- Antimicrobial and antiproliferative study of chalcone clubbed 2,4-dimethylpyrrole-3-carboxamide derivatives: Synthesis and in vitro evaluation
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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.
- Rasal, Nishant Kisan,Jagtap, Sangeeta Vijay,Bhange, Dattatraya Soma
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p. 119 - 130
(2021/10/06)
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- Low-cost clean method for preparing 2,4-dimethyl pyrrole-3,5-dicarboxylate
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The invention discloses a low-cost clean method for preparing 2,4-dimethyl pyrrole-3,5-dicarboxylate. The method comprises the following steps: mixing ethyl acetoacetate or tert-butyl acetoacetate with glacial acetic acid, slowly introducing inert gas into the mixed solution for 30 minutes, then introducing a nitrosation reagent nitric oxide gas at the flow rate of 0.5-1mL/min, conducting reacting at room temperature for 10 hours, controlling the temperature of the reaction solution to be 40 DEG C or lower, adding zinc powder in batches, dropwise adding ethyl acetoacetate at the same time, conducting reacting at 95 DEG C for 4 hours, conducting cooling, adding a reaction solution into ice water, conducting filtering, recrystallizing a filter cake with ethanol to obtain white ethyl 2,4-dimethyl pyrrole-3,5-dicarboxylate, and concentrating a filtrate to recover zinc acetate and acetic acid so as to realize the cleanness of the preparation process.
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Paragraph 0035-0036; 0039
(2021/07/24)
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- Synthesis, biological evaluation, and in silico study of pyrazoline-conjugated 2,4-dimethyl-1H-pyrrole-3-carboxylic acid derivatives
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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.
- Rasal, Nishant K.,Sonawane, Rahul B.,Jagtap, Sangeeta V.
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- Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents
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Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure-activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 μM. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.
- Zhou, Qifan,Jia, Lina,Du, Fangyu,Dong, Xiaoyu,Sun, Wanyu,Wang, Lihui,Chen, Guoliang
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supporting information
p. 2247 - 2255
(2020/02/20)
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- Novel RIP1 kinase inhibitor containing pyrrole ring and indoline structure and application thereof
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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.
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Paragraph 0024-0025
(2018/07/30)
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- Development of a novel conjugatable sunitinib analogue validated through in vitro and in vivo preclinical settings
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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.
- 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.
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p. 515 - 523
(2018/07/06)
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- 5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: Design, synthesis and cytotoxicity against cancer cells
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Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.
- Shah, Sajita,Lee, Chaemin,Choi, Hyukjae,Gautam, Jaya,Jang, Hyeonjin,Kim, Geum Jin,Lee, Yu-Jeong,Chaudhary, Chhabi Lal,Park, Sang Won,Nam, Tae-Gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
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p. 4829 - 4841
(2016/06/13)
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- Synthesis and in vitro antitumor activity of 1-(3-dimethylamino)propyl indolin-2-one derivatives
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A series of 1-(3-dimethylaminopropyl)indolin-2-one derivatives were designed and synthesized based on the structural features of TMP-20, LK-B030, and BX-517. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and three HUVECs. Results revealed that all of the target compounds 1a-h generally show potent activity against these cancer cell lines and higher selectivity on VEGF- and bFGF-stimulated HUVECs than HUVEC. In particular, 1f (IC50s: 1.10-1.47 μM) is 1.8-6.0-fold more potent than sunitinib against MDA-MB-231, A549, HL-60 and K-562, and 1.6-2.8-fold more potent than LK-B030 against MDA-MB-231 and A549.
- Lv, Kai,Wang, Li-Li,Zhou, Xin-Bo,Liu, Ming-Liang,Liu, Hong-Ying,Zheng, Zhi-Bing,Li, Song
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p. 1723 - 1729
(2013/07/26)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF NEURODEGENERATIVE DISEASE
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Compounds, compositions, kits and methods for treating conditions related to neurodegeneration or ocular disease, are disclosed.
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Page/Page column 31
(2011/10/13)
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- PROCESS FOR THE PREPARATION OF HIGH PURITY SUNITINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALT
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The present invention relates to an improved process for the preparation of N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide—Sunitinib base of formula (I) and its pharmaceutically acceptable malate salt of formula (I(a)).
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Page/Page column 14
(2011/05/03)
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- Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5- halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3- carboxamides
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We report herein the design and synthesis of novel 1-[3-(dimethylamino) propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC50's: 0.45-5.08 μM) are more active than Sunitinib (IC 50's: 1.35-6.61 μM), and the most active compound 1h (IC 50: 0.47-3.11 μM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.
- Lv, Kai,Wang, Li-Li,Liu, Ming-Liang,Zhou, Xin-Bo,Fan, Shi-Yong,Liu, Hong-Ying,Zheng, Zhi-Bing,Li, Song
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scheme or table
p. 3062 - 3065
(2011/06/24)
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- In vivo Positron Emission Tomography (PET) imaging of Mesenchymal - Epithelial Transition (MET) receptor
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We report the radiosynthesis and evaluation of 3-[3,5-dimethyl-4-(4-[ 11C]methylpiperazinecarbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2, 3-dihydro-1H-indole-5-sulfonic acid (3-chlorophenyl)methylamide, termed [ 11C]SU11274 ([11C]14) for in vivo imaging of mesenchymal - epithelial transition (MET) receptor by positron emission tomography (PET). Following the synthesis of the precursor (13) that was achieved in 10 steps with a total yield of 9.7%, [11C]14 was obtained through radiomethylation in a range of 5-10% radiochemical yield and over 95% radiochemical purity. For in vivo PET studies, two human lung cancer xenograft models were established using MET-positive NCI-H1975 and MET-negative NCI-H520 cell lines. Quantitative [11C]14-PET studies showed that the tumor uptake of [ 11C]14 in the NCI-H1975 xenografts was significantly higher than that in the NCI-H520 xenografts, which is consistent with their corresponding immunohistochemical tissue staining patterns of MET receptors from the same animals. These studies demonstrated that [11C]14-PET is an appropriate imaging marker for quantification of MET receptor in vivo, which can facilitate efficacy evaluation in the clinical development of MET-targeted cancer therapeutics. 2009 American Chemical Society.
