CN113876784B - Novel application of boro-leucine compound - Google Patents
Novel application of boro-leucine compound Download PDFInfo
- Publication number
- CN113876784B CN113876784B CN202111139521.1A CN202111139521A CN113876784B CN 113876784 B CN113876784 B CN 113876784B CN 202111139521 A CN202111139521 A CN 202111139521A CN 113876784 B CN113876784 B CN 113876784B
- Authority
- CN
- China
- Prior art keywords
- boroleucine
- apn
- boro
- compound
- dinoate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- A61K31/69—Boron compounds
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention discloses application of a boro-leucine compound in preparation of an aminopeptidase N inhibitor and preparation of a medicament for inhibiting tumor growth. The boro-leucine compound is boro-leucine with a structure shown in a formula 1 or boro-leucine dinoate with a structure shown in a formula 2;the invention uses the boroleucine and the boroleucine dinoate to prepare the APN inhibitor, which can obviously inhibit the activity of the APN. The compound can be used as an APN inhibitor primer for developing new drugs, and can also be used for synthesizing a fluorescent probe targeting APN for early detection of tumors.
Description
Technical Field
The invention relates to the technical field of aminopeptidase N inhibitors, in particular to application of boroleucine and boroleucine dinoate in preparation of an aminopeptidase N inhibitor.
Background
Aminopeptidase N (Aminopepidase N, APN/CD13, EC 3.4.11.2) is a zinc ion-dependent transmembrane metalloproteinase that localizes to the outer surface of cell membranes by non-covalent binding to form homodimers. APN is closely related to the occurrence, development and metastasis of tumors, and inhibition of APN can inhibit metastasis of tumor cells. In addition, the APN is a biomarker of the semi-resting liver cancer stem cells, and the enhancement of APN expression can promote survival of the liver cancer stem cells. The above suggests that targeted inhibition of APN may have good effect on tumor treatment.
The boroleucine ((S) -1-amino-3-methyl butyl boric acid) and boroleucine dinoate ((S) -1-amino-3-methyl butyl boric acid pinanediol ester) belong to alpha-amino boric acid derivatives, and are intermediates for preparing proteasome inhibitor bortezomib. In addition, it was found that such compounds also inhibit the activity of the metalloprotease enkephalinase (EC 3.4.24.11). Therefore, the compounds are attracting more and more attention in drug design.
In the early stage, in the process of researching a micromolecular APN inhibitor, an AHPA-LEU dipeptide boric acid citrate compound with APN and proteasome double-target inhibition activity is found, and the AHPA-LEU dipeptide boric acid citrate compound has good anti-tumor activity, but the citrate is unstable, the proteasome inhibition activity is weak, and the killing activity on tumor cells is not strong enough. Therefore, finding small molecular compounds that effectively inhibit APN activity and for anti-tumor drug development has been a research hotspot in the field of pharmaceutical chemistry.
Disclosure of Invention
Aiming at the prior art, the invention aims to provide a new application of the boro-leucine compound. The invention uses the boroleucine and the boroleucine dinoate to prepare the APN inhibitor or synthesize the fluorescent probe of the targeting aminopeptidase N, and the boroleucine dinoate can obviously inhibit the activity of the APN.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides application of a boro-leucine compound in the following 1) or 2):
1) Preparing an aminopeptidase N inhibitor;
2) Preparing the medicine for inhibiting tumor growth.
Preferably, the boroleucine-like compound inhibits tumor growth by inhibiting two-dimensional tube production of HUVEC cells.
Preferably, the boro-leucine compound inhibits tumor growth by inhibiting tumor cell migration.
Preferably, the boro-leucine compound inhibits tumor growth by inhibiting tumor cell invasion.
Preferably, the boro-leucine compound is boro-leucine with a structure shown in a formula 1 or boro-leucine dinoate with a structure shown in a formula 2;
the boroleucine is an intermediate for preparing bortezomib, and the preparation method can be seen in: asolind-phase approach for the synthesis of a-aminoboronic acid peptides (Blake E. Daniels and Craig E. Stivala, RSC adv.,2018,8,3343-3347) at page 3345: synthesis of boronic acid 8, and a preparation method thereof.
