provide polyvalent alcohol (flow process 4 and 5) equally.It is upright German-Chinese to be expected at all handkerchief Monots, and the stereochemistry of C-19 and C-20 is identical, so the ozone degradation production of upright moral B of handkerchief Monot and C can provide the identical product that contains described stereocenter (13).For the upright moral B of handkerchief Monot, two kinds of new degraded products (24,25) have been produced.24 the two kinds of enantiomers that obtained by D-and L-L-glutamic acid all are known (Brunner etc., 1989; Larcheveque etc., 1984), after measuring ordering, can provide chirality optics relatively.Can obtain to have the product 25 of triol functional end-group by flow process 2 technology, can choose wantonly if desired and adopt other sugar to begin reaction, and adopt C derived from the 3-bromopropyl alcohol
3Wittig reagent carries out homologization.
The ozone of the upright moral B (6) of flow process 4. handkerchief Monots decomposes
The ozone of the upright moral C (7) of flow process 5. handkerchief Monots decomposes
Penta-alcohol, 26 (flow processs 5) of decomposing derived from upright moral C (7) reduction of handkerchief Monot ozone can be by being selected from C
5The precursor in carbohydrate storehouse (pool) is prepared (flow process 6), if suitably, can determine stereochemistry by spectrum.
Flow process 6.i) ethyl vinyl ether, PPTS, CH
2Cl
2, ii) Ph
3PCH
2CH
2CH
2OH, (TMS)
2NLi.iii)H
2/Pd。Iv) 1N HCl, room temperature.
Flow process 1-6 has summed up the evidence of the upright stereochemical degrading texture of moral A-G of handkerchief Monot.During the upright moral of the handkerchief Monot who makes new advances when separation, they can be handled according to this to confirm all stereochemistry orderings.
Structure-the activity research of the upright moral of embodiment X-handkerchief Monot
The upright moral of handkerchief Monot has the melanoma activity by suppressing vacuole's apysase (V-ATPases).They are that polyprotein is striden the film enzyme, proton can be transported from the endochylema transfer, thereby regulate intracellular pH, and be homeostatic important function (Sun-Wadaa etc., 2004).They are ubiquity in eukaryotic cells, and also idol is found to some extent in prokaryotic organism.Two territories of this enzyme are formed by about six subunits, contain 20 protein altogether and gather (protein assemblage).Embed V in the film
0The territory is the locus of proton transhipment, and Asia-film (sub-membrance) V
1The territory has catalysis (ATP to ADP) active (Nishi etc., 2002).Except pH regulator, V-ATPases has participated in following process: endocytosis, film merge (Morel etc., 2003), bone resorption (Nomiyama etc., 2005) and be not other function (Nishi etc., 2002) of simple acidification (functions of acidity).Yet, they may play special effect in cancer-adjusting path, described path and cell growth, differentiation (Martinez-Zaguilan etc., 1993), vasculogenesis (Martinez-Zaguilan etc., 1999a), multiple medicines thing-resistance (Laurencot etc., 1995; Raghunand etc., 1999; Martinez-Zaguilan etc., 1999b; Sennoune etc., 2004) relevant with transfer (Martinez-Zaguilan etc., 1998).
Can understand the interaction of ligand/receptor better to structure research of V-ATPases, described research comprises NMR research (Jones etc., 2001) and the protokaryon V-type Na to the F subunit
+The K of-ATPase ring subunit (it and eucaryon H
+The c/c ' of V-ATPases/c " encircle similar) the research of X-ray data (Murata etc., 2005) of renewal.The importance of this X-ray data is known H
+The V-ATPases inhibitor combines (Pali etc., 2004 with the c subunit; Huss etc., 2002), the X-ray data has proved the ligand/receptor combination of inhibitor.
V-ATPases is relevant with various disease states, comprises type i diabetes (Myers etc., 2003a; Myers etc., 2003b), osteoporosis (Nomiyama etc., 2005; Sundquist etc., 1990) and multiple cancer (Sennoune etc., 2004), for example cervical cancer (Ellegaard etc., 1975), mammary cancer (Martinez-Zaguilan etc., 1999b) and melanoma (Martinez-Zaguilan etc., 1998).Verified on the cytolemma of transitivity breast cancer cell the quantity of V-ATPase enzyme significantly increase (Martinez-Zaguilan etc., 1993; Sennoune etc., 2004).Cancer cell need be hanged down the endochylema of pH and mainly depend on V-ATPases and be kept acidity (Martinez-Zaguilan etc., 1993; Raghunand etc., 1999).
Ba Foluo mycin A1 (4, Fig. 3) be prototype V-ATPase inhibitor (Zhang etc., 1994), although its associativity and specificity are good not as the following inhibitor of recent findings: salicylihalamides (vis 5) (Erickson etc., 1997 for example; Boyd etc., 2001), oximidines (Kim etc., 1999), lobatamides (McKee etc., 1998; Shen etc., 2002) and the upright moral of handkerchief Monot.Except the Ba Foluo mycin, concanamycins (Huss etc., 2002) is similarly big lopps, although poecillastrins and chondropsins (Xie etc., 2004) are bigger Macrolide, except lactone bond, it also contains lactam bond.
