4-amino-1-naphthol
4-amino-1-naphthol
CAS: 2834-90-4
Molecular Formula: C10H9NO
4-amino-1-naphthol - Names and Identifiers
| Name | 4-amino-1-naphthol |
| Synonyms | 4-amino-1-naphthol 1-Amino-4-naphthol 4-Amino-1-naphthalenol 4-azanylnaphthalen-1-ol 1-Amino-4-hydroxynaphthalene |
| CAS | 2834-90-4 |
4-amino-1-naphthol - Physico-chemical Properties
| Molecular Formula | C10H9NO |
| Molar Mass | 159.18 |
| Physical and Chemical Properties | Acicular crystals of chemical nature. Easily oxidized to 1, 4-naphthoquinone. |
| Use | Uses for organic synthesis. |
4-amino-1-naphthol - Method for preparing 4-amino -1-naphthol ether compounds
from Baidu Library
Application (patent) number:
CN02816708.2
application date:
2002-08-19
Public/Announcement Number:
CN1547568
applicant (patent):
Bayer Chemicals, Inc.
inventor:
J. Comosinski H · Dil
National and provincial code:
Germany
Abstract:
The present invention relates to a method for producing a 4-amino -1-naphthol ether compound, characterized in that the naphthol ether compound is first produced from a 1-naphthol phenol compound, this is subsequently converted to the corresponding 4-acetylamino-1-naphthol Ether and the acyl group is cleaved. The present invention also relates to certain 4-acetylamino-1-naphthol ether compounds.
sovereignty:
1. Process for the preparation of 4-amino-1-naphthol ethers, characterized in that a) a substituted or unsubstituted 1-naphthol compound is reacted with a reactive alkyl compound, 1-Naphthol ethers are obtained, B) then 1-Naphthol ethers are converted to the corresponding 4-acyl amino -1-Naphthol ethers with hydroxylammonium salts and carboxylic acids and c) these 4-acylamino-1-naphthol ethers are converted into free 4-amino-1-naphthol ethers or similar ammonium salts by cleavage of acidic or basic acyl groups.
Last Update：2023-08-16 22:09:08
4-amino-1-naphthol - Design, synthesis and preliminary activity of 4-amino -1-naphthol ABL and AKT1 protein kinase inhibitors
from Wanfang
Author:
Abstract:
Objective: abnormal angiogenesis, including endothelial cell activation, degradation of basement membrane, directional movement and proliferation of endothelial cells, neovascularization, new basement membrane synthesis of endothelial cells, A series of steps, such as Bud growth and formation of blood vessels, is a prerequisite for tumor cell proliferation, invasion and metastasis. Abl and Akt (protein kinase B, PKB) are two important signaling pathways in tumor cells and vascular endothelial cells, they can regulate many important physiological processes in tumor cells and endothelial cells by phosphorylating downstream substrates, including cell survival, proliferation, migration and angiogenesis. Protein kinase inhibitors are divided into three groups according to the difference in the Kinase binding site: protein kinase inhibitors acting on the ATP binding site, protein kinase inhibitors acting on the regulatory region, and competitive allosteric inhibitors of protein kinase substrates. In recent years, a variety of drugs targeting protein kinases such as Sunitinib,Sorafenib, and Pazopanib have been successfully introduced into the market for the treatment of various tumors. Although these tumor angiogenesis inhibitors have great advantages, there are still some tumors in the practical application of angiogenesis dependence is not strong, mutation and tumor signal transduction compensatory lead to drug resistance, adverse reactions and toxicity. Therefore, further development of more selective, more active and less toxic small molecule protein kinase inhibitors is still very necessary. With the deepening of the research on Bcr-Ab1 and Akt related signaling pathways, the research on Bcr-Abl and/or Akt inhibitors has become a hot spot in the research of anti-tumor drugs. Methods: In this study, we first found a compound with obvious anti angiogenesis effect in the process of computer virtual screening. The later enzyme screening work showed that 6a can selectively inhibit Abl and Akt1 kinase, and the target is very clear. After that, we designed and synthesized five series of 6a analogs based on 4-amino -1-naphthol skeleton, and studied their anti-tumor cell proliferation, anti-angiogenesis and protein kinase inhibitory activity in vitro, on the one hand, the structure-activity relationship (SAR) of this class of structural framework compounds is studied, and on the other hand, we also hope to obtain a better lead structure than the anti-tumor and anti-angiogenic activity of Hitachi