The bortezomib is prepared by using the bortezomib as an intermediate, and the preparation method can be seen in the following steps: application No. 201210156068.X a method for preparing (1R) - (S) -pinanediol-1-amino-3-methylbutane-1-borate and salts thereof discloses a method for preparing (1R) - (S) -pinanediol-1-amino-3-methylbutane-1-borate, and the compound of formula ii prepared by the method has the same structure as the boroleucine dinoester in the invention.
The invention has the beneficial effects that:
the invention discovers that the novel micromolecule compounds of boroleucine and boroleucine dinoate can inhibit the enzyme activity of APN, and the APN is closely related to tumor metastasis, and can promote the tumor cells to metastasize to a remote tissue to form a metastasis site no matter whether the APN is expressed by tumor cells per se or the APN of an organism. In the tumor metastasis process, tumor tissue neovascularization facilitates tumor cell metastasis, so that inhibition of tumor tissue neovascularization and tumor cell migration invasion both contribute to inhibition of tumor metastasis. Experiments show that boroleucine and boroleucine-ester can inhibit umbilical vein endothelial cell (HUVEC) two-dimensional tube formation and tumor cell migration and invasion. Therefore, the compound can be used as an APN inhibitor primer for developing new drugs, and can also be synthesized into a fluorescent probe targeting APN for early detection of tumors.
Drawings
Fig. 1: schematic docking of boroleucine and boroleucine dinoate with APN;
fig. 2: photographs of two-dimensional tube production assays of HUVEC cells were inhibited;
fig. 3: photographs of an assay for inhibiting breast cancer cell migration;
fig. 4: quantification of the test value for inhibiting breast cancer cell migration;
fig. 5: photographs of inhibition breast cancer cell invasion assay;
fig. 6: quantitative analysis of the inhibition breast cancer cell invasion test;
fig. 7: photographs of inhibition in vivo lung metastasis assays;
fig. 8: quantification of lung nodule count in vivo;
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As described in the background section, AHPA-LEU dipeptide boric acid citrate compounds with APN and proteasome double-target inhibition activity have good anti-tumor activity, but citrate is unstable, the proteasome inhibition activity is weaker, and the killing activity on tumor cells is not strong enough.
Based on the above, the invention aims to provide a new application of the boro-leucine compound. Based on the background technology, further structure-activity relationship research shows that an ILeu, an N-protecting group CBZ and a boric acid protecting group dinoate are inserted between AHPA and LEU to be fully reserved, and the novel compound boroleucine dinoate is formed, so that the APN inhibitory activity and the antitumor activity can be greatly improved. The compound has the inhibition of APN enzyme activity level which is obviously superior to that of the control drugs ubenimex and bortezomib, and also has good activity in the aspects of two-dimensional tube generation resistance, migration resistance and invasion resistance. APN is closely related to tumor metastasis, and can promote tumor cells to metastasize to a remote tissue to form a metastasis, whether the APN is expressed by tumor cells per se or the APN of an organism. In the tumor metastasis process, tumor tissue neovascularization facilitates tumor cell metastasis, so that inhibition of tumor tissue neovascularization and tumor cell migration invasion both contribute to inhibition of tumor metastasis. Experiments show that boroleucine and boroleucine-ester can inhibit umbilical vein endothelial cell (HUVEC) two-dimensional tube formation and tumor cell migration and invasion. Therefore, the compound can be used as an APN inhibitor primer for developing new drugs, and can also be synthesized into a fluorescent probe targeting APN for early detection of tumors.
In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention are all conventional in the art and are commercially available.
Description: the boroleucine in the examples was prepared according to the preparation method of Synthesis of boronic acid 8 disclosed in "A solid-phase approach for the synthesis of a-aminoboronic acid peptides".