Ba Foluo mycin A
1(4) Salicylihalamide A (5)
The V-ATPase inhibitor becomes new drug target (Chene etc., 2003 of cancer therapy; Beutler etc., 2003).The key that produces first-class medicine (for example taxol is to be used to suppress tubulin depolymerization (Horwitz etc., 2004)) finds that the medicine that has finally caused being used for this indication increases, and has greatly enriched the selection of treatment.Histone deacetylase (HDAC) inhibitor (Arts etc., 2003) has excited the interest of people to this respect too, and Food and Drug Admistraton (FDA) has ratified the clinical application researchs of several new drugs (IND) application recently.In present known several effective V-ATPase inhibitor, expection has a kind of can entering very soon to apply for the IND stage.
The modification of target functional group is carried out according to " 5 rules (the Rule of5) " that Lipinski equals the calendar year 2001 elaboration, to solve absorption, distribution, metabolism, drainage and toxicity (ADMET) problem.In the Lipinski rule, the handkerchief Monot founds the dry straight of moral: have 5 or H-key donor still less, MLogP is about 1.8 to 2.76 and (adopts SimulationsPlus, Inc. (Lancaster, CA) the ADMET forecasting software calculates), exist to be less than 10 H-key acceptors.Molecular weight is higher, and span is about 550 to 610; The upright moral E of handkerchief Monot be unique one less than 500, but its lacks and has an active desired vinylamide of V-ATPase.Adopt the ADMET prediction to improve research method, clearly, solubleness and perviousness are to need to concentrate two aspects of carrying out derivatization research, still, and these two both directions that the aspect seemingly deviates from mutually.So the solubleness raising is accompanied by polar functional group to be increased, infiltrative raising then needs to remove polar functional group.These the two kinds mediations that need on the contrary need be carried out according to biological assessment: according to aforesaid method melanoma and/or V-ATPase activity according to the compound of this paper method preparation are estimated, the compound that only can keep enough biological activitys (Asia-millimole) to those and have a good ADMET characteristic (according to the ADMET prediction and evaluation) carries out the tubular fibre analysis and/or xenograph analyzes.
The disappearance of C-24 acid amides causes active the reduction, and another of C-6 and C-12 hydroxylation/alkylene type reset and equally also made active the reduction, and this can prove that they all pass through NCI 60 clone bioanalysiss by upright moral C (7) of handkerchief Monot and E (9).The upright moral of other handkerchief Monot is analyzed too.
For the research of chemical derivatization, the overall structure of the upright moral of handkerchief Monot can be divided into three important areas: the vinylamide (SAR that (1) C-24 is terminal and continuous
1The zone, flow process 7); (2) hydroxylation/alkylene (SAR that links to each other on C-7 to the C-12 position
2The zone, flow process 7); (3) olefin group, they all can carry out chemical treatment.
Flow process 7: based on the diversity of the natural product of structure-active pattern
Carry out derivatization research: increase each regional polar group, reduce each regional polar group and under the situation that does not change polar group quantity, modify.The replacement of carrying out polar group on the different sites of core texture may produce other possible modification.Along with the accumulation gradually of biological data, people can select the biological activity pattern (curative effect and ADMET prediction characteristic) of needs, and are not only to produce a large amount of derivatives.Described below is this area treatment process and interpolation of concentrating, the treatment process of removing or keep the polar group invariable number.
I.SAR
1
The zone
Be appointed as SAR
1The zone can estimate by at least four kinds of natural products.It is just different in the character of the end of the upright moral fundamental chain of handkerchief Monot that the handkerchief Monot founds moral A (1), D (8), E (9) and F (10).The synthetic modification of the further detection C-24 end of introducing can comprise following chain end group:
Keep polar functional group:
Unconjugated:
Conjugated:
Some polar group is reduced:
Add polar functional group:
Unconjugated:
Conjugated:
By the catalytic vinylamide prepared in reaction of copper derivative 30 to 45 (flow process 8) (Shen etc., 2000).Adopting thiophene carboxylic acid's copper (I) be catalyzer (CuTC), and acid amides and the vinyl iodide 46 of needs carried out coupling, can prepare the E vinylamide analogue that solid that the handkerchief Monot founds moral is controlled with high yield.
Flow process 8.i:CuTC, N, N '-dimethyl-quadrol, K
2CO
3, 50 ℃, R ' CONH
2Ii:HF ' pyridine/pyridine.