A. Results: five series of 81 Hitachi 6A analogs based on 4-amino -1-naphthol skeleton were designed and synthesized, the structure of the synthesized target compound was confirmed by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. It was confirmed by consulting literature that the synthesized target compounds were all new compounds except some compounds, there is no literature report. We studied the in vitro anti-tumor cell proliferation activity, anti-angiogenesis activity and anti-enzyme activity of the synthesized compounds. The experimental results show that, the structure-activity relationship of the synthesized 4-amino-1-naphthol compounds in the study of inhibiting enzyme activity and in the study of anti-tumor cell proliferation and anti-angiogenesis activity in vitro the relationship law has a high degree of consistency, furthermore, the anti-angiogenic activity of the compounds is not associated with inhibition of VEGF/VEGFR, which gives us this indication, that is, the synthesis of 4-amino -1-naphthol compounds is through the inhibition of Abl and Aktl protein kinase activity to achieve its anti-tumor cell proliferation and anti-angiogenesis activity. Structure-activity relationship studies show that the naphthol ring (Figure5-1, Part a) of Hitachi a can bind to the hydrophobic pocket of the kinase active site through hydrophobic interaction or & pi;-& pi; Stacking, after the naphthalene ring is changed into smaller Benzene ring (D series), the binding ability of the compound to the receptor is decreased, the activity of inhibiting enzyme activity and anti-vascular activity are obviously decreased, and the anti-tumor cell proliferation activity is almost lost; the introduction of two methoxy groups at the 6,7 positions of the naphthalene ring (E series) will enhance the hydrophobicity of the compound, enhance the binding ability to the receptor, and then inhibit the enzyme activity of the compound, the anti-vascular activity and anti-tumor cell proliferation activity were significantly enhanced. On the one hand, the water solubility of the compound is improved, and on the other hand, the binding force of the compound and the receptor is enhanced by hydrogen bonding when the methoxy group is kept at the 7 position and the propyl morpholine side chain (33a) is introduced at the 6 position, the compound can fully occupy the cavity area of the binding pocket, and the activity of inhibiting enzyme activity, anti-vascular activity and anti-tumor cell proliferation activity of the compound are improved. The triazole five-membered aromatic heterocycle (Figure5-1, Part B) of Hitachi a can extend to the DFG motif of Abl and Aktl kinases and to the DGF in conformation (the conformation in which the protein is in an activated state). The amino acid ASP forms hydrogen bonds; When it is 5-methyl -1,3, 4-thiadiazole, 1,3, 4-thiadiazole or 1-methyl-tetrazolium ring replacement after hydrogen bonds disappear, while causing the compound molecules in the receptor binding pocket binding position and conformation changes, resulting in a sharp decrease in the inhibition of enzyme activity, anti-vascular activity and anti-tumor cell proliferation activity greatly weakened; And when the triazole five-membered aromatic heterocyclic ring is replaced by the purine ring (B series), it causes changes in the binding position and conformation of the compound molecule in the receptor binding pocket, but the purine ring can form hydrogen bonds with amino acids at other positions in the binding pocket, and finally inhibit the enzyme activity slightly, the anti-vascular activity and anti-tumor cell proliferation activity were slightly weakened. It should be noted that the substitution of the triazole five-membered heterocyclic ring by the purine ring reduces the specificity of the compound (e. G., 9n) for kinase selection, which is not what we expected. The sulfonamido-so2nh-(Figure5-1, Part c) of Hitachi a can form hydrogen bonds with amino acid residues in the hinge region, G-loop or P-loop region of the Ab1 and Akt1 kinase activity pocket, the binding force of the compound and the kinase is improved, and the group can keep the compound in a conformation that is easy to bind to the active pocket; And the hydrogen bond disappears after the substitution of the-CONH-group, the spatial conformation of the compound is not conducive to the binding to the active pocket (compare 9d and 13q in Figure4-1), which leads to the inhibition of enzyme activity is greatly reduced or even disappeared, and the anti-vascular activity and anti-tumor cell proliferation activity are greatly weakened. The 2-naphthyl group (Figure5-1, Part d) in the R position of Hitachi A can be the hinge region in the active pocket of Abl and Aktl kinases, and the aromatic group (R) in this position is different the effect of the group on the kinase inhibitory activity of the compounds showed a certain regularity.