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1.
Eur J Med Chem ; 271: 116435, 2024 May 05.
Article in English | MEDLINE | ID: mdl-38648728

ABSTRACT

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.


Subject(s)
Antineoplastic Agents , Drug Resistance, Neoplasm , Multiple Myeloma , Small Molecule Libraries , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Humans , Drug Resistance, Neoplasm/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Proteasome Inhibitors/pharmacology , Proteasome Inhibitors/chemistry , Proteasome Inhibitors/therapeutic use , Molecular Structure
2.
J Med Chem ; 67(6): 4346-4375, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38484122

ABSTRACT

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.


Subject(s)
Lung Neoplasms , Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Proto-Oncogene Proteins c-ret/genetics , Precision Medicine , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Mutation , Lung Neoplasms/drug therapy
3.
Bioorg Med Chem ; 100: 117631, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38330848

ABSTRACT

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.


Subject(s)
Leukemia, Myeloid, Acute , fms-Like Tyrosine Kinase 3 , Humans , Apoptosis , Cell Line, Tumor , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Pyridines/pharmacology
4.
Biomed Pharmacother ; 169: 115905, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-38000356

ABSTRACT

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Animals , Mice , Zebrafish , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Mutation
5.
Eur J Med Chem ; 260: 115726, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37597436

ABSTRACT

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.


Subject(s)
Biological Products , Drug-Related Side Effects and Adverse Reactions , Humans , Antiviral Agents/pharmacology , Biological Products/pharmacology , Cell Movement
6.
Eur J Med Chem ; 257: 115464, 2023 Sep 05.
Article in English | MEDLINE | ID: mdl-37235998

ABSTRACT

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.


Subject(s)
Brain Neoplasms , Glioma , Humans , Isocitrates , Ligands , Isocitrate Dehydrogenase/metabolism , Glioma/drug therapy , Glioma/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Mutation
8.
Drug Dev Res ; 84(2): 296-311, 2023 04.
Article in English | MEDLINE | ID: mdl-36644989

ABSTRACT

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacology , Amines/pharmacology , Leukemia, Myeloid, Acute/drug therapy , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/pharmacology , fms-Like Tyrosine Kinase 3/therapeutic use , Apoptosis , Cell Proliferation
9.
Future Med Chem ; 15(1): 57-71, 2023 01.
Article in English | MEDLINE | ID: mdl-36651264

ABSTRACT

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.


Subject(s)
Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors , Mutation , Cell Line , Apoptosis , fms-Like Tyrosine Kinase 3/genetics , Cell Line, Tumor
10.
Bioorg Med Chem ; 70: 116937, 2022 09 15.
Article in English | MEDLINE | ID: mdl-35863236

ABSTRACT

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Amines/pharmacology , Antineoplastic Agents/chemistry , Apoptosis , Cell Line, Tumor , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Mutation , Protein Kinase Inhibitors/chemistry , fms-Like Tyrosine Kinase 3
11.
J Med Chem ; 65(11): 7415-7437, 2022 06 09.
Article in English | MEDLINE | ID: mdl-35594541

ABSTRACT

Despite significant efficacy, one of the major limitations of small-molecule Bruton's tyrosine kinase (BTK) agents is the presence of clinically acquired resistance, which remains a major clinical challenge. This Perspective focuses on medicinal chemistry strategies for the development of BTK small-molecule inhibitors against resistance, including the structure-based design of BTK inhibitors targeting point mutations, e.g., (i) developing noncovalent inhibitors from covalent inhibitors, (ii) avoiding steric hindrance from mutated residues, (iii) making interactions with the mutated residue, (iv) modifying the solvent-accessible region, and (v) developing new scaffolds. Additionally, a comparative analysis of multi-inhibitions of BTK is presented based on cross-comparisons between 2916 unique BTK ligands and 283 other kinases that cover 7108 dual/multiple inhibitions. Finally, targeting the BTK allosteric site and uding proteolysis-targeting chimera (PROTAC) as two potential strategies are addressed briefly, while also illustrating the possibilities and challenges to find novel ligands of BTK.


