2199-59-9Relevant academic research and scientific papers
Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase
Sun, Li,Liang, Chris,Shirazian, Sheri,Zhou, Yong,Miller, Todd,Cui, Jean,Fukuda, Juri Y.,Chu, Ji-Yu,Nematalla, Asaad,Wang, Xueyan,Chen, Hui,Sistla, Anand,Luu, Tony C.,Tang, Flora,Wei, James,Tang, Cho
, p. 1116 - 1119 (2003)
To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rβ tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
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
, p. 5882 - 5885 (2018)
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.
Antimicrobial and antiproliferative study of chalcone clubbed 2,4-dimethylpyrrole-3-carboxamide derivatives: Synthesis and in vitro evaluation
Rasal, Nishant Kisan,Jagtap, Sangeeta Vijay,Bhange, Dattatraya Soma
, p. 119 - 130 (2021/10/06)
The presented study explores the anticancer potency of a novel series of chalcone clubbed 2,4-dimethyl-1H-pyrrole-3-carboxamide derivatives. In vitro antimicrobial screening concluded that five compounds are potential against Candida albicans having inhibition of growth in the range of 46.38%–73.05% against at the concentration of 32 μg/mL. The antiproliferative screening against 60 cancer cell lines revealed that seven compounds have great potential against the various types of cancer cell lines with inhibition of growth in the range of 41%–71%. The structure–activity relationship study concluded that the hydrazide bond is more significant than the carboxamide bond. In silico study of highly potential derivatives obeys each parameter of Lipinski rule of five and qualified drug-likeness behavior. The presented pyrrole-chalcone template delivered various candidates as anticancer agents, and those could be a potential scaffold to develop the new anticancer drug.
Synthesis, biological evaluation, and in silico study of pyrazoline-conjugated 2,4-dimethyl-1H-pyrrole-3-carboxylic acid derivatives
Rasal, Nishant K.,Sonawane, Rahul B.,Jagtap, Sangeeta V.
, (2020/10/22)
A potential molecular hybridization strategy was used to develop 24 novel pyrazoline-conjugated 2,4-dimethyl-1H-pyrrole-3-carboxylic acid and amide derivatives. The preliminary in vitro antimicrobial assay delivered four potential derivatives with growth inhibition in the range of 50.87–56.60% at the concentration of 32 μg/ml. In the search of an anticancer candidate, all derivatives were screened by NCI-60 at 10 μM concentration, revealing that 12 derivatives were potential agents against the various types of cancer cell lines, with growth inhibition in the range of 50.21–108.37%. The in vitro cytotoxicity assay against the cell line HEK293 (human embryonic kidney cells) and the hemolysis assay of the representative potent compounds propose their potential for a good therapeutic index. In silico studies of the most potent derivatives qualified their significant pharmacokinetic properties with good predicted oral bioavailability and their adherence to Lipinski's rule of five for druglikeness. A molecular docking study against VEGFR-2 with the best-scored conformations reinforced their anticancer potency. The docking study of the most potent compound against VEGFR-2 with the best-scored conformations displayed a binding affinity (?9.5 kcal/mol) comparable with the drug sunitinib (?9.9 kcal/mol) and exhibited that tighter interactions at the active adenosine triphosphate site might be responsible for anticancer potency.
IBX-TfOH mediated oxidation of alcohols to aldehydes and ketones under mild reaction conditions
Kumar, Kamlesh,Kumar, Prashant,Joshi, Penny,Rawat, Diwan S
supporting information, (2020/03/04)
An efficient, practical and facile procedure has been developed for the oxidation of primary and secondary alcohols using IBX-TfOH catalytic system in 1,4-dioxane at ambient temperature. The reaction affords quantitative yields of the corresponding carbonyl compounds without the formation of over oxidized products. The present synthetic protocol is compatible with a variety of substrates having arene, heteroarene and alkene functionalities. The developed synthetic protocol can be used for higher scale reactions as evident by the oxidation of alcohol at 1 g scale in higher yields by a simple filtration process.
Preparation method of sunitinib intermediate
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, (2019/05/04)
The invention discloses a preparation method of a sunitinib intermediate. The method includes the following steps of 1, synthesis of 2, 4-dimethylpyrrole-3, 5-diethyl dicarboxylate, 2, synthesis of 4-ethoxycarbonyl-3, 5-dimethylpyrrole-2-carboxylic acid, 3, synthesis of 2, 4-dimethyl-3-ethyl pyrrole-2-carboxylate, 4, synthesis of 2, 4-dimethyl-5-aldehyde-1H-pyrrole-3-ethyl formate, and 5, synthesis of 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid. The method has the advantages that the raw materials are cheap, the environmental pollution is small, the industrial production is easy to achieve, the processing steps are fewer, the operation is simple, the reaction yield is very high, the mass production of enterprise is facilitated, and application and popularization are facilitated.
Enhanced fluorescence sensor for targeting recognition of receptor tyrosine kinase and application of fluorescence sensor in cell membrane fluorescence imaging
-
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.
Novel RIP1 kinase inhibitor containing pyrrole ring and indoline structure and application thereof
-
, (2018/07/30)
The invention relates to a novel RIP1 kinase inhibitor containing a pyrrole ring and an indoline structure and application in preparing drugs for treating inflammation, ischemic diseases and cell injury type diseases.
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.
Design and synthesis of new potent PTP1B inhibitors with the skeleton of 2-substituted imino-3-substituted-5-heteroarylidene-1,3-thiazolidine-4-one: Part I
Meng, Ge,Zheng, Meilin,Wang, Mei,Tong, Jing,Ge, Weijuan,Zhang, Jiehe,Zheng, Aqun,Li, Jingya,Gao, Lixin,Li, Jia
, p. 756 - 769 (2016/08/18)
A new series of 2-substituted imino-3-substituted-5- heteroarylidene-1,3-thiazolidine-4-ones as the potent bidentate PTP1B inhibitors were designed and synthesized in this paper. All of the new compounds were characterized and identified by spectra analysis. The biological screening test against PTP1B showed that some of these compounds have the positive inhibitory activity against PTP1B. The activity of the compounds with 5-substituted pyrrole on 5-postion of 1,3-thiazolidine-4-one are more potent than that of those compounds with 5-substituted pyridine group. Compound 14b, 14h and 14i showed IC50values of 8.66?μM, 6.83?μM and 6.09?μM against PTP1B, respectively. Docking analysis of these active compounds with PTP1B showed the possible interaction modes of these biheterocyclic compounds with the active sites of PTP1B. The inhibition tests against oncogenetic CDC25B were also conducted on this set of compounds to evaluate the selectivity and possible anti-neoplastic activity. Compound 14b also showed the lowest IC50of 1.66?μM against CDC25B among all the possible inhibitors, including 14g, 14h, 14i and 15c. Some pharmacological parameters including VolSurf, steric and electric descriptors of all the compounds were calculated to give some hints about the relative relationship with the biological activity. The result of this study might give some light on designing the possible anti-cancer drugs targeting at phosphatases. The most active compound 14i might be used as the lead compound for further structure modification of the new low molecular weight PTP1B inhibitors with the N-containing heterocyclic skeleton.