The preparation method of the (1R) - (S) -pinanediol-1-amino-3-methylbutane-1-borate disclosed in the preparation method of the (1R) - (S) -pinanediol-1-amino-3-methylbutane-1-borate is used for preparing the compound shown in the formula II, namely the borinedi-noate according to the application number 201210156068. X.
Example 1 in vitro enzyme inhibition activity assay of boroleucine dinoate:
a method for preparing APN enzyme source (patent application No. 201810629864.8) is used for evaluating the enzyme inhibition activity of boroleucine and boroleucine dinoate on aminopeptidase N, and ubenimex positive control 1 and bortezomib are used as positive control 2.
The test steps are as follows:
(1) Preparing cell homogenate after ultrasonic disruption of K562-APN cells, and inoculating the cell homogenate into a 96-well plate;
(2) Adding compounds of different concentration gradients to the wells;
(3) After 5min APN substrate is added to 1.6mM and incubated for 1h;
(4) The absorbance at 405nm was measured and the IC50 was calculated using Origin software.
Note that: the compound used in the test was boroleucine, boroleucine dinoate, ubenimex or bortezomib.
The results show that the IC50 value of the borrelidin on the APN inhibitory activity is 0.15+/-0.003 mu M, the IC50 value of the borrelidin on the APN inhibitory activity is 0.007+/-0.001 mu M, the positive control 1 ubenimex is 20.167 +/-1.84 mu M, the positive control 2 bortezomib is 65.69 +/-5.94 mu M, and the inhibition effect of the borrelidin and the borrelidin on the APN enzymatic activity is obviously better than that of ubenimex and bortezomib.
The invention predicts the combination of the boroleucine Dinoate and the boroleucine with the APN active site through molecular docking. As shown in fig. 1, the hydrogen bonding and hydrophobic interactions facilitate the binding of boroleucine dinoate and boroleucine to the active site of APN. The boronic acid group in boroleucine direnoate can form multiple hydrogen bonding interactions with surrounding residues such as Ala262 and Glu298, and the amino group has hydrogen bonding interactions with Glu121, met263 and Glu 264. One oxygen atom in the boro-leucine borate forms hydrogen bond interaction with the amino group of Ala262, and hydrogen bond interaction exists between the amino group of the boro-leucine and surrounding Glu264 and Glu 320. Residues Met260, ala262, met263, tyr376 and Tyr381 play an important role in the hydrophobic interaction of APN with boroleucine dinoate and boroleucine. In zinc binding, the boronic acid group of boroleucine, di-noate, binds to zinc ions, while the amino group of boroleucine also binds to zinc ions. Thus, differences in zinc binding patterns may lead to different enzyme inhibition activities.
EXAMPLE 2 two-dimensional tube production experiments of boroleucine and boroleucine Dinoester inhibited HUVEC cells
The tumor tissue angiogenesis can facilitate tumor cell metastasis, two-dimensional tube generation tests are carried out by using HUVEC cells, the capability of inhibiting tumor tissue angiogenesis of a compound can be reflected, the capability of inhibiting HUVEC cell two-dimensional tube generation of boroleucine and boroleucine dinoate is respectively examined, a DMSO solvent is used as a blank control (marked as Ctrl), and bortezomib is used as a positive control.
The test steps are as follows:
(1) 50 μl of Matrigel gel diluted by M199 culture medium 1:1 is spread in a 96-well plate, and incubated in an incubator;
(2) After 30min, 100 μl of compound was added to make the wells up with 50 μl of cells and the compound concentration was brought to working concentration;
(3) Cells were treated, counted, 20000 cells/50 μl/well added per well;
(4) After 6h of incubation, photographs were taken.
Note that: the compounds used in the assay were boroleucine, boroleucine dinoate, DMSO solvent or bortezomib.
The results show that boroleucine and boroleucine-dienoate significantly inhibited two-dimensional tube production in HUVEC cells compared to the blank and positive controls, as shown in fig. 2.