Subject(s)
Chemistry, Pharmaceutical , Protein Kinase Inhibitors , Agammaglobulinaemia Tyrosine Kinase , Ligands , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
12.
Apoptosis ; 26(11-12): 639-656, 2021 12.
Article in English | MEDLINE | ID: mdl-34743246

ABSTRACT

Resistance to epidermal growth factor receptor-tyrosin kinase inhibitors (TKIs, e.g. icotinib) remains a major clinical challenge. Non-small cell lung cancer patients with wild-type EGFR and/or K-RAS mutation are primary resistance to EGFR-TKIs. Berberine has been found to have potent anticancer activities via distinct molecular mechanism. In this study, we sought to investigate the therapeutic utility of BBR in combination with icotinib to overcome icotinib resistance in NSCLC cells, and explore the molecular mechanism of synergism of icotinib and BBR to EGFR-resistant NSCLC cells. We used the two EGFR-resistant NSCLC cell lines H460 and H1299 for testing the inhibitory effect of icotinib and/or BBR on them. Moreover, xenograft mouse model was applied for assessing the anti-tumor activities of BBR and icotinib in combination. Results showed that BBR and icotinib have a synergistic inhibitory effect on H460 and H1299 cells through induction of autophagic cell death and apoptosis. Accordingly, the anti-cancer effect of BBR plus icotinib was further confirmed in the NSCLC xenograft mouse models. Combination of BBR and icotinib significantly inhibited the protein expression and the activity of EGFR by inducing autophagic EGFR degradation. BBR plus icotinib resulted in intracellular ROS accumulation, which could mediated autophagy and apoptosis and involved in the suppression of cell migration and invasion. In conclusions, combination application of BBR and icotinib could be an effective strategy to overcome icotinib resistance in the treatment of NSCLC.


Subject(s)
Autophagic Cell Death , Berberine , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Apoptosis , Berberine/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Crown Ethers , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mice , Quinazolines , Signal Transduction
13.
J Med Chem ; 63(21): 12403-12428, 2020 11 12.
Article in English | MEDLINE | ID: mdl-32659083

ABSTRACT

Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.


Subject(s)
Protein Kinase Inhibitors/chemistry , Small Molecule Libraries/chemistry , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Humans , Indoles/chemistry , Indoles/pharmacology , Indoles/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Signal Transduction/drug effects , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Urea/analogs & derivatives , Urea/pharmacology , Urea/therapeutic use , fms-Like Tyrosine Kinase 3/metabolism
14.
Eur J Med Chem ; 189: 112038, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-31945667

ABSTRACT

Bufadienolides are a type of natural cardiac steroids and originally isolated from the Traditional Chinese Medicine Chan'Su, they have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy with potent anti-tumor activities. Due to their unique molecular structures with unsaturated six-membered lactones attached to the steroid core, bufadienolides have received great attention in the synthetic organic community. This review presents total synthetic efforts to some representative bufadienolides, chemical modification of bufadienolides will also be given to discuss their structure-activity relationship in anti-tumor.


Subject(s)
Bufanolides/chemical synthesis , Animals , Cell Line, Tumor , Humans , Mice , Molecular Structure , Structure-Activity Relationship
15.
Eur J Med Chem ; 186: 111884, 2020 Jan 15.
Article in English | MEDLINE | ID: mdl-31761386

ABSTRACT

Mutation or abnormal expression of protein tyrosine kinases (PTKs) is one of the main causes of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, which have four subtypes including FGFR1, FGFR2, FGFR3 and FGFR4. Their abnormal expression in cells is considered to be the main cause of tumorigenesis, so inhibiting FGFRs is thought to be important targets for cancer treatment. This article mainly summarizes the recent development of FGFR inhibitors in the past 5 years, and hopes to guide the future research on the design and synthesis of FGFR inhibitors.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Humans , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptors, Fibroblast Growth Factor/metabolism
16.
Huan Jing Ke Xue ; 40(7): 2967-2976, 2019 Jul 08.
Article in Chinese | MEDLINE | ID: mdl-31854693

