CN108969519A - Purposes of the big cyclic lipopeptide compound in the preparation of target on cancer stem cell drugs - Google Patents
Purposes of the big cyclic lipopeptide compound in the preparation of target on cancer stem cell drugs Download PDFInfo
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- CN108969519A CN108969519A CN201710406111.6A CN201710406111A CN108969519A CN 108969519 A CN108969519 A CN 108969519A CN 201710406111 A CN201710406111 A CN 201710406111A CN 108969519 A CN108969519 A CN 108969519A
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- stem cell
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The present invention provides purposes of the big cyclic lipopeptide compound of formula 1 in the preparation of target on cancer stem cell drugs, the big cyclic lipopeptide compound of formula 1 is characterized in that can be with target on cancer stem cell, reduce the ratio that cancer stem cell accounts for all cancer cells, microballoon is reduced in the test of tumour microballoon and forms number, can eliminate the ability that cancer cell forms tumour.
Description
Technical field
The present invention relates to purposes of the big cyclic lipopeptide compound in the preparation of target on cancer stem cell drugs, belong to drug
Field.
Background technique
Cancer stem cell, also known as tumour initiator cell, refer to the cancer cell with stem cell properties.Cancer stem cell can be with
Start tumour and driving tumor proliferation, the infinite multiplication of cancer cell can be realized by self-renewing, can be generated by differentiation
More mature common cancer cell [T. Reya, S. J. Morrison, M. F. Clarke, and I. L.
Weissman, , Nature2001. 414: 105–111.].Generation due to cancer stem cell to tumour, transfer and drug
Drug resistance in play an important role [J. E. Visvader, G. J. Lindeman,Cell Stem Cell 2012, 10,
717-728], target on cancer stem cell may be a kind of strategy of more effectively treating cancer.BE-43547 is by Streptothrix
Espy A43547(Streptomyces) generate, one kind has the general name of the big cyclic lipopeptide compound of anticancer activity.According to the report,
BE-43547 series compound has inhibitory activity [H. to cancer cells such as P388, colon26, DLD-1, PC-13 and MKN-45
Nishioka, S. Nakajima, M. Nagashima, K. Ojiri, H. Suda, (Banyu Pharm Co Ltd)
Japanese patent 10147594-A].2017, Poulsen et al. probed into BE-43547A1、BE-43547A2Withent-BE-43547A1To the cell activity of pancreatic cancer cell Panc-1, wherein such compound under the conditions of normoxia
IC50It is 1.6 ~ 3.2 μM, and IC under anoxic conditions50For 41 ~ 53 nM, extraordinary hypoxemia selection is shown
Cytotoxicity.[N. L. Villadsen, K. M. Jacobsen, U. B. Keiding, E. T. Weibel, B.
Christiansen, T. Vosegaard, M. Bjerring, F. Jensen, M. Johannsen, T. Torring,
T. B. Poulsen, Nat. Chem. 2017, 9, 264-272.].And currently, commercially available most of anti-tumor drugs exist
Anticancer activity under hypoxia condition reduces, and this is one of the reason of tumour cell generates drug resistance to anticancer drug.This hair
Bright to provide the purposes of such big cyclic lipopeptide compound target on cancer stem cell, such big cyclic lipopeptide compound can reduce
Cancer stem cell accounts for the ratio of all cancer cells, reduces tumour microballoon in the test of tumour microballoon and forms number, can eliminate cancer
The ability of cell formation tumour.
Summary of the invention
The present invention relates to the big cyclic lipopeptide compound of formula 1 target on cancer stem cell drugs preparation in purposes,
Wherein, R1For the alkyl of 2 to 20 carbon.
Wherein, cancer stem cell is pancreas cancer stem cell, colon cancer stem cell, lung cancer stem cell, prostate stem cell, stomach
Cancer stem cell, ovary cancer stem cell, breast carcinoma stem cell, esophagus cancer stem cell, human brain glioma stem cells, liver-cancer stem cell.