EXAMPLE 3 experiments on inhibition of breast cancer cell migration by boroleucine and boroleucine Dinoate
The scratch test can reflect the migration capacity of breast cancer cells, examine the capacity of boroleucine and boroleucine dinoate for inhibiting the migration of breast cancer cells, and take DMSO solvent as a blank control (marked as Ctrl) and bortezomib as a positive control.
The test steps are as follows:
(1) Spreading breast cancer MDA-MB-231 cells into 6-well plate, and adding 10 μM compound for 2 days;
(2) The white gun head is used for scribing with the aid of a pipette, so that the thickness of the scribed line is consistent;
(3) And photographing at 0 and 36 hours, and measuring the migration distance by a computer.
Note that: the compound used in the assay was boroleucine, boroleucine dinoate, DMSO solvent or bortezomib.
As shown in figures 3-4, compared with a blank control and a positive control, the boroleucine and the boroleucine dinoate can obviously inhibit the migration of breast cancer cells, and the inhibition effect of the boroleucine and the boroleucine dinoate is superior to that of the positive control medicament bortezomib.
Note that: d is the migration distance.
EXAMPLE 4 experiments on inhibition of breast cancer cell invasion by boroleucine and boroleucine Dinoate
The invasion test can reflect the metastasis capability of breast cancer cells, examine the capability of boroleucine and boroleucine dinoate to inhibit the invasion of the breast cancer cells, and take DMSO solvent as a blank control (marked as Ctrl) and bortezomib as a positive control.
The test steps are as follows:
(1) Metricel glue 1:19, mixing uniformly, and adding 50 μl into the chamber;
(2) Placing a Transwell plate into an incubator, solidifying for 1-2h, adding 1640 30 μl of hydrated basal membrane without serum, adding 1×10 breast cancer cells without serum culture medium after 30min 5 In each case, 10% FBS was added to the lower chamberA culture medium;
(3) After adding 10 mu M compound into the chamber for culturing for 24 hours, washing the chamber once by PBS, and fixing the chamber by methanol for 10 minutes;
(4) Soaking in 0.1% crystal violet for 2-3min after sucking the liquid;
(5) Washing with PBS for two times, and wiping off the gel in the upper chamber and the cells which do not penetrate the membrane by using a cotton swab;
(6) Photographing under a microscope, and counting.
Note that: the compound used in the assay was boroleucine, boroleucine dinoate, DMSO solvent or bortezomib.
The smaller the number of cells passing through the membrane in this example, the better the effect of inhibiting cancer cell invasion. As shown in figures 5-6, compared with a blank control and a positive control, the boroleucine and the boroleucine dinoate can obviously inhibit the invasion of breast cancer cells, and the inhibition effect of the boroleucine and the boroleucine dinoate is superior to that of the positive control medicament bortezomib.
Example 5 evaluation of anti-metastatic Activity of Compounds in tumor-bearing mice
The mouse liver cancer H22 cells are injected into the tail of the Kunming rat for the experiment, the transfer resistance of the mouse liver cancer H22 cells in vivo is evaluated by simulating the transfer of blood channels, and the in vivo anti-transfer activity of the boroleucine and the boroleucine dinozate is evaluated by taking DMSO solvent as a blank control (marked as Ctrl) and bortezomib as a positive control.
The test steps are as follows: h22 cells were expanded by culture, cells were collected, and after washing twice with sterile PBS solution, the cells were counted (cell count: 2.5X10) 7 One per ml), mice were injected i.v. with 200 μl each. 1 day after inoculation, the mice were sacrificed by pulling the neck after two weeks, randomly grouped and started to be administered by intraperitoneal injection, and after dissecting the lung tissue and fixing with picric acid, the number of lung nodules was observed.
