56341-41-4Relevant articles and documents
DENDRIMER COMPOSITIONS AND METHODS FOR DRUG DELIVERY TO THE EYE
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Paragraph 0214; 0215, (2021/06/11)
Dendrimer compositions and methods for the treatment of one or more inflammatory and/or angiogenic diseases and/or disorders of the eye include hydroxyl-terminated dendrimers complexed or conjugated with one or more active agents for the treatment or alleviation of one or more symptoms of the diseases of the eye, and/or for diagnosing the diseases and/or disorders of the eye. The dendrimers may include one or more ethylene diamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation-4, 5, 6, 7, 8, 9, or 10 dendrimers. The active agents may be VEGFR tyrosine kinase inhibitors including sunitinib or analogues thereof. Preferably, the compositions are suitable for administration via a systemic route to target activated microglia/macrophages in retina/choroid.
Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold
Wang, De-pu,Liu, Kai-li,Li, Xin-yang,Lu, Guo-qing,Xue, Wen-han,Qian, Xin-hua,Mohamed O, Kamara,Meng, Fan-hao
, (2020/12/21)
In the past five years, our team had been committed to click chemistry research, exploring the biological activity of 1,2,3-triazole by synthesizing different target inhibitors. In this study, a series of novel indole-2-one derivatives based on 1,2,3-triazole scaffolds were synthesized for the first time, and their inhibitory activity on vascular endothelial growth factor receptor-2 (VEGFR-2) was tested. Most of the compounds had shown promising activity in the VEGFR-2 kinase assay and had low toxicity to human umbilical vein endothelial cells (HUVECs). The compound 13d (IC50 = 26.38 nM) had better kinase activity inhibition ability than sunitinib (IC50 = 83.20 nM) and was less toxic to HUVECs. Moreover, it had an excellent inhibitory effect on HT-29 and MKN-45 cells. On the one hand, by tube formation assay, transwell, and Western blot analysis, compound 13d could inhibit VEGFR-2 protein phosphorylate on HUVECs, thereby inhibiting HUVECs migration and tube formation. In vivo study, the zebrafish model with VEGFR-2 labeling also verified that compound 13d had more anti-angiogenesis ability than sunitinib. On the other hand, molecular docking and molecular dynamics (MD) simulation results showed that compound 13d could stably bind to the active site of VEGFR-2. Based on the above findings, compound 13d could be considered an effective anti-angiogenesis drug and has more development value than sunitinib.
A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids
Huang, Tiao,Kong, Dulin,Li, Yue,Liu, Li,Wu, Mingshu
, p. 2321 - 2328 (2021/09/22)
A novel method for the synthesis of 3-monohalooxindoles by acidolysis of isatin-derived 3-phosphate-substituted oxindoles with haloid acids was developed. This synthetic strategy involved the preparation of 3-phosphate-substituted oxindole intermediates and SN1 reactions with haloid acids. This new procedure features mild reaction conditions, simple operation, good yield, readily available and inexpensive starting materials, and gram-scalability.
Enhanced fluorescence sensor for targeting recognition of receptor tyrosine kinase and application of fluorescence sensor in cell membrane fluorescence imaging
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Paragraph 0014; 0015, (2019/02/13)
The invention discloses an enhanced fluorescence sensor for targeting recognition of receptor tyrosine kinase and application of the fluorescence sensor in cell membrane fluorescence imaging, and belongs to the technical field of bioluminescence sensing. Effective parts of sunitinib are adopted as recognition groups of the fluorescence sensor SP1, pyrene is adopted as a fluorescent group, and connection is formed through linking groups; and the receptor tyrosine kinase which is protein on cell membranes is abundantly enriched in the process of generation of tumor cells and vessels. The fluorescent sensor SP1 can effectively act on the intracellular domains of the cell membranes of the receptor tyrosine kinase, and compared with amino acids, inorganic salts and other interfering substancesin cells, the fluorescence sensor SP1 exhibits high selectivity and a targeted recognition effect on the receptor tyrosine kinase; the SP1 has good selectivity and high sensitivity in recognition of the receptor tyrosine kinases, fluorescence imaging of the receptor tyrosine kinase can be achieved in the cells, tissue and living bodies, and the enhanced fluorescence sensor has potential application prospects in early cancer diagnosis, visualization therapy and other fields.
Preparation method for 5-fluoroindole-2-ketone
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Page/Page column 6-7, (2018/12/13)
The invention discloses a preparation method for 5-fluoroindole-2-ketone. The preparation method comprises the following steps: taking 2,4-difluoronitrobenzene as a raw material, enabling the 2,4-difluoronitrobenzene to perform condensation reaction with dimethyl malonate in an aprotic polar solvent under an inorganic alkaline condition, and performing post-treatment to obtain 4-fluoro-2-(dimehtylmalonate) nitrobenzene; in the presence of the aprotic polar solvent and lithium chloride, enabling the 4-fluoro-2-(dimehtyl malonate) nitrobenzene to generate 5-fluoro-2- nitrobenzene methyl acetate; mixing the 5-fluoro-2- nitrobenzene methyl acetate, a catalyst and alcohol solvents to perform hydrogenation cyclization reaction to obtain a 5-fluoroindole-ketone crude product; taking water as thesolvent by the crude product, filtering active carbon while hot, and re-crystallizing to obtain high-purity 5-fluoro-indole-2-ketone. The method adopts easily available raw materials, is simple in process; and a Raney nickel catalyst and a recrystallization aqueous solution can be used for many times, the raw material cost is relatively low, industrialization is easily realized, and the application prospect is relatively great.