Essential E-vinyl iodide 46 can prepare according to one of two kinds of methods.The most direct approach comprises the homologization (vis 47, flow process 9) of the upright moral E of handkerchief Monot of chromium catalytic (Takai alkylene, Takai etc., 1986) tri-tert silyl protection.Should be noted that: because the functionalization of the upright moral of handkerchief Monot is unlike the functionalization (Gunasekera etc. of discodermolide, 1990), so, they can be confirmed by the synthetic method that is applied to discodermolide the stability of condition described herein, described synthetic method is (Paterson etc., 2001 as known in the art; Smith etc., 2000).
The handkerchief Monot founds moral E (9): R=H
47:R=TBS
Flow process 9.i:TBSCl, imidazoles.Ii:CHI
3,CrCl
2,THF,℃。
Perhaps, vinyl iodide 46 can be from the upright moral A preparation of handkerchief Monot; Although relate to more step, because founding moral A, the handkerchief Monot in urochordates, has comparative advantage, so this needs.Therefore; the handkerchief Monot can be stood the suitable protection (flow process 10) of moral A, thereby the oxygen functional group of C-7 and C-10 position and the oxygen functional group difference of C-11 position are come, then with acid amides selective hydrolysis (Eaton etc.; 1988), the phthalic imidine hydrolysis that obtains is produced aldehyde 48.Adopt Danishefsky method (DiGrandi etc., 1993) that aldehyde 48 is converted into vinyl iodide, the Danishefsky method also can directly produce vinyl iodide by ketone.Obtain thermokinetics E vinyl iodide (49).Under the condition of using with the carbamate hydrolysis; Adopt right-methoxy-benzyl ether (PMBO (C=NH) CCl in this position
3, PPTS) (Nakajima etc., 1988) blocking group is so that come functional group's difference of itself and C-7 and C-10 oxidation in other method.
Flow process 10.i) TBSCl, imidazoles.Ii) tetrachloro is for Tetra hydro Phthalic anhydride, Δ.Iii) a. hydrazine, b.TsOH/H
2O.Iv) hydrazine.v)I
2,DBU。
If Danishefsky method (flow process 9) is undesirable; also can aldehyde (48) be degraded to the upright moral E (47 of handkerchief Monot of protection by the Baeyer-Villiger oxidation; R=PMB); with the formyl radical ester hydrolysis that produces; pass through Dess-Martin oxidation (Dess etc., 1991) then and obtain aldehyde (flow process 11).Shown in flow process 9, intermediate 47 can be prepared as vinyl iodide 46 then.Attention: Baeyer-Villiger reagent (for example those adopt the reagent of the acid catalyzed trimethyl silyl superoxide of Lewis-) can carry out in the presence of alkene usually, need not to worry epoxidation (Brink etc., 2004)
Flow process 11.i) Baeyer-Villiger (Nakajima etc., 1988).ii)TsOH/H
2O。iii)DMP,NaHCO
3。
The upright moral analogue 39-41 of handkerchief Monot can be prepared as follows: make the upright moral E (47) of protected handkerchief Monot carry out Wittig reaction (obtaining 39) with first base three phenyl phosphonium bromide/BuLi, make hydroxymethyl derivative 48 through NaBH
4/ CoCl
2Reduction (obtaining 40) perhaps makes 40 through acetylize (obtaining 41).
Ii.SAR
2The zone
C-7 to C-12 SAR
2The zone can comprise that the handkerchief Monot founds moral A (1), B (6) and C (7) finds out that described natural product is only at SAR by natural product
2The zone is different.The upright moral C of handkerchief Monot is than the upright moral A weak effect of handkerchief Monot.By keeping, reduce and adding polar functional group template 51 is modified, other synthetic derivatization can be judged the effect of alcohol groups.Perhaps can easily obtain other modifications.
SAR
2Modify template 1 (51)
Keep polar group:
R
1 R
2 R
3
52:?p-OHBn H CONH
2
53:?H p-OH?Bn CONH
2
54:?p-OH?Bn p-OH?Bn CONH
2
55:?H H H
56:?H H p-OH?Bn
56A:(CH
3)
2CHCHNHCO H CONH
2
56B:(CH
3)
2CHCHNHCO (CH
3)
2CHCHNHCO CONH
2
Reduce polar group
R
1 R
2 R
3
57:Me H CONH
2
58:H Me CONH
2
59:Me Me CONH
2
60:H H Me
61:=O H CONH
2
62:H =O CONH
2
63:CONH
2 H CONH
2
64:H CONH
2 CONH
2
65:CONH
2 CONH
2 CONH
2
SAR
2Modify template 2 (66)
Add polar group (template 2):
R
1 R
2 R
3
67:CONH
2 H CONH
2
68:H CONH
2 CONH
2
69:CONH
2 CONH
2 CONH
2
The preparation of derivative 52-69:
Reaction on the C-7 position is carried out (Diyabalanage etc., 2006) prior to the reaction on the C-10 position.So the compound of C-7 position list-derivatize can directly prepare.C-10 position list-derivative can be by C-7 protection (tri-tert silyl ether)/go protection preparation.Descarbamato (55) is reflected in the flow process 10 and describes; C-7 position and C-10 position alcohols are carried out suitable protection modification to the C-11 position can be provided.If the biological activity of acetic ester 63-65 is secure, carbamate can be in the C-7 position so, C-10 position and C-11 position exchange (Cl
3CC (O) NCHO, K then
2CO
3) (Kocovsky, 1986).L- valine ester 62 and 63 has proved that by similar valacyclovir prodrug model preparation the latter can significantly improve pharmacokinetics performance (Guglielmo etc., 2004).Compound 67-69 can be prepared (form the diastereomer product, thereby each obtaining two products from 63-65 through separating the back) by perosmic anhydride (osmimum tetroxide) dihydroxy of 63-65.