The results show that, as shown in fig. 7-8, compared with the blank control, bortezomib, boroleucine and boroleucine dinoate can obviously inhibit tumor cell metastasis, and the in vivo anti-tumor metastasis capability of the boroleucine and the boroleucine dinoate is superior to that of the positive control bortezomib.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims (1)
1. Application of boro-leucine compound in preparing medicament for inhibiting liver cancer or breast cancer;
the boro-leucine compound is boro-leucine with a structure shown in formula 1 or boro-leucine dinoate with a structure shown in formula 2;
formula 1;
formula 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111139521.1A CN113876784B (en) | 2021-09-27 | 2021-09-27 | Novel application of boro-leucine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111139521.1A CN113876784B (en) | 2021-09-27 | 2021-09-27 | Novel application of boro-leucine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113876784A CN113876784A (en) | 2022-01-04 |
| CN113876784B true CN113876784B (en) | 2023-07-21 |
Family
ID=79007185
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111139521.1A Active CN113876784B (en) | 2021-09-27 | 2021-09-27 | Novel application of boro-leucine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113876784B (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531613A (en) * | 2009-04-16 | 2009-09-16 | 山东大学 | Aminopeptidase N inhibitor bestatin dino ester, synthesis and application thereof |
| CN101781326A (en) * | 2010-02-11 | 2010-07-21 | 上海百灵医药科技有限公司 | Intermediate for preparing chiral aminoboronic acid and preparation method thereof |
| CN102382014A (en) * | 2011-09-08 | 2012-03-21 | 潍坊博创国际生物医药研究院 | Aminopeptidase N inhibitor, preparation method and application |
| CN103421033A (en) * | 2012-05-17 | 2013-12-04 | 上海希迈医药科技有限公司 | Method for preparing (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester and salt thereof |
| CN105622658A (en) * | 2016-03-18 | 2016-06-01 | 中国药科大学 | Non-peptide proteasome inhibitor as well as medicine composition, preparation method and application thereof |
| WO2017198194A1 (en) * | 2016-05-19 | 2017-11-23 | 成都奥璟生物科技有限公司 | Boronic acid and borate ester compound and applications thereof |
| CN107827916A (en) * | 2017-11-07 | 2018-03-23 | 宜昌人福药业有限责任公司 | A kind of (R)（The methyl of 1 amino 3）The synthetic method of the boric acid pinane diol ester of butyl 1 |
| CN110809467A (en) * | 2017-04-26 | 2020-02-18 | 纳维托制药有限公司 | Modulators of SESTRIN-GATOR2 interaction and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008134761A2 (en) * | 2007-04-30 | 2008-11-06 | Intezyne Technologies, Inc. | Modification of biological targeting groups for the treatment of cancer |
-
2021
- 2021-09-27 CN CN202111139521.1A patent/CN113876784B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531613A (en) * | 2009-04-16 | 2009-09-16 | 山东大学 | Aminopeptidase N inhibitor bestatin dino ester, synthesis and application thereof |
| CN101781326A (en) * | 2010-02-11 | 2010-07-21 | 上海百灵医药科技有限公司 | Intermediate for preparing chiral aminoboronic acid and preparation method thereof |
| CN102382014A (en) * | 2011-09-08 | 2012-03-21 | 潍坊博创国际生物医药研究院 | Aminopeptidase N inhibitor, preparation method and application |
| CN103421033A (en) * | 2012-05-17 | 2013-12-04 | 上海希迈医药科技有限公司 | Method for preparing (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester and salt thereof |
| CN105622658A (en) * | 2016-03-18 | 2016-06-01 | 中国药科大学 | Non-peptide proteasome inhibitor as well as medicine composition, preparation method and application thereof |
| WO2017198194A1 (en) * | 2016-05-19 | 2017-11-23 | 成都奥璟生物科技有限公司 | Boronic acid and borate ester compound and applications thereof |
| CN110809467A (en) * | 2017-04-26 | 2020-02-18 | 纳维托制药有限公司 | Modulators of SESTRIN-GATOR2 interaction and uses thereof |
| CN107827916A (en) * | 2017-11-07 | 2018-03-23 | 宜昌人福药业有限责任公司 | A kind of (R)（The methyl of 1 amino 3）The synthetic method of the boric acid pinane diol ester of butyl 1 |