Detailed description of the invention
Fig. 1 compound 1a can reduce CD24+CD44+ESA+The ratio schematic diagram of cell
Tumour microballoon forms situation schematic diagram under Fig. 2 microscope
Fig. 3 tumour microballoon forms number statistical schematic diagram
Nude mice tumor formation situation schematic diagram in the test of Fig. 4 tumor cell transplantation
Wherein, * * indicates that p value indicates p value less than 0.001 less than 0.05, * * *.
Specific embodiment
In order to understand the present invention, the present invention is further illustrated by embodiment of compound 1a below, but is not meant to limitation originally
The protection scope of invention.Wherein the structure of compound 1a is
。
Embodiment 1: big influence of the cyclic lipopeptide compound to human pancreas cancer stem cell ratio
CD24+CD44+ESA+It is acknowledged as the label of pancreas cancer stem cell, detects CD24+CD44+ESA+The change of ratio can be examined
Survey the selectivity of compounds on pancreatic cancer stem cell.
(1) the Panc-1 cell of logarithmic growth phase, vitellophag simultaneously carry out cell count, adjustment cell concentration be 5 ×
104/ mL is added in 24 orifice plates with every 1 mL of hole, is placed in 37oC cell incubator, 5%CO2Culture 6 hours.
(2) experimental group is according to concentration gradient diluted compounds 1a, be added in 24 orifice plates be allowed to final concentration be respectively 0.5 μM,
1 μM and 2 μM.Positive controls, which are added, dilutes adriamycin according to concentration gradient, is allowed to final concentration of 1 μM.And it is empty to test setting
White control group is compareed.After gently concussion mixes, it is placed in 37 DEG C of cell incubators, 5%CO2Culture 48 hours.
(3) collect cell in streaming pipe, 1500 turns centrifugation 8 minutes after abandon supernatant, with 100 μ L PBS be resuspended cell, point
The not CD24-PE of 5 μ L of label, the CD44-APC of 5 μ L, the ESA-FITC of 5 μ L, after gently concussion mixes, room temperature is protected from light incubation
30 minutes.
(4) 1500 turns are abandoned supernatant after centrifugation 8 minutes, and after precipitating is resuspended with the PBS buffer solution of 300 μ L, flow cytometer is examined
Survey CD24+CD44+ESA+Pancreas cancer stem cell ratio.
Embodiment 2: the influence that big cyclic lipopeptide compound forms pancreatic cancer cell tumour microballoon
The pancreas cancer stem cell of people and mouse all has the ability that tumour microballoon is formed in suspension medium.Research has shown that only have
The pancreatic cancer cell of ability with self-renewing just has the external ability for forming tumour microballoon, therefore forms tumour microballoon
The number of number the number of stem cell population in cell mass reflected to a certain extent.Tumour is micro- after detection compound processing
The formation number of ball can be used to detection compound to the selective killing effect of pancreas cancer stem cell.
(1) Panc-1 cell is collected, 1000 rpm are centrifuged 8 min, and PBS washes one time, with MGM complete medium by cell
Density is adjusted to 2 × 104A/mL, cell is blown even, prevents cell agglomerating, it is made to be in unicellular as far as possible.
(2) cell is added in the 6 orifice plates of low adhesion strength, 3 mL culture mediums are added in every hole, and it is outstanding that 50 μ L cells are then added
Liquid mixes, and 3 repeating holes are arranged in every group of cell；
(3) for experimental group according to concentration gradient diluted compounds 1a, being added and being allowed to final concentration in 24 orifice plates is respectively 0.25 μM, 0.5
μM and 1 μM.Adriamycin and taxol is added in positive controls, and being allowed to final concentration is respectively 1 μM and 10 nM.Test setting is empty
White control group is compareed, and gently concussion mixes.
(4) 37 DEG C, 5% CO2Incubator in cultivate 7 days or so, counted under microscope formed in each hole of each group it is swollen
The number of tumor microballoon, and take pictures.