(a)R group is phenyl group than larger groups (such as naphthyl, quinolinyl, 4-tert-butylphenyl and 4-(1,1 '-biphenyl)) or longer (styryl) groups are active (13a and 13b vs13c and 13d,9f and 9p vs9a and 9g).(B) when the R group is phenyl, an electron-withdrawing group (13d/13c-NO2/-Cl) is attached to the benzene ring. The activity of the compound is better than that of the compound (13e/13i-OMe/-Me) attached to the pushing group.(c) the inhibitory activity of the compound when the R group is a double substituent is better than that of the single substitution (9e,9K, 9n vs9j,9d,9b). Based on the above results of structure-activity relationship studies, in the E series inhibitor design, we have preserved the compound intermediate skeleton naphthol ring, sulfonamide group and triazole five-membered heterocyclic ring, while in the naphthalene ring 6, the introduction of two methoxy groups at position 7 can further enhance the hydrophobic effect of naphthol fragments, thus improving the inhibitory activity and selectivity of Abl and Akt1 kinase. The series of compounds 26a-26g in vitro inhibition of enzyme activity was significantly better than the previous four series, the overall IC50 value below 1 state, the best activity of compound 26g on Abl and Aktl kinase IC50 values were 0.16 and 0.46 μm, which was about 10 times higher than that of Hitachi A; however, the introduction of methoxy group leads to the poor water solubility of the compound. When we improved the water solubility of 26G, we designed and synthesized a compound 33a containing a propyl morpholine side chain on the 6-position oxygen, the activity test results showed that 33a had ICs0 values of 0.13 and 0.28 states for Abl and Aktl kinases, respectively. The introduction of the side chain of the propyl morpholine can not only improve the water solubility of the compound 26G, but also keep the activity of the compound, therefore, compound 33a is a very promising dual-target inhibitor of Abl and Akt1 with good water solubility and antitumor activity. Conclusion: This study is based on the crystal structure of Abl and Akt1 and the binding mode of Hitachi A with active sites, A total of 81 4-amino -1-naphthol skeleton-based analogs of Hitachi A were synthesized in five series. Through the preliminary evaluation of biological activity in vitro, we found several compounds with further research and development value, such as: compound 26g and 33a, and further study on its structure-activity relationship based on molecular docking, discusses its binding mode with Abl and Akt1 target, for the design of new small molecule Abl and Akt1 inhibitors in the future, the basis for the synthesis. Direct endothelial cells as the research target, based on the in-depth understanding of the related molecules of vascular endothelial cell proliferation and inhibition, using the corresponding drugs to block the key proteins Abl and Akt in the intracellular signal transduction pathway, inhibit the proliferation of vascular endothelial cells and tumor angiogenesis, it has been proved to be of great significance for tumor treatment.
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Key words:
ABL AKT1 Protein kinase Human Umbilical Vein Endothelial Cells thoracic aortic ring angiogenesis
degree level:
PhD
degree year:
2014
DOI:
10.7666/d.Y2598732
Last Update：2024-01-02 23:10:35
4-amino-1-naphthol - Reference Information
| use | for organic synthesis. |
| production method | using 1-naphthol as raw material, obtained by coupling and reduction. First, p-aminobenzenesulfonic acid is dissolved in sodium carbonate aqueous solution, cooled to below 15 ℃, and sodium nitrite is used to prepare p-aminobenzenesulfonic acid diazonium salt in the presence of concentrated hydrochloric acid. Then, the 1-naphthol sodium salt solution was coupled with the diazonium salt solution at 5-6°C. Then add sodium sulfate and heat it to 70°C for reduction, cool it and filter it, and wash the resulting crystal with 1% sodium sulfate aqueous solution. |
Last Update：2024-04-10 22:29:15
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