Iii. the effect of alkene
At last, the effect of olefin functionalities adopts selective hydrogenation catalyst to estimate.By adopting H
2, Pd/C handles the upright moral A of handkerchief Monot to carry out the perhydro-reaction synthetic 70, makes dibasic alkene (71) selective hydration (Choi etc., 1996) by nickel borides.Can carry out and α the selective reduction (Ram etc., 1992) of the alkene that β-undersaturated carbonyl (vis 72) is relevant by 10%Pd/C and ammonium formiate.By multiple hydrogenation technology, for example adopt hydroborate exchange resin/Ni
2The B catalyzer can carry out the selective reduction (Yoon 1996) of lonely non-conjugated alkene (73).Except the upright moral natural product of other handkerchief Monot that can produce different hydrogenated products, the evidence that the upright moral A derivative of these handkerchiefs Monot provides alkene to work in the upright moral biological activity of handkerchief Monot.
Iv. the applied in any combination of derivatization
If biological activity and/or ADMET prognosis modelling need, then be used for SAR
1, SAR
2And/or the modification of hydrogenization can easily be used in combination.
When determining the clear and definite structure of compound, the complete synthesis of natural product is main tool.Complete synthesis also as the successful strategies of synthesis of natural product analogue, can carry out by the simple change of each reaction in raw material or the synthesis flow.The study on the synthesis for the upright moral of handkerchief Monot of contriver's suggestion has described the method for convergence (convergent) in detail, in described method, each composition all can change, thereby the analogue of studying and adopt the computer forecast generation of ADMET by the X-ray cocrystallization that carries out with V-ATPase can be provided.This synthetic method also can be used to confirm the structure and the absolute stereo chemistry of the upright moral of handkerchief Monot.The upright moral of this handkerchief Monot for a small amount of existence is particularly important, and for example the handkerchief Monot founds moral D, E and F, because they can isolated just trace.
Should synthetic can so strictly not carry out at fragment, these fragments are available from the Study on degradation (as mentioned above) that adopts the upright moral A reduction of handkerchief Monot ozone to decompose.According to aforementioned Study on degradation result, the contriver has designed the retrosynthetic analysis (flow process 12) of the upright moral A of handkerchief Monot.This retrosynthesis is divided into 3 main fragments with molecule.Can easily form the big ring parent nucleus (Grubbs etc., 1995) of the upright moral A of handkerchief Monot by the closed replacement(metathesis)reaction of ring of precursor 76.By forming described metathetical precursor 76 with 78 esterifying alcohols 77.It is right that fragment 79 and 80 can be used as the coupling of Heck reaction, produces the pure fragment 77 (Harris etc., 1996) that needs.By copper-catalytic amidate action, acid amides 80 can be embedded the C-21 side chain, described reaction directly relates to the promoted prolongation of Co-PI (develop) (Shen etc., 2000:Klapars etc., 2001; Jiang etc., 2003).The vinyl iodide 82 that amidate action needs can adopt the Takai alkene reaction of corresponding aldehyde precursor to be prepared (Takai etc., 1986).Then, adopt the Schlosser improvement reaction of Wittig reaction can form the two keys (Schlosser etc., 1966) of C-22.This has just optionally formed (E)-alkene.Can determine the stereochemistry (Evans etc., 1981) of C-20 and C-21 by the cis-selectivity aldol reaction with high predictability of Evans exploitation.Then, adopt the asymmetric dihydroxy reaction of Sharpless to prepare chiral diol 79 (Jacobsen etc., 1988) in enantioselectivity ground.Also can adopt asymmetric dihydroxy reaction synthesis of chiral alcohol fragment 78.This with regard to enantioselectivity formed chiral, secondary alcohols on the C-8 position.Similar vinyl acetate in the fragment 78 (vinylogous ester) can be passed through Horner-Wadsworth-Emmons alkene prepared in reaction (Stocksdale etc., 1998).
The retrosynthetic analysis of the upright moral A (1) of flow process 12. handkerchief Monots
Structure from fragment 79 begins the upright moral A of synthetic handkerchief Monot.According to known method (Hanessian etc., 1975), adopt imidazoles and TBDPS-Cl to handle alcohol, be TBDPS ether with deriving from commercial alkynol 85 (flow process 13) protection.Adopt Paraformaldehyde 96 and n-BuLi to handle alkynes 86 and form known propargyl ethanol 87 (Nicolaou etc., 1989).Adopt Red-Al (two (2-methoxy ethoxy) sodium aluminum hydride) to handle 87 and form the allyl alcohol 88 that known E-replaces.Adopt the Sharpless condition, 88 asymmetric dihydroxies are formed the glycol 89 (Jacobsen etc., 1988) that needs with the height enantioselectivity.It should be noted that: at this moment, should carry out the asymmetric hydroxy amino reaction of Sharpless (Li etc., 1996) in this stage of reaction.This has just formed 1 of enantiomer-pure, the 2-amino alcohol.The acid amides nucleophilic group is had a preference for alkene carbon usually and is had less obstruction.Observe in view of the above, the amine of protection should be positioned on the C-11 of the upright moral A of handkerchief Monot.This hydroxy amino reaction path can provide the handkerchief Monot azepine variant of upright moral.Adopt acetone and TsOH to handle, two secondary alcohol groups of compound 89 can optionally be protected and be acetonide (Coe etc., 1989).Because the thermodynamic stability of this product, this can protect two secondary alcohol, helps primary alconol.At this moment, the primary alconol in 90 can adopt TIPS radical protection (Cunico etc., 1980).Then, acetonide can adopt FeCl in chloroform
3And SiO
2Open (Kim etc., 1986).This can open acetonide and can not influence the alcohol that silyl is protected.At this moment, the secondary alcohol on the C-12 can adopt TBS-Cl and imidazoles protection (Corey etc., 1972).Because the volume of the TIPS blocking group that exists on the C-10 hydroxyl, the C-12 alcohol of protection should be primary product.At this moment, C-11 alcohol can adopt MOM-Cl, NaH protection (Kluge etc., 1972) at THF.Adopting different blocking groups to protect the ability of all oh groups is very important for this research, because it can reach the derivatization of the upright moral A of major objective-Pa Monot of this research.By the TBDPS selectivity is sloughed, adopt Dess-Martin oxygenant oxidation (Dess etc., 1983) then, can prepare aldehyde 92.By Takai alkene reaction (Jiang etc., 2003), this aldehyde can be converted into vinyl iodide 93 then.This alkene reaction preference ground forms (E)-vinyl iodide.This vinyl iodide has that Heck reacts needed correct stereochemistry in the route of synthesis of back.
Flow process 13.i) TBDPSCl, imidazoles, DMF.ii)BuLi,(CH
2O)n,THF。iii)Red-Al,Et
2O。iv)AD-mix?β,t-BuOH/H
2O。V) acetone, TsOH.Vi) TIPS-Cl, pyridine.vii)FeCl
3/SiO
2,CHCl
3。Viii) TBS-Cl, imidazoles, DMF.ix)MOM-Cl,NaH,THF。x)5N?NaOH,EtOH。Xi) Dess-Martin oxygenant, DCM.xii)CHI
3,CrCl
2,THF,℃。
The next key step of the upright moral A synthetic of handkerchief Monot is for to prepare fragment 78 according to retrosynthesis.78 synthesize from adopting Dess-Martin oxygenant (Dess etc., 1983) oxidation 94 beginnings (flow process 14).The asymmetric dihydroxy reaction of the Sharpless of alkene can form glycol 95 (Jacobsen etc., 1988) in enantioselectivity ground.Primary alconol can adopt TBDPS-Cl and imidazoles optionally to be protected (Hanessian etc., 1975).In methylene dichloride, adopt SEM-Cl and DIPEA, secondary hydroxyl can be converted into SEM ether 96 (Lipshutz etc., 1980).Can form 97 (Stocksdale etc., 1998) by the reaction of Horner-Wadsworth-Emmons alkene.In EtOH, adopt 5N NaOH to slough the TBDPS group then, adopt the Dess-Martin oxygenant, obtain compound 98 (Dess etc., 1983) pure oxidation.The Petassis alkene reaction of aldehyde functional group can obtain alkene 99 (Petassis etc., 1990).With DIBAL the ester functional group of compound 99 is reduced and to obtain aldehyde 100 (Sunazuka etc., 2000).Under the Jones oxidizing condition, make this formoxy-ization can form carboxylic acid 101 (Bowden etc., 1946).In the reaction of back, compound 101 can be directly used in the formation ester bond.Yet, adopt oxalyl chloride 102 that the reaction that acid is converted into acyl chlorides may be produced slight esterification.
Flow process 14.i) Dess-Martin oxygenant, DCM.ii)AD-mix?β,t-BuOH/H
2O。Iii) TBDPS-Cl, imidazoles, DMF.iv)SEM-Cl,DIPEA,DCM。V) phosphine acyl acetic acid three ethyl, KHMDS, 18-hat-6, toluene.vi)5N?NaOH,EtOH。Vii) Dess-Martin oxygenant.Viii) Cp
2Ti (Me
2), THF refluxes.ix)DIBAL-H,Et
2O。X) NaClO
2, NaH
2PO
4, 2-methyl-2-butene, t-BuOH.Xi) (COCl)
2, benzene.
The molecule fragment that needs at last to prepare is C-17 to a C-25 amide side chains.Synthetic this segmental the first step (flow process 15) is carried out the PDC oxidizing reaction for deriving from commercial geraneol, obtains 103 (Reiter etc., 2003).At this moment, adopt Evans cis-selectivity aldol condensation can form 104 (Evans etc., 1981).This Evans method has been proved to be the chemosynthesis worker and has been used for one of the most reliable instrument of synthesizing cis-selectivity aldol product.R group that can Gai Bian oxazolidone is with the excessive acquisition product of the highest diastereomer.The alcohol of compound 104 is protected formation 105 (Lipshutz etc., 1980).Then, by being exposed to Chu Qu oxazolidone auxiliary group in the methanol solution of NaOMe with 105, form ester 106 (Evans etc., 1981).Adopt LiAlH
4With ester 106 reduction, adopt PPh subsequently
3And Br
2Carry out bromination, form bromide 107 (Wiley etc., 1964).Adopt the Schlosser alternative of Wittig reaction, make 107 and 108 to react single-minded formation (E)-alkene 109 (Schlosser etc., 1966).With the synthesis step of compound 109, subsequently acetal is gone protection then through flow process 16.This has just synthesized the upright moral E of handkerchief Monot.Acetal goes to carry out the reaction of Takai alkene after the protection, forms compound 110 (Takai etc., 1986; Hagiwara etc., 1987).Under copper-catalysis, make vinyl iodide and necessary acid amides carry out coupling and obtain 111 (Shen etc., 2000; Klapars etc., 2001; Jiang etc., 2003).Change the acid amides that adopts in this coupled reaction and can synthesize upright moral D of handkerchief Monot and F respectively.
Flow process 15.i) a) Bu
2BOTf, DIPEA, DCM, ℃, add 103 ,-78 to 0 ℃ then.b)MeOH/30%H
2O
2。Ii) imidazoles, SEM-Cl, DMF.iii)NaOMe
3,MeOH,0℃。iv)LiAlH
4,Et
2O。V) PPh
3, Br
2, triglyme.Vi) PPh
3, PhLi, LiBr, Et
2O, toluene adds 108 then.Vii) PPTS, acetone, H
2O, Δ.viii)CHI
3,CrCl
2,THF,0℃。Ix) acid amides, CuTC, N, N '-dimethyl-quadrol, K
2CO
3, 50 ℃.
The final step (flow process 16) of the upright moral A of synthetic handkerchief Monot begins from the Heck coupling of vinyl iodide 93 and alkene 111, and this reaction forms diene 112 (Harris etc., 1996).Slough the TIPS group earlier and carry out the reaction of Petasses alkene then, obtain compound 113 (Petassis etc., 1990).The contriver selects to adopt the reaction of Petassis alkene, because this method can allow to have functional group in the compound 112.Slough the SEM group of compound 113 earlier, adopt compound 101 to carry out esterification then, form 114 (Schlessinger etc., 1986).Employing s-generation Grubbs catalyzer carries out ring-closed replacement(metathesis)reaction of 114, forms big ring 115 (Grubbs etc., 1995).According to observations, this replacement(metathesis)reaction has been successfully used to the natural product of the upright moral A structural similitude of handkerchief Monot the big ring closure in synthetic.For example, the RCM method helps to form (E)-two keys (Meng etc., 1997) in the ebormycine family of natural product.Adopt isocyanic acid and CuCl to handle 115 and can form carbamate 116 (Duggan etc., 1989).The final step of the upright moral A of synthetic handkerchief Monot is at Et
2Adopt MgBr among the O
2Remaining blocking group is all removed (Kim etc., 1991) with BuSH.This is the guard method of going of a gentleness, can not open the carbamate-functional that lactone or cracking exist.
Flow process 16.i) Pd (PPh
3)
4, Et
3N, DMF.Ii) 40%KOH, MeOH refluxes.Iii) Cp
2Ti (Me
2), toluene.iv)TFA,DCM,0℃。v)NaH,DMF,101。Vi) Grubb s-generation catalyzer, toluene, Δ.vii)AcOH,H
2O,THF。viii)HNCO,CuCl,DMF。Ix) MgBr
2, Et
2O, BuSH, room temperature.
Be appreciated that embodiment as herein described and embodiment only are used for illustrative purposes, those skilled in the art can carry out various modifications or change to it, and these modifications or change in the application and claim spirit and scope required for protection.In addition, all key elements of any invention disclosed herein or embodiment or limit and can be used in combination with any key element of other inventions disclosed herein or embodiment or qualification and/or all key elements or qualification (single or any combination), this type of all combinations all do not add and limit ground not within the scope of the present invention.
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Claims (51)
1. the handkerchief Monot of isolating formula I founds Dehua compound and isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form:
Wherein:
Singly-bound or two key;
R
1For formaldehyde ,-CHCHNHC (O)-alkyl ,-the OC-alkyl ,-the OC-aryl ,-OC-amino, aryl, amino ,-vinyl amido, aryl amido, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl; Alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen or-CHO, they each all can choose wantonly and replace by following groups: H, alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen or-CH
3
R
2Independent be OH, O-acyl group, carbamate, H, O-alkyl, amino ,-OSO
3H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen and/or oxo;
R
3Be H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
R
4Independent be H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, mix alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
2. the handkerchief Monot of claim 1 founds Dehua compound, wherein at least one R
2For-OC (NH
2) O.
3. the handkerchief Monot of claim 1 founds Dehua compound, wherein R
3Be methyl.
4. the handkerchief Monot of claim 1 founds Dehua compound, wherein at least one R
4Be methyl, in another embodiment, two R
4Be methyl.
5. the handkerchief Monot of claim 1 founds Dehua compound, wherein R
1For-CHCHNHC (O) CHC (CH
3)
2
6. the handkerchief Monot of claim 1 founds Dehua compound, wherein R
1For-CHCHNHC (O) CHC (CH
3) CH
2C (CH
3) CH
2.
7. the handkerchief Monot of claim 1 founds Dehua compound, wherein R
1For-CHCH-NHC (O) CH
2C (CH
3) CH
2
8. the handkerchief Monot of claim 1 founds Dehua compound, wherein R
1For-CH=O.
9. the handkerchief Monot of claim 1 founds Dehua compound, wherein at least one R
2For-OH.
10. the handkerchief Monot of claim 1 founds Dehua compound, wherein at least one R
2For-OSO
3H.
11. the upright Dehua of the handkerchief Monot of claim 1 compound, wherein at least two R are-OH and at least one R
2For-OC (NH
2) O, optional R
3And R
4For-CH
3
17. the upright Dehua of the handkerchief Monot of claim 1 compound, wherein said compound has following array structure:
19. the upright Dehua compound of the handkerchief Monot of isolating formula II and isomer, racemic modification or its racemic mixture or its pharmacy acceptable salt or crystallized form:
Wherein:
R
1Be formaldehyde,-CHCHNHC (O)-alkyl,-OC-alkyl,-OC-aryl,-OC-amino, aryl, amino,-vinyl amido, the aryl amido, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, the heteroaryl carbonyl, the Heterocyclylalkyl carbonyl, aryloxycarbonyl, the heteroaryloxy carbonyl, the heterocycle alkoxy carbonyl, halogen or-CHO, they each all can choose wantonly and replace by following groups: H, alkyl, alkoxyl group,-OH,-NO
2,-NH
2,-COOH, halogen or-CH
3
R
2Independent be OH, O-acyl group, carbamate, H, O-alkyl, amino ,-OSO
3H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl; Alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen and/or oxo;
R
3Be H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, assorted alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
R
4Independent be H, alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy, aryloxy, alkyl-carbonyl, alkoxy carbonyl, naphthene base carbonyl, cyclo alkoxy carbonyl, mix alkyl, Heterocyclylalkyl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, Heterocyclylalkyl carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, heterocycle alkoxy carbonyl, halogen, they each all can choose wantonly and replace by following groups: alkyl, alkoxyl group ,-OH ,-NO
2,-NH
2,-COOH, halogen and/or-CH
3
20. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein at least one R
2For-OC (NH
2) O.
21. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein R
3Be methyl.
22. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein at least one R
4Be methyl, in another embodiment, two R
4Be methyl.
23. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein R
1For-CHCHNHC (O) CHC (CH
3)
2
24. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein R
1For-CHCHNHC (O) CHC (CH
3) CH
2C (CH
3) CH
2
25. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein R
1For-CHCH-NHC (O) CH
2C (CH
3) CH
2
26. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein R
1For-CH=O.
27. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein at least one R
2For-OH.
28. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein at least one R
2For-OSO
3H.
29. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein at least two R
2For-OH and at least one R
2For-OC (NH
2) O, optional R
3And R
4For-CH
3
31. the upright Dehua of the handkerchief Monot of claim 19 compound, wherein said compound has following array structure:
32. composition, said composition contain, and each handkerchief Monot founds Dehua compound and pharmaceutically acceptable carrier among the claim 1-31.
33. suppress the method for V-ATPase enzyme, described method comprises the upright Dehua of the handkerchief Monot compound that makes the contact of described V-ATPase enzyme or be exposed among the claim 1-32 each, and the amount of described compound can suppress the active of described V-ATPase effectively or block the function of described V-ATPase.
34. the treatment and the method for V-ATPase expression of enzymes diseases associated, described method comprise that each handkerchief Monot founds Dehua compound among the claim 1-32 of the human or animal's significant quantity that needs treatment.
35. treatment suffers from human or animal's the method for cancer or tumor disease, described method comprises the upright Dehua of the handkerchief Monot compound that gives among the claim 1-32 that described human or animal treats significant quantity each.
36. separate the method for the upright moral of handkerchief Monot, described method comprises:
A) solvent extraction Synoicum tunicate;
B) remove described solvent and obtain extract; With
C) the described extract of fractionation is to separate the upright moral of described handkerchief Monot.
37. the method for claim 36, wherein said solvent are CH
2CH
2/ MeOH.
38. the method for claim 36, wherein said extract adopt flash chromatography to separate.
39. the method for claim 38, wherein said flash chromatography are silica gel gradient flash chromatography.
39. the method for claim 36 is wherein at the flow point that obtains after the fractionation described in step c) process gradient elution on silica gel.
40. the method for claim 36, the flow point that wherein obtains after fractionation described in the step c) is through high performance liquid chromatography (HPLC), for example reversed-phase HPLC.
41. the method for claim 36, wherein said solvent is removed by evaporation.
42. the method for claim 36, wherein after the step (b), described extract distributes in solvent.
43. the method for claim 42, wherein said solvent are ethyl acetate.
44. the method for claim 42, the solvent of wherein said distribution extract is through washing and dry.
45. comprising in addition, the method for claim 36, wherein said method obtain described urochordates.
46. the method for claim 36, wherein said urochordates are Synoicum adareanum.
47. the method for claim 36, wherein said urochordates are cryodesiccated.
48. the method for claim 36, the upright moral of wherein said handkerchief Monot is the upright moral A of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot or the upright moral K of handkerchief Monot.
49. test kit, this test kit contain the upright moral of each handkerchief Monot among the claim 1-32 in one or more container.
50. the test kit of claim 49, the upright moral of wherein said handkerchief Monot is the upright moral A of handkerchief Monot, the upright moral B of handkerchief Monot, the upright moral C of handkerchief Monot, the upright moral D of handkerchief Monot, the upright moral E of handkerchief Monot, the upright moral F of handkerchief Monot, the upright moral G of handkerchief Monot, the upright moral H of handkerchief Monot or the upright moral K of handkerchief Monot.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US71759805P | 2005-09-16 | 2005-09-16 | |
US60/717,598 | 2005-09-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101277942A true CN101277942A (en) | 2008-10-01 |
Family
ID=37889469
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CNA2006800366454A Pending CN101277942A (en) | 2005-09-16 | 2006-09-18 | Cytotoxin compounds and methods of isolation |
Country Status (7)
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EP (1) | EP1934196A4 (en) |
JP (1) | JP2009508878A (en) |
KR (1) | KR20080059213A (en) |
CN (1) | CN101277942A (en) |
AU (1) | AU2006292268A1 (en) |
CA (1) | CA2622912A1 (en) |
WO (1) | WO2007035734A2 (en) |
Families Citing this family (3)
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US7838691B2 (en) | 2007-04-05 | 2010-11-23 | Board Of Regents, Of The University Of Texas System | Palmerolides: methods of preparation and derivatives thereof |
US9416085B2 (en) * | 2008-07-08 | 2016-08-16 | Solvay Specialty Polymers Italy S.P.A. | Process for the manufacture of fluorosurfactants |
WO2012045451A1 (en) | 2010-10-05 | 2012-04-12 | Ludwig-Maximilians-Universitaet Muenchen | Novel therapeutic treatment of progranulin-dependent diseases |
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-
2006
- 2006-09-18 CA CA002622912A patent/CA2622912A1/en not_active Abandoned
- 2006-09-18 KR KR1020087009037A patent/KR20080059213A/en not_active Application Discontinuation
- 2006-09-18 CN CNA2006800366454A patent/CN101277942A/en active Pending
- 2006-09-18 JP JP2008531434A patent/JP2009508878A/en not_active Withdrawn
- 2006-09-18 AU AU2006292268A patent/AU2006292268A1/en not_active Abandoned
- 2006-09-18 WO PCT/US2006/036484 patent/WO2007035734A2/en active Application Filing
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KR20080059213A (en) | 2008-06-26 |
EP1934196A4 (en) | 2011-05-18 |
JP2009508878A (en) | 2009-03-05 |
CA2622912A1 (en) | 2007-03-29 |
WO2007035734A3 (en) | 2007-05-03 |
AU2006292268A1 (en) | 2007-03-29 |
WO2007035734A2 (en) | 2007-03-29 |
EP1934196A2 (en) | 2008-06-25 |
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