Embodiment 3: big influence of the cyclic lipopeptide compound to one-tenth knurl ability in pancreatic cancer cell body
It is current studies have shown that the content of pancreas cancer stem cell and the one-tenth knurl ability of pancreatic cancer cell have direct relationship.Therefore
The one-tenth knurl ability of pancreatic cancer cell reflects the level of pancreas cancer stem cell.
(1) the Panc-1 cell of logarithmic growth phase digests and carries out cell count, adjusts cell concentration.Experimental group is pressed
According to concentration gradient diluted compounds 1a, being allowed to final concentration is respectively 0.25 μM, 0.5 μM and 1 μM.Positive controls be added Ah
Mycin is allowed to final concentration of 1 μM.Test setting blank control group is compareed.The additionization after Panc-1 cell is completely adherent
It closes object 1a and positive control medicine acts on 48 hours.
(2) group of cells is collected respectively, carries out cell count, and adjustment cell concentration is 5 × 107/mL、5×106/mL、5×
105/mL。
(3) subcutaneous transplantation enters Balb/C nude mice oxter, and every mouse transplants 100 μ L volumes.
(4) tumor formation rate (TIF) of each group mouse is observed and recorded.
The above result shows that:
1, CD24 in cancer of pancreas Panc-1 cell can be significantly reduced in big cyclic lipopeptide compound of the present invention+CD44+ESA+
The ratio of cell.Compared with blank control group, CD24 of the compound 1a under 1 μM of concentration+CD44+ESA+The ratio of cell declines
94 times.
2, big cyclic lipopeptide compound of the present invention can inhibit tumour microballoon to be formed.Compared with blank control group,
The formation number of tumour microballoon of the compound 1a under 1 μM of concentration has dropped 70 times.
3, compound 1a of the present invention can eliminate the ability that cancer cell forms tumour in vivo.
Claims (2)
1. purposes of the big cyclic lipopeptide compound of formula 1 in the preparation of target on cancer stem cell drugs,
Wherein, R1For the alkyl of 2 to 20 carbon.
2. according to claim 1, cancer stem cell is that pancreas cancer stem cell, colon cancer stem cell, lung cancer stem cell, prostate are dry
Cell, gastric cancer stem cell, ovary cancer stem cell, breast carcinoma stem cell, esophagus cancer stem cell, human brain glioma stem cells, liver cancer are dry
Cell.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2014203645A1 (en) * | 2007-06-05 | 2014-07-24 | Yale University | Inhibitors of receptor tyrosine kinases and methods of use thereof |
| US20150224169A1 (en) * | 2012-09-06 | 2015-08-13 | Mcmaster University | Compounds and methods for selectively targeting cancer stem cells |
| CN105504025A (en) * | 2014-10-16 | 2016-04-20 | 南开大学 | Rakicidin a and preparation method thereof |
| CN105753936A (en) * | 2016-03-28 | 2016-07-13 | 福建省微生物研究所 | Rakicidins compounds Rakicidin B1 and preparation method thereof |
-
2017
- 2017-06-02 CN CN201710406111.6A patent/CN108969519A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2014203645A1 (en) * | 2007-06-05 | 2014-07-24 | Yale University | Inhibitors of receptor tyrosine kinases and methods of use thereof |
| US20150224169A1 (en) * | 2012-09-06 | 2015-08-13 | Mcmaster University | Compounds and methods for selectively targeting cancer stem cells |
| CN105504025A (en) * | 2014-10-16 | 2016-04-20 | 南开大学 | Rakicidin a and preparation method thereof |
| CN105753936A (en) * | 2016-03-28 | 2016-07-13 | 福建省微生物研究所 | Rakicidins compounds Rakicidin B1 and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| NIKOLAJ L. VILLADSEN 等: "Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products", 《NATURE CHEMISTRY》 * |
| 张伟杰等: "缺氧与肿瘤干细胞"干性"的关系研究进展", 《山东医药》 * |
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Application publication date: 20181211 |