- Wu, Chunying,Tang, Zhe,Fan, Weiwen,Zhu, Wenxia,Wang, Changning,Somoza, Edurado,Owino, Norbert,Li, Ruoshi,Ma, Patrick C.,Wang, Yanming
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experimental part
p. 139 - 146
(2010/04/26)
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- PROCESS FOR THE PREPARATION OF HIGH PURITY SUNITINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALT
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The present invention relates to an improved process for the preparation of N- [2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro- 1,2-dihydro-2-oxo-3H-indol-3-ylidine) methyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide - Sunitinib base of formula (I) and its pharmaceutically acceptable malate salt of formula (I(a)).
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Page/Page column 27
(2010/01/30)
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- FerriBRIGHT: A rationally designed fluorescent probe for redox active metals
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The novel catechol-BODIPY dyad, 8-(3,4-dihydroxyphenyl)-2,6- bis(ethoxycarbonyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene(FerriBRIGHT) was rationally designed with the aid of computational met hods. FerriBRIGHT could be prepared by standard one-pot synthesis of BODIPY fluorophores from 3,4-bis(benzyloxy)benzaldehyde (1) and 3,5-dimethyl-4-(ethoxycarbonyl)pyrrole (3); however, isolating the dipyrrin intermediate 8-[3,4-bis(benzyloxy)phenyl]-2,6-bis(ethoxycarbonyl)-1,3,5,7- tetramethyl-4,4-diaza-s-indacene (7) prior to reaction with excess BF 3·OEt2 led to marked improvements in the isolatedoverall yield of the desired compound. In addition to these improvement s in fluorophore synthesis, microwave-assisted palladium-catalyzed hydrogenolysis of benzyl ethers was used to reduce reaction times and catalyst loading in preparation of the desired compound. When FerriBRIGHT is exposed to excess FeCl3, CuCl2, [Co(NH3)5Cl]Cl 2, 2,3-dichloro-5,6-dicyanobenzoquinone, or ceric ammonium nitrate in methanol, a significant enhancement of fluorescence is observed. FerriBRIGHT-Q, the product resulting from the oxidation of the pendant catechol to the corresponding quinone, was found to bethe emissive species. FerriBRIGHT-Q was synthesized independently, isol ated, and fully characterized to allow for direct comparison with the spectroscopic data acquired in solution. Biologically relevant reactive oxygen species, such as H2O2, ?OH, 1O2, O2?-, and bleach (NaOCl), failed to cause any changes in the emission intensity of FerriBRIGHT. In accordance with the quantum mechanical calculations, the quantumyield of fluorescence for FerriBRIGHT (Φfl ' 0) and F erriBRIGHT-Q (Φfl = 0.026, λex/ λem = 490 nm/510 nm) suggests that photoinduced electron transfer between the catechol and the BODIPY dye is attenuated upon oxidation, which results in fluorescence enhancement. Binding studies of FerriBRIGHT with Ga(NO3)3, a redox-inactive analogue of Fe(III), provided conditional binding constant log β12′) 13.3 ± 0.2 for a [Ga(FerriBRIGHT)2]- complex. A 2.8-fold enhancement of fluorescence intensity upon addition of Ga(III) to FerriBRIGHT suggests the possibility of metal ion sensing with this new class of compounds.
- Kennedy, Daniel P.,Kormos, Chad M.,Burdette, Shawn C.
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experimental part
p. 8578 - 8586
(2009/10/23)
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- MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
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The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.
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Page/Page column 200
(2008/06/13)
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- SUBSTITUTED 2-INDOLINONE AS PTK INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to substituted 2-indolinone containing zinc- binding moiety based derivatives that have enhanced or unique properties as inhibitors of protein tyrosine kinase (PTK) receptors and their use in the treatment of PTK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 53; 55-56
(2008/06/13)
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- Sulfonamide substituted indolinones as inhibitors of DNA dependent protein kinase (DNA-PK)
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The present invention relates generally to the field of radiosensitizing agents which are capable of enhancing radiotherapy by inhibiting DNA-PK (DNA-protein kinase). In particular, it relates to sulfonamide substituted indolinones which inhibit DNA-PK.
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- 5-sulfonamido-substituted indolinone compounds as protein kinase inhibitors
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The present invention relates to 5-sulfonamido substituted indolinones that modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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Page/Page column 14-15
(2010/02/08)
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- 4-aryl substituted indolinones
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The present invention relates to 4-arylindolinones, as well as pharmaceutical compositions thereof, capable of modulating protein kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation. The present invention also relates to methods for treating protein kinase related disorders.
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- 5-ARALKYSUFONYL-3-(PYRROL-2-YLMETHYLIDENE)-2-INDOLINONE DERIVATIVES AS KINASE INHIBITORS
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The present invention relates to certain 5-aralkylsulfonyl-3-(pyrrol-2-yl-methylidene)-2-indolinone derivatives that inhibit kinases, in particular met kinase. Pharmaceutical compositions comprising these compounds, methods of treating diseases mediated by kinases utilizing pharmaceutical compositions comprising these compounds, and methods of preparing them are also disclosed.
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- 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
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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.
- 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
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p. 1116 - 1119
(2007/10/03)
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