ABSTRACT

With the constraint that all six major pollutants in Nanjing must meet the air quality standards by 2030, on the basis of the 2015 emission inventory, the CMAQ air quality model was used to conduct PM2.5 sensitivity tests, and scenario analysis was used to predict the emission inventory and the air quality of four emission reduction scenarios were simulated. Finally, the total control index under the constraint of meeting the standards was obtained. The results show that primary particulate matter (PPM) reduction is the most effective at reducing the concentration of PM2.5 in the atmosphere, on the basis of emission reduction in surrounding areas, PPM emission reduction accounts for 88% of the total reduction of the annual average concentration of PM2.5, followed by NH3, NOx, SO2, and VOCs, which contribute to 10.3%, 5.5%, 3.2%, and 0.5%, respectively. Compared to 2015, the reduction ratios of the major pollutants are between 22% and 53%. Controlling the activity level is more effective for SO2, NH3 and CO emissions reduction, while there is still more opportunity for NOx and VOCs end treatment. When the emissions of SO2, NOx, PM10, PM2.5, BC, OC, CO, VOCs, and NH3 are controlled to 2.43×104, 8.47×104, 9.42×104, 3.74×104, 0.19×104, 0.30×104, 26.56×104, 13.08×104, and 1.50×104 t, respectively, it is expected that the levels of the six pollutants in Nanjing can meet the national ambient air quality level 2 standards.

17.
Bioorg Med Chem Lett ; 29(24): 126772, 2019 12 15.
Article in English | MEDLINE | ID: mdl-31711785

ABSTRACT

Inhibition of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain ß-amyloid (Aß) peptide's formation is a potential effective approach to treat Alzheimer's disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 µM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 µM, logP = 2.49).


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Protein Precursor/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Humans , Structure-Activity Relationship
18.
Beilstein J Org Chem ; 15: 291-298, 2019.
Article in English | MEDLINE | ID: mdl-30800179

ABSTRACT

Herein we report a novel palladium-catalyzed reaction that results in phenanthrene derivatives using aryl iodides, ortho-bromobenzoyl chlorides and norbornadiene in one pot. This dramatic transformation undergoes ortho-C-H activation, decarbonylation and subsequent a retro-Diels-Alder process. Pleasantly, this protocol has a wider substrate range, shorter reaction times and higher yields of products than previously reported methods.

19.
Bioorg Med Chem ; 26(16): 4735-4744, 2018 09 01.
Article in English | MEDLINE | ID: mdl-30121211

ABSTRACT

Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor ß (PDGFR-ß) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.


Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Urea/chemistry , Binding Sites , Cell Line , Cell Proliferation/drug effects , Humans , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Structure-Activity Relationship , Urea/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/metabolism
20.
Med Chem ; 14(5): 478-484, 2018.
Article in English | MEDLINE | ID: mdl-28875860

ABSTRACT

BACKGROUND: Discovery of novel agents with anticoagulant and antioxidant activity is very important to treat cerebrovascular disease. Lead compound LR3d discovered in our laboratory exhibited stronger anticoagulant ability and good antioxidant activity, compared with scutellarein (2), which is the major in vivo active metabolite of the natural product scutellarin (1). OBJECTIVE: Design and synthesis novel scutellarein derivatives with improved anticoagulant and antioxidant activity. METHODS: By utilizing a scaffold hopping strategy on LR3d, we describe the design and synthesis of a series of novel hexacyclic scutellarein derivatives 4 with a 1,3-oxazine ring fused at positions 7 and 8 in A ring. The thrombin inhibitory activities of all these new compounds were studied by the analysis of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). The antioxidant abilities of these analogs were evaluated by using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method through 1,1- diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay. RESULTS: Nine new hexacyclic scutellarein derivatives with a 1,3-oxazine ring fused at A-ring were synthesized, the results of the biological activity evaluation showed that compound 4e exhibited stronger anticoagulant and antioxidant ability compared to LR3d. CONCLUSION: 4e could be used for further development to treat ischemic cerebrovascular disease.


Subject(s)
Antioxidants/pharmacology , Antithrombins/pharmacology , Apigenin/pharmacology , Oxazines/pharmacology , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antithrombins/chemical synthesis , Antithrombins/chemistry , Apigenin/chemical synthesis , Apigenin/chemistry , Drug Design , Fibrinogen/metabolism , Male , Molecular Docking Simulation , Oxazines/chemical synthesis , Oxazines/chemistry , Partial Thromboplastin Time , Prothrombin Time , Rabbits , Thrombin/chemistry , Thrombin Time
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