Non-Patent Citations (6)
| Title |
|---|
| " Targeting the ubiquitin-proteasome pathway in cancer therapy";Ishii Y, Waxman S, Germain D.;《Anti-Cancer Agents in Medicinal Chemistry 》;第7卷(第3期);第359-365页 * |
| "A solid-phase approach for the synthesis of α-aminoboronic acid peptides";Daniels B E, Stivala C E.;《RSC advances》;第8卷(第6期);第3343-3347页 * |
| "Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer";Lei M, et al.;《Organic & Biomolecular Chemistry》;第17卷(第3期);第683-691页 * |
| "The structure and main functions of aminopeptidase N";Luan Y, Xu W.;《Current medicinal chemistry》;第14卷(第6期);第639-647页 * |
| "新型氨肽酶抑制剂4Q通过活性氧增强5FU的抗肝癌活性";孙志朋,王学健.;《2015医学前沿论坛暨第十四届全国肿瘤药理与化疗学术会议摘要汇编》;第128页 * |
| "氨肽酶N在乳腺癌血管生成中的作用及其与VEGF的相关性";曹文庆,等;《天津医科大学学报》;第21卷(第1期);第39-42页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113876784A (en) | 2022-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Velmourougane et al. | Synthesis of new (−)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase | |
| CN105263915B (en) | Glutamine enzyme inhibitor and application method | |
| CN111559991B (en) | Preparation method and application of naphthylamine compound and salt thereof | |
| CN104120164A (en) | Specific fluorescence probe substrates of human carboxylesterase 2 and application thereof | |
| CN112062755B (en) | Near-infrared fluorescent molecular probe for detecting aspartyl aminopeptidase, preparation method and application | |
| CN105037371A (en) | Deuterated indoleamine-2,3-dioxygenase inhibitor | |
| CN106146611B (en) | It is a kind of measure dipeptidyl peptidase IV activity fluorescence probe substrate and its application | |
| Perrone et al. | Effect of mofezolac-galactose distance in conjugates targeting cyclooxygenase (COX)-1 and CNS GLUT-1 carrier | |
| WO2022213878A1 (en) | Use of compound ramipril targeting soat1 protein in preparation of drug for preventing and/or treating liver cancer | |
| CN113876784B (en) | Novel application of boro-leucine compound | |
| CN101948467B (en) | Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines | |
| Anifowose et al. | Upregulation of p53 through induction of MDM2 degradation: amino acid prodrugs of anthraquinone analogs | |
| CN111747882B (en) | Indole NEDD8 activating enzyme inhibitor, preparation method thereof and application thereof in antitumor drugs | |
| CN108727437A (en) | One curcuminoids metal aryl complex and its synthetic method and application | |
| CN108409608A (en) | Aryl nitrogen mustard histone deacetylases inhibitor and its preparation method and application | |
| CN104744351A (en) | Small molecule inhibitor and application thereof to inhibiting ornithine decarboxylase (ODC) | |
| CN102382014A (en) | Aminopeptidase N inhibitor, preparation method and application | |
| CN1339970A (en) | Anticancer agent potentiators | |
| CN115737632A (en) | Application of LSD1 inhibitor in medicine for resisting acute myelogenous leukemia | |
| CN109550056B (en) | Matrix metalloproteinase inhibitory polypeptide gold nanoparticle composition and application and preparation method thereof | |
| CN115403561A (en) | Intracellular self-assembly protein degradation agent based on thalidomide analogue and preparation method and application thereof | |
| Shang et al. | Design, synthesis and SAR studies of tripeptide analogs with the scaffold 3-phenylpropane-1, 2-diamine as aminopeptidase N/CD13 inhibitors | |
| CN106496053A (en) | A kind of inhibitors of histone deacetylase N (2 ' aminocarbonyl phenyl) 4 (double (2 chloroethyl) amidos) benzamide and its preparation method and application | |
| CN113149980A (en) | Tert-butyloxycarbonyl micromolecule organic compound targeting PUF60, derivative thereof and application thereof | |
| CN109438339A (en) | RBP2 enzyme inhibitor small molecule compound WXSA-072A and preparation method thereof and anti-gastric cancer application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |