CN106008531A - Pancreas cancer prevention use of polycyclic fused macrocyclic lactam compounds - Google Patents
Pancreas cancer prevention use of polycyclic fused macrocyclic lactam compounds Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
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Abstract
The invention discloses a pancreas cancer prevention use of polycyclic fused macrocyclic lactam compounds. The structural formula of the polycyclic fused macrocyclic lactam compounds is shown in the description; and in the formula, R1 is OCH3 or H, R2 is Cl or OH, and R3 is OCH3 or H. The polycyclic fused macrocyclic lactam compounds are separated through separating and purifying a fermentation liquid of Streptomyces xiamenensis CGMCC No.4.3534 from mangrove soil. Prepared ikarugamycin and derivatives thereof can inhibit proliferation and vitality of human pancreas cancer cells, and can be used to prepare pancreas cancer prevention drugs.
Description
Technical field
The invention belongs to field of natural medicinal chemistry, be specifically related to a kind of multi-ring and condense Macrocyclic lactams compounds
The anti-pancreatic cancer purposes of (polycyclic tetramate macrolactam, be called for short PTM afterwards).
Background technology
Ductal adenocarcinoma of pancreas (Pancreatic ductal adenocarcinoma, PDAC, be called for short cancer of pancreas afterwards) is to disappear
Change is one of common malignant tumor, and mortality rate is close to incidence rate, and within 5 years, overall survival is less than 6% [T.
Seufferlein and J.Mayerle,"Pancreatic cancer in 2015Precision medicine in
pancreatic cancer-fact or fiction?,"Nat.Rev.Gastroenterol.Hepatol.,vol.
13,pp.74-75,2016.].Its M & M presents rising trend in worldwide in recent years, becomes
For one of malignant tumor that prognosis is worst [J.D.Byrne, et al., " Iontophoretic device delivery
for the localized treatment of pancreatic ductal adenocarcinoma,"Proc.Natl.
Acad.Sci.U.S.A.,p.Ahead of Print,2016.].Spy due to cancer of pancreas the most easily Invasion and Metastasis
Property, late period has been belonged to when making a definite diagnosis more than 80%, only having about 10%-20% patient can carry out radical surgery, and therefore Drug therapy exists
The Comprehensive Treatment of cancer of pancreas has very important position [C.Scafoglio, et al., " Functional
expression of sodium-glucose transporters in cancer,"Proc.Natl.Acad.Sci.
U.S.A.,vol.112,pp.E4111-E4119,2015.].The standard one line medication of present stage treatment cancer of pancreas
Being gemcitabine (gemcitabine), for destroying the Difluoronucleosides class metabolism agonist drug of cellular replication, but the later stage is easy
Drug resistance seriously constrains drug effect.In addition scheme of combination drug therapy FOLFIRINOX, including irinotecan (irinotecan),
Oxaliplatin (oxaliplatin), 5-fluorouracil (5-fluorouracil) and folinic acid (leucovorin),
Also confirm to extend the life cycle of Pancreas cancer patients in clinic, but irinotecan is as the compound of camptothecin, its poison
Property effect very important [X.Liu, et al., " Irinotecan Delivery by Lipid-Coated Mesoporous
Silica Nanoparticles Shows Improved Efficacy and Safety over Liposomes for
Pancreatic Cancer,"ACS Nano,p.Ahead of Print,2016.].Therefore, research and development have anti-pancreas
Adenocarcinoma activity new small molecule compound be treatment cancer of pancreas in the urgent need to.
Summary of the invention
It is an object of the invention to provide the multi-ring anti-pancreatic cancer purposes condensing Macrocyclic lactams compounds of a kind of activity.
In the present invention, described for wild type Xiamen streptomycete (Streptomyces xiamenensis) in 2007 4
The moon submits the center preservation of CGMCC China Committee for Culture Collection of Microorganisms common micro-organisms, and preservation address is Beijing
Great Tun road, Chaoyang District, (the present address of Institute of Microorganism, Academia Sinica is Beijing in Institute of Microorganism, Academia Sinica
North Star West Road, Chaoyang District, city 1 institute 3), culture presevation numbered CGMCC No.4.3534.
The present invention seeks to be achieved through the following technical solutions:
First aspect, the present invention relates to a kind of multi-ring condense Macrocyclic lactams compounds, its structural formula such as formula I,
(II), shown in (III) or (IV):
Wherein, R1 is OCH3Or H, R2 are Cl or OH, R3 is OCH3Or H.
Second aspect, the invention still further relates to a kind of aforesaid multi-ring preparation method condensing Macrocyclic lactams compounds, institute
The method of stating comprises the steps:
S1, Xiamen streptomycete Streptomyces xiamenensis CGMCC No.4.3534 carry out liquid fermentation and culture;
S2, fermentation liquid is centrifuged process, take supernatant and be extracted with ethyl acetate;
S3, the method using C18 Solid-Phase Extraction, with methanol-water gradient elution, i.e. obtain described many at methanol-eluted fractions
Ring condenses Macrocyclic lactams compounds.
Preferably, in step S3, described methanol-water gradient elution is particularly as follows: 50%, 80%, 100% methanol-water gradient
Eluting, each gradient elution volume is 200mL.
The third aspect, the invention still further relates to a kind of aforesaid multi-ring Macrocyclic lactams compounds that condenses in preparation anti-pancreatic cancer
Purposes in medicine.
Fourth aspect, the invention still further relates to a kind of anti-pancreatic cancer medicament compositions, wherein contains and aforesaid multi-ring condenses macro ring
Lactam analog compound, or its pharmaceutically acceptable acid or the salt of alkali, or solvated compounds is as effective ingredient.
Preferably, described pharmaceutical composition is oral formulations or ejection preparation.
There is advantages that
1, the present invention is carrying from-Xiamen streptomycete (Streptomyces xiamenensis) CGMCC No.4.3534
Take thing and prepare anti-pancreatic cancer medicament compound, and ingredient is natural;
2, the multi-ring Macrocyclic lactams compounds that condenses of the present invention has propagation and the vigor that can suppress human pancreatic cancer cell,
The IC50 value of its anti-pancreatic cancer activity is 1 μM;
3, cancer of pancreas fatality rate is high, existing anti-pancreatic cancer medicament limitednumber;Found by clinical research, chemotherapy for
The therapeutical effect of cancer of pancreas is little, research show this be due to tumor around feltwork reaction hinder medicine enter pancreas
The ability of adenocarcinoma cell, the new compound finding special construction the most targetedly is to find treatment of pancreatic cancer medicine
Essential step.The multi-ring anti-pancreatic cancer activity condensing Macrocyclic lactams compounds and toxicity are surveyed by the present invention first
Fixed, the multi-ring of the present invention condenses macrolactams compound activity clearly, has good market application and promotion prospect.
Accompanying drawing explanation
The detailed description made non-limiting example with reference to the following drawings by reading, other of the present invention is special
Levy, purpose and advantage will become more apparent upon:
Fig. 1 is the multi-ring structure chart condensing Macrocyclic lactams compounds of the present invention;
Fig. 2 is quantitative at the multi-ring CCK-8 condensed in Macrocyclic lactams compounds suppression human pancreatic cancer cell proliferation experiment
Schematic diagram;Wherein, A) for suppressing the CCK-8 qualitative diagram in human pancreatic cancer cell PANC-1 proliferation experiment, B) be
CCK-8 qualitative diagram in suppression human pancreatic cancer cell BxCP1 proliferation experiment;
Fig. 3 is the toxicity schematic diagram of lactic dehydrogenase enzyme method detection compound 1-3.
Detailed description of the invention
The present invention is described in detail with specific embodiment below in conjunction with the accompanying drawings.Following example will assist in this area
Technical staff is further appreciated by the present invention, but limits the present invention the most in any form.It should be pointed out that, to this area
For those of ordinary skill, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement.These
Broadly fall into protection scope of the present invention.
Embodiment 1, the multi-ring Structural Identification condensing Macrocyclic lactams compounds
Take S.xiamenensis M6 bacterial strain (i.e. Xiamen streptomycete (Streptomyces xiamenensis) CGMCC No.
4.3534 carry out liquid fermentation and culture (30 liters), and 7 days, centrifuged supernatant was extracted with ethyl acetate 3 times.To extract
Liquid merges, and concentrates, obtains total extract 3 grams.Take and add 9 grams instead after the appropriate chloroform-methanol mixed solvent of total extract dissolves
Mix sample mutually, on to being filled with on 50 grams of purification on normal-phase silica gel glass decompression posts, with methanol-water gradient elution particularly as follows: 50%,
80%, 100% methanol-water gradient elution, each gradient elution volume is 200mL, and 150~100 milliliters/bottle graft is received, and washes
The polarity of desolventizing is carried out gradient by the consumption of methanol in raising chloroform and is incremented by, and each eluting stream part receives 200 milliliters respectively,
According to thin layer chromatography combining data detection stream part.Use half preparation C18 chromatographic column, obtain compound 1-7.Use nuclear magnetic resonance, NMR
The structure of compound 1-7 is resolved by method, and its structure is coincide with shown in Fig. 1.
Table 1, the nucleus magnetic hydrogen spectrum data of compound 1-7
Table 2, the nuclear-magnetism carbon modal data of compound 1-7
In table 1,2, the nuclear magnetic data of compound 2-7 is for find first.
Embodiment 2, the multi-ring propagation condensing Macrocyclic lactams compounds suppression human pancreatic cancer cell and viability experiment
Material is as follows:
Cell: human pancreatic cancer cell PANC-1, BxCP1;Medicine: the compound 1 obtained by above-described embodiment.Wherein,
Use compound 1 for drug treating experimental group, using compound 2 is drug treating contrast groups.
Method: PANC-1, BxCP1 cell is inoculated in 96 orifice plates, every hole 0.5 × 103Individual cell.Change after 24 hours
Liquid dosing, matched group is DMSO, final concentration of 1/1000.Dosing 0,1, surveys after 2,3,4,5,6 days respectively
Amount cell viability.Measuring method is, sucking-off culture medium, and every hole adds complete medium 100 μ l and CCK-8 reagent 10 μ l,
Incubator hatch 60 minutes after microplate reader measure light absorption value, wavelength is 450nm.Experiment is repeated 3 times.
Experimental result is as in figure 2 it is shown, can be learnt by accompanying drawing 2: compound 1 can suppress the propagation of human pancreas cancer.Its IC50
Value is 1.3 and 1.439 μMs.Compound 2 and compound 3 are the most active, and IC50 is 3 μMs.
The toxicity of compound 1-7 uses Lactic dehydrogenase detection kit to be evaluated.As shown in fig. 3, it was found that at IC50
Near concentration range, its toxicity is inconspicuous, is so very promising for later stage drug development.
Above the specific embodiment of the present invention is described.It is to be appreciated that the invention is not limited in above-mentioned spy
Determining embodiment, those skilled in the art can make various deformation or amendment within the scope of the claims, this not shadow
Ring the flesh and blood of the present invention.
Claims (6)
1. a kind of multi-ring condenses Macrocyclic lactams compounds, its structural formula such as formula (I), (II), (III) or (IV)
Shown in:
Wherein, R1 is OCH3Or H, R2 are Cl or OH, R3 is OCH3Or H.
2. the multi-ring preparation method condensing Macrocyclic lactams compounds as claimed in claim 1, its feature exists
In, described method comprises the steps:
S1, Xiamen streptomycete Streptomyces xiamenensis CGMCC No.4.3534 carry out liquid fermentation and culture;
S2, fermentation liquid is centrifuged process, take supernatant and be extracted with ethyl acetate;
S3, the method using C18 Solid-Phase Extraction, with methanol-water gradient elution, i.e. obtain described many at methanol-eluted fractions
Ring condenses Macrocyclic lactams compounds.
The most multi-ring preparation method condensing Macrocyclic lactams compounds, it is characterised in that
In step S3, described methanol-water gradient elution is particularly as follows: 50%, 80%, 100% methanol-water gradient elution, Mei Geti
Degree elution volume is 200mL.
4. the multi-ring Macrocyclic lactams compounds that condenses as claimed in claim 1 is in preparation anti-pancreatic cancer medicament
Purposes.
5. an anti-pancreatic cancer medicament compositions, wherein contains benzopyran compounds as claimed in claim 1, or
Its pharmaceutically acceptable acid of person or the salt of alkali, or solvated compounds is as effective ingredient.
6. anti-pancreatic cancer medicament compositions as claimed in claim 5, it is characterised in that described pharmaceutical composition is oral
Preparation or ejection preparation.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111253408A (en) * | 2020-02-11 | 2020-06-09 | 中国科学院南海海洋研究所 | Antibiotic pactamide G, preparation method thereof and application thereof in preparation of antibacterial drugs |
CN111511746A (en) * | 2017-12-19 | 2020-08-07 | 特普医药公司 | Macrocyclic compounds for the treatment of diseases |
CN113121545A (en) * | 2021-04-25 | 2021-07-16 | 山东大学 | Polycyclic macrocyclic lactam compound and preparation method and application thereof |
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CN104073507A (en) * | 2014-03-27 | 2014-10-01 | 中国科学院南海海洋研究所 | Biosynthetic gene cluster of ikarugamycin and application of biosynthetic gene cluster |
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2016
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009045443A2 (en) * | 2007-10-02 | 2009-04-09 | The University Of Rochester | Methods and compositions related to synergistic responses to oncogenic mutations |
CN104073507A (en) * | 2014-03-27 | 2014-10-01 | 中国科学院南海海洋研究所 | Biosynthetic gene cluster of ikarugamycin and application of biosynthetic gene cluster |
Non-Patent Citations (4)
Title |
---|
BAO-SHENG WANG,等: "Identification of genes and candidate agents associated with pancreatic cancer", 《TUMOR BIOLOGY》 * |
JUN XU,等: "Streptomyces xiamenensis sp. nov., isolated from mangrove sediment", 《INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY》 * |
MARCELO BERTASSO 等: "Ripromycin and other polycyclic macrolactams from Streptomyces sp. Tü 6239: Taxonomy, fermentation, isolation and biological properties", 《THE JOURNAL OF ANTIBIOTICS》 * |
MIN-JUAN XU 等: "Deciphering the streamlined genome of Streptomyces xiamenensis 318 as the producer of the anti-fibrotic drug candidate xiamenmycin", 《SCIENTIFIC REPORTS》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111511746A (en) * | 2017-12-19 | 2020-08-07 | 特普医药公司 | Macrocyclic compounds for the treatment of diseases |
CN111511746B (en) * | 2017-12-19 | 2024-01-09 | 特普医药公司 | Macrocyclic compounds for the treatment of diseases |
CN111253408A (en) * | 2020-02-11 | 2020-06-09 | 中国科学院南海海洋研究所 | Antibiotic pactamide G, preparation method thereof and application thereof in preparation of antibacterial drugs |
CN113121545A (en) * | 2021-04-25 | 2021-07-16 | 山东大学 | Polycyclic macrocyclic lactam compound and preparation method and application thereof |
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