Conformationally Induced Off-On Cell Membrane Chemosensor Targeting Receptor Protein-Tyrosine Kinases for in Vivo and in Vitro Fluorescence Imaging of Cancers
Jiao, Yang,Yin, Jiqiu,He, Haiyang,Peng, Xiaojun,Gao, Qianmiao,Duan, Chunying
supporting information, p. 5882 - 5885 (2018/05/23)
Molecules capable of monitoring receptor protein-tyrosine kinase expression could potentially serve as useful tools for cancer diagnosis due to the overexpression of tyrosine kinases during tumor growth and metastasis. In this work, a conformationally induced "off-on" tyrosine kinase cell membrane fluorescent sensor (SP1) was designed and evaluated for the detection and imaging of receptor protein-tyrosine kinases in vivo and in vitro. SP1 consists of sunitinib and pyrene linked via hexamethylenediamine and displays quenched fluorescence as a dimer. The fluorescence of SP1 is restored in the presence of receptor protein-tyrosine kinases upon strong interaction with SP1 at the target terminal. The unique signal response mechanism enables SP1 use for fluorescence microscopy imaging of receptor protein-tyrosine kinases in the cell membranes of living cells, allowing for the rapid differentiation of cancer cells from normal cells. SP1 can be used to visualize the chick embryo chorioallantoic membrane and mouse model tumors, suggesting its possible application for early cancer diagnosis.
Development of a novel conjugatable sunitinib analogue validated through in vitro and in vivo preclinical settings
El Mubarak, Mohamed A.,Leontari, Iliana,Efstathia, Giannopoulou,Vrettos, Eirinaios I.,Shaikh, Abdul kadar,Konstantinos, Siatis E.,Danika, Charikleia,Kalofonos, Haralabos P.,Tzakos, Andreas G.,Sivolapenko, Gregory B.
, p. 515 - 523 (2018/07/06)
Sunitinib is an oral FDA/EMEA approved multi-targeted tyrosine kinase inhibitor. It possesses anti-angiogenic and antitumor activity against a variety of advanced solid tumors. However, its chemical core does not allow a potential linkage to tumor-homing elements that could eventually enhance its potency. Therefore, a novel linkable sunitinib derivative, designated SB1, was rationally designed and synthesized. The pharmaceutical profile of SB1 was explored both in vitro and in vivo. Mass spectrometry and NMR spectroscopy were utilized for characterization, while MTT assays and LC-MS/MS validated protocols were used to explore its antiproliferative effect and stability, respectively. Cytotoxicity evaluation in three glioma cells showed that SB1 preserved the antiproliferative effect of sunitinib. SB1 was stable in vitro after 24 h incubation in mouse plasma, while both agents exhibited bioequivalent pharmacokinetic characteristics after i.v. administration in Balb/c mice. To evaluate the levels of SB1 in mouse plasma, a novel analytical method was developed and validated in accordance to the US FDA and the EU EMA guidelines. We formulated a novel linkable sunitinib analog exhibiting similar antiproliferative and apoptotic properties with native sunitinib in glioma cell lines. Both SB1 and native sunitinib showed identical in vitro stability in mouse plasma and pharmacokinetics after i.v. administration in Balb/c mice.
Synthesis of novel 3-(benzothiazol-2-ylmethylene)indolin-2-ones
Zhang, Chao,Xu, Juan,Zhao, Xinyu,Kang, Congmin
, p. 537 - 540 (2017/10/03)
A mild method for the synthesis of 3-(benzothiazol-2-ylmethylene)indolin-2-ones via the aldol condensation of substituted indolin-2-ones and benzothiazole-2-carbaldehyde is described. This new procedure has significant advantages, such as mild conditions, high yields and simple work-up.
Synthesis of Novel c(AmpRGD)-Sunitinib Dual Conjugates as Molecular Tools Targeting the αvβ3 Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis
Sartori, Andrea,Portioli, Elisabetta,Battistini, Lucia,Calorini, Lido,Pupi, Alberto,Vacondio, Federica,Arosio, Daniela,Bianchini, Francesca,Zanardi, Franca
, p. 248 - 262 (2017/04/26)
On the basis of a previously discovered anti-αVβ3 integrin peptidomimetic (c(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds 1-3), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward αVβ3 (using both isolated receptors and αVβ3-overexpressing endothelial progenitor EP cells) and the kinase inhibitory activity (toward both isolated kinases and EPCs) remained almost untouched and comparable to the activity of the single active units. Compounds 1-3 showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate 3 strongly inhibited in vivo angiogenesis in Matrigel plug assays in FVB mice. These results offer proof-of-concept of how the covalent conjugation of two angiogenesis-related small modules may result in novel and stable molecules, which impair tumor-related angiogenesis with equal or even superior ability as compared to the single modules or their simple combinations.
Discovery of novel polycyclic spiro-fused carbocyclicoxindole-based anticancer agents
Zhang, Lidan,Ren, Wen,Wang, Xiaoyan,Zhang, Jiaying,Liu, Jie,Zhao, Lifeng,Zhang, Xia
, p. 1071 - 1082 (2016/12/28)
A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in?vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 10l, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC50values of less than 30?μM. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, CT26, and HCT116?cells. Further studies illustrated that compound 10i arrested cell cycle in G1 phase and induced apoptosis of HCT116?cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 10i could bind well to the p53-binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions.
