- Navigating into the chemical space between MGCD0103 and SAHA: Novel histone deacetylase inhibitors as a promising lead
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Histone deacetylase inhibitors (HDIs) are an increasingly important class of cancer-targeting agents. Two kinds of small molecule histone deacetylase inhibitors, mainly employing the motifs of the two known HDAC inhibitors MGCD0103 and SAHA as the basic scaffolds, were designed, synthesized and evaluated for the preliminary biological activity. Strikingly, these two compounds regained a long half-life potency like MGCD0103 and retained the non-selectivity for HDAC1 versus HDAC6 derived from SAHA. Together, these two compounds combining both the advantages of MGCD0103 and SAHA could be considered as novel histone deacetylase inhibitors in targeted drug development and possibly anticipated to be more effective under the clinical trials.
- Zhang, Xin,Lv, Peng-Cheng,Li, Dong-Dong,Zhang, Wei-Ming,Zhu, Hai-Liang
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Read Online
- Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14
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Imatinib (Gleevec) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia and acute lymphocytic leukemia. Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14C-labeling and radiosynthesis of [14C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy. 14C-labeling of imatinib was performed by the synthesis of 14C-labeld 2-aminopyrimidine intermediate using [14C]guanidine·HCl, which includes an in situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.
- Kang, Julie,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo
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p. 174 - 182
(2020/02/13)
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- Computer Modeling and Synthesis of Potential Inhibitors of Tyrosine Kinase BCR-ABL with the T315I Mutation
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Abstract—: A comparative analysis of the interaction of the chimeric protein BCR-ABL, of the normal type and with the T315I mutation, with known inhibitors as well as compounds potentially capable of inhibiting the mutant protein has been carried out by computer modeling. It has been shown that the compounds proposed are incorported into the structure of the protein with the retention of the basic hydrogen bonds and intermolecular interactions. Two structures containing the pyrrole cycle have been synthesized, which, according to the results of computer modeling, appear to be most promising.
- Fedarkevich, A. N.,Sharko, O. L.,Shmanai, V. V.
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p. 187 - 198
(2020/05/04)
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- Preparation method and application of N-(pyrimidine-2-yl) coumarin-7-amine derivative as protein kinase inhibitor
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The invention discloses a cyclin-dependent kinase inhibitor. The cyclin-dependent kinase inhibitor comprises an N-(pyrimidine-2-yl) coumarin-7-amine derivative shown as a general formula (I). In-vitropharmacodynamic tests prove that the compound has a high-selectivity inhibition effect on CDK9 kinase, and can be applied to reducing or inhibiting the activity of CDK9 kinase in cells. The inventionalso discloses a preparation method of the inhibitor and application of the inhibitor in drugs for CDK family kinase mediated diseases, especially hyperproliferative diseases, virus-induced infectious diseases and cardiovascular diseases.
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Paragraph 0223; 0227-0229
(2020/12/14)
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- Smo inhibitor as well as synthesis method and application thereof
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The invention discloses an Smo inhibitor as well as a synthesis method and application thereof. A structural formula of the Smo inhibitor is shown by a formula (I) as shown in the specification. The invention also discloses the synthesis method and the application of the Smo inhibitor. According to the invention, nilotinib is optimized into the dual-targeted inhibitor being active against Smo andBcr-Abl, and the inhibitor can overcome the tolerance problem caused by single-targeted drugs, has the advantages of improving anti-tumor efficacy and reducing toxic or side effects, and provides a reference for future research on dual-targeted anti-hematologic malignant drugs.
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Paragraph 0044; 0052-0056
(2019/09/17)
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- Live-cell imaging and profiling of c-Jun N-terminal kinases using covalent inhibitor-derived probes
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c-Jun N-terminal kinases (JNKs) are involved in critical cellular functions. Herein, small-molecule JNK-targeting probes are reported based on a covalent inhibitor. Together with newly developed two-photon fluorescence Turn-ON reporters and chemoproteomic studies, we showed that some probes may be suitable for live-cell imaging and profiling of JNKs.
- Qian, Linghui,Pan, Sijun,Lee, Jun-Seok,Ge, Jingyan,Li, Lin,Yao, Shao Q.
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supporting information
p. 1092 - 1095
(2019/01/29)
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- SPIRO THREE-MEMBERED RING, SPIRO FIVE-MEMBERED RING PEPTIDE DEFORMYLASE INHIBITOR AND USE THEREOF IN ANTIBACTERIA AND ANTI-TUMOUR.
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Disclosed are the anti-bacterial activity and the anti-tumor activity of a class of new spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, are effective against many antibiotic-resistant Gram-positive strains by inhibiting the activity of the peptide deformylase required in the synthesis of bacterial proteins, and do not affect the synthetic process of the main proteins of the human body, thus selectively killing bacteria. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, can affect the energy balance of the cancer cells through inhibiting the peptide deformylase of the mitochondria in the cells, so that the mitochondrial membrane is depolarized, ATP is exhausted and cell apoptosis is promoted, and has good inhibitory activities on many cancer cell strains such as colorectal cancer, leukemia, lung cancer, gastric cancer, cervical cancer, breast cancer, prostatic cancer, liver cancer and osteosarcoma at relatively lower concentrations.
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Paragraph 0077
(2019/05/22)
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- Design, synthesis and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine kinase inhibitors
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Novel serious of pyrimidine scaffold benzamide derivatives (9 a-k) were synthesized and characterized by IR, HRMS, and NMR. Docking study of compounds 9 g, 9 h exhibited H-bonding interacts with Met769 into ATP binding site of EGFR-TK which showed similar binding mode to Lapitinib (PDB code: 1M17). Results indicated the ability to potent and selective inhibitors of the Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK). The molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs) and HOMO-LUMO energy gap of the title compounds were investigated by using the B3LYP/6-31G method. The synthesized compounds were screened for in vitro anti-inflammatory activity.
- Thirumurugan,Lakshmanan, Sivalingam,Govindaraj, Dharman,Daniel Prabu, D. Sam,Ramalakshmi,Arul Antony
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p. 541 - 550
(2018/06/20)
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- Efficient synthesis of 4- And 5-substituted 2-aminopyrimidines by coupling of β-Chlorovinyl Aldehydes and Guanidines
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A general, practical, and simple synthesis of functionalized 2-aminopyrimidines starting from β-chlorovinyl aldehydes and amidines is reported. In the presence of potassium carbonate, various ketones have been efficiently transformed into the pyrimidine derivatives by a two-step sequence involving the Vilsmeier-Haack reaction followed by a condensation reaction with guanidines. The protocol is distinguished by operational simplicity, inexpensive reagents, and functional-group tolerance. In many cases, pure solid products can be obtained in high to excellent yields without using column chromatography. The synthetic value of the method was demonstrated by the efficient synthesis of steroidal pyrimidines and a precursor of the antitumor agents Imatinib and Mocetinostat.
- Komendantova, Anna S.,Komkov, Alexander V.,Volkova, Yulia A.,Zavarzin, Igor V.
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supporting information
p. 4247 - 4254
(2018/08/24)
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- Synthesis of C5-tethered indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors
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A series of C5-tethered Indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in?vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 7f displayed cytotoxicity of IC50?=?140?nM towards DU145 cancer cell line. The treatment of DU145?cells with 7f led to inhibition of cell migration ability. Futher, the detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 7f induced apoptosis in DU145?cells. The influence of the cytotoxic compound 7f on the cell cycle distribution was assessed on the DU145?cell line, exhibiting a cell cycle arrest at the G2/M phase (hallmark of tubulin polymerization) and next inhibited tubulin polymerization with IC500.40?μM. Furthermore, the treatment with compound 7f caused collapse of mitochondrial membrane potential and elevated intracellular superoxide ROS levels in DU145?cells. Western blotting was performed to examine the levels of apoptotic proteins (Bcl-2 and Bax); the study confirmed that compound 7f induced apoptosis through apoptosis-related protein expression. Thus, these studies provided a new molecular scaffold for the further development of anticancer agents that target tubulin.
- Guggilapu, Sravanthi Devi,Lalita, Guntuku,Reddy, T. Srinivasa,Prajapti, Santosh Kumar,Nagarsenkar, Atulya,Ramu, Shymala,Brahma, Uma Rani,Lakshmi, Uppa Jaya,Vegi, Ganga Modi Naidu,Bhargava, Suresh K.,Babu, Bathini Nagendra
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- Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives
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In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.
- Manchanda, Priyanka,Parshad, Badri,Kumar, Amit,Tiwari, Rakesh K.,Shirazi, Amir N.,Parang, Keykavous,Sharma, Sunil K.
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- Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine derivatives as potential cytotoxic agents
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In our endeavor towards the development of effective cytotoxic agents, a series of oxindole linked indolyl-pyrimidine derivatives were synthesized and characterized by IR, 1H NMR, 13C NMR and Mass spectral analysis. All the newly synthesized target compounds were assessed against PA-1 (ovarian), U-87MG (glioblastoma), LnCaP (prostate), and MCF-7 (Breast) cancer cell lines for their cytotoxic potential, with majority of them showing inhibitory activity at low micro-molar concentrations. Significantly, compound 8e was found to be most potent amongst all the tested compounds with an IC50 value of (2.43 ± 0.29 μM) on PA-1 cells. The influence of the most active cytotoxic compound 8e on the cell cycle distribution was assessed on the PA-1 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, acridine orange/ethidium bromide staining and annexin V binding assay confirmed that compound 8e can induce cell apoptosis in PA-1 cells. These preliminary results persuade further investigation on the synthesized compounds aiming to the development of potential cytotoxic agents.
- Prajapti, Santosh Kumar,Nagarsenkar, Atulya,Guggilapu, Sravanthi Devi,Gupta, Keshav Kumar,Allakonda, Lingesh,Jeengar, Manish Kumar,Naidu,Babu, Bathini Nagendra
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supporting information
p. 3024 - 3028
(2016/06/13)
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- An optimized approach in the synthesis of imatinib intermediates and analogues
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We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt 4, one of the key steps to the imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of nilotinib and its analogues intermediates.
- Kinigopoulou,Filippidou,Gogou,Giannousi,Fouka,Ntemou,Alivertis,Georgis,Brentas,Polychronidou,Voulgari,Theodorou,Skobridis
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p. 61458 - 61467
(2016/07/12)
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- A Practical Preparation of Imatinib Base
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A practical preparation of imatinib base was reported in this article. Compared with reported works, the features of this work were the concise procedures, the industrially available starting materials, the avoidance of expensive or highly toxic transition-metal catalysts or reagents, and the genotoxic impurities 6-methyl-N 1-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine and 4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. The method was scalable to at least 100 mmol, and the products were separated by simple recrystallizations.
- Zhang, Xu,Sun, Jingjing,Chen, Tian,Yang, Chenggen,Yu, Lei
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p. 2233 - 2236
(2016/10/24)
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- Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis
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A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.
- Obermayer, David,Znidar, Desiree,Glotz, Gabriel,Stadler, Alexander,Dallinger, Doris,Oliver Kappe
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p. 11788 - 11801
(2016/12/09)
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- New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment
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The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.
- Lv, Fengping,Chen, Chen,Tang, Yang,Wei, Jianhai,Zhu, Tong,Hu, Wenhao
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supporting information
p. 3714 - 3718
(2016/07/21)
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- Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation
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The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.
- Korch, Katerina M.,Eidamshaus, Christian,Behenna, Douglas C.,Stoltz, Brian M.,Nam, Sangkil,Horne, David
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supporting information
p. 179 - 183
(2015/02/05)
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- Synthesis and Biological Activity of Some Novel Aryl-Substituted 1,3,4-Oxadiazole Mannich Bases Containing Pyrimidine Rings
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A series of novel Mannich base derivatives (E1-E15) of 5-aryl-1,3,4-oxadiazole-2-thione with substituted pyrimidine were synthesized and characterized by elemental analysis, IR, 1H-NMR. The antifungal activities of these compounds were also originally studied. The results showed that most of the title compounds exhibited relatively good fungicidal activities. Especially compounds E8 and E13 showed better antifungal activity than comparison compound hymexazol. The relationship of structure and activity revealed that the presence of the methyl group at four and six positions of pyrimidine ring remarkably enhanced the antifungal activity of title compounds.
- Shen, Shengqiang,Sun, Xiaohong,Liu, Yuanfa,Chen, Bang,Jin, Ruyi,Ma, Haixia
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p. 1296 - 1301
(2015/10/06)
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- Oligomer-protein tyrosine kinase inhibitor conjugates
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The invention relates to (among other things) oligomer-PTK inhibitor conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over PTK inhibitor compounds lacking a water-soluble, non-peptidic oligomer.
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- BENZIMIDAZOLE DERIVATIVES AS SELECTIVE PROTEINE KINASE INHIBITORS
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. Wherein n, R1, R2, R3, R4, R5, A, Q and X are as defined in the description. These compounds selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant proteine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective native and/or mutant c-kit inhibitors.
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- An expeditious synthesis of imatinib and analogues utilising flow chemistry methods
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A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
- Hopkin, Mark D.,Baxendale, Ian R.,Ley, Steven V.
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supporting information
p. 1822 - 1839
(2013/04/23)
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- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
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Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
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p. 8551 - 8556
(2013/09/12)
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- Completely N1-selective palladium-catalyzed arylation of unsymmetric imidazoles: Application to the synthesis of nilotinib
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The completely N1-selective Pd-catalyzed arylation of unsymmetric imidazoles with aryl halides and triflates is described. This study showed that imidazoles have a strong inhibitory effect on the in situ formation of the catalytically active Pd(0)-ligand complex. The efficacy of the N-arylation reaction was improved drastically by the use of a preactivated solution of Pd2(dba)3 and L1. From these findings, it is clear that while imidazoles can prevent binding of L1 to Pd, once the ligand is bound to the metal, these heterocycles do not displace it. The utility of the present catalytic system was demonstrated by the regioselective synthesis of the clinically important tyrosine kinase inhibitor nilotinib.
- Ueda, Satoshi,Su, Mingjuan,Buchwald, Stephen L.
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supporting information; experimental part
p. 700 - 706
(2012/03/07)
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- Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: Synthesis of Imatinib
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CuO nanoflakes bound on polystyrene beads (PS-CuO) were prepared through the oxidation of copper(I) bromide in a suspension of polystyrene. The use of PS-CuO as a catalyst in the presence of KOtBu in the coupling reactions of aryl bromides and amines afforded the coupled products with a yield range of 15-89%. This catalytic system also afforded the key fragment in good yield for the synthesis of Imatinib (Gleevec).
- Heo, Yumi,Hyun, Dajung,Kumar, Manian Rajesh,Jung, Hyun Min,Lee, Sunwoo
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supporting information
p. 6657 - 6661
(2013/01/15)
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- N-[2-methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a Scaffold for the synthesis of inhibitors of Bcr-Abl
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N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized and evaluated invitro for their potential use as inhibitors of Bcr-Abl. The design is based on the bioisosterism between the 1,2,3-triazole ring and the amide group. The synthesis involves a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as the key step, with the exclusive production of anti-(1,4)-triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line. Willing and Abl inhibitors! N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized by a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step, with anti-(1,4)-triazole derivatives as the exclusive products. One of these compounds shows general activity similar to that of imatinib, and in particular, it is more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line.
- Arioli, Federica,Borrelli, Stella,Colombo, Francesco,Falchi, Federico,Filippi, Irene,Crespan, Emmanuele,Naldini, Antonella,Scalia, Giusy,Silvani, Alessandra,Maga, Giovanni,Carraro, Fabio,Botta, Maurizio,Passarella, Daniele
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experimental part
p. 2009 - 2018
(2012/06/30)
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- Formation of pyrimidin-2-ylcyanamide and 2-aminopyrimidine in the reaction of aniline derivatives with cyanamide and dimethylamino-1-pyridyl-2-propenone
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Substituted o- and p-nitroanilines and m-benzylaminoanilines in the reaction with cyanamide failed to yield the corresponding arylguanidines, and in the presence of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one formed 4-pyridyl-substituted pyrimidin-2-ylcyanamides and 2-amino-pyrimidines.
- Koroleva,Ignatovich, Zh.V.,Ignatovich,Gusak
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experimental part
p. 1222 - 1226
(2011/12/01)
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- A flow-based synthesis of Imatinib: The API of Gleevec
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A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates. The Royal Society of Chemistry.
- Hopkin, Mark D.,Baxendale, Ian R.,Ley, Steven V.
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supporting information; experimental part
p. 2450 - 2452
(2010/08/05)
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- Design and synthesis of new anticancer pyrimidines with multiple-kinase inhibitory effect
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A new series of N-substituted-2-aminopyrimidines based on the '4-(pyridin-3-yl)pyrimidin-2-amine' scaffold of Imatinib has been designed and synthesized. A selected group from the target compounds was tested over a panel of 60 cancer cell lines at a single dose concentration of 10 μM, and the two most active compounds, 25b and 30, were further tested in a five-dose testing mode to determine their IC50 values over the 60 cell lines. Compound 30 has showed good potencies and high efficacies, and was accordingly tested at a single dose concentration of 10 μM over a panel of 54 kinases. At this concentration, the compound has showed multiple inhibitions over a number of oncogenic kinases, including ABL1, AKT1, LCK, C-SRC, PIM1, FLT3, FYN, and KDR. A molecular modeling study was made by docking of the most active compound 30 and its inactive analog 29 into the kinase domain of ABL1 to investigate their possible binding interactions.
- El-Deeb, Ibrahim Mustafa,Lee, So Ha
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experimental part
p. 3860 - 3874
(2010/08/22)
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- Small molecule probes that target Abl kinase
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Two different strategies, namely a dialdehyde-based cross-linking and photo-affinity labeling, have been developed to generate small molecule activity-based probes (ABPs) for the Abelson (Abl) tyrosine kinase, of which probe 13, derived from the photo-affinity approach, showed specific labeling of Abl kinase present in a crude mammalian proteome.
- Kalesh, Karunakaran A.,Sim, Derek S. B.,Wang, Jigang,Liu, Kai,Lin, Qingsong,Yao, Shao Q.
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supporting information; experimental part
p. 1118 - 1120
(2010/06/18)
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- AMIDES AS KINASE INHIBITORS
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The present invention is directed to amides, and pharmaceutical compositions thereof, which are inhibitors of kinases such as BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.
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Page/Page column 36
(2010/09/17)
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- Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry
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Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl) tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potent inhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.
- Kalesh, Karunakaran A.,Liu, Kai,Yao, Shao Q.
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experimental part
p. 5129 - 5136
(2010/04/04)
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- A facile total synthesis of imatinib base and its analogues
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Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed iV-arylation of heteroarylamme in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N2H 4.H2O/FeCl3/C system using water as a solvent in good yield.
- Liu, Yi-Feng,Wang, Cui-Ling,Bai, Ya-Jun,Han, Ning,Jiao, Jun-Ping,Qi, Xiao-Li
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p. 490 - 495
(2013/01/03)
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- SOLID PHASE SYNTHESES OF AMINO PYRIMIDINE COMPOUNDS
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The invention methods for the solid-phase syntheses of amino pyrimidine compounds, such as imatinib and analogs thereof.
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Page/Page column 15-16
(2008/12/08)
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- Synthesis of new N-arylpyrimidin-2-amine derivatives using a palladium catalyst
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New N-aryl-4-(pyridin-3-yl)pyrimidin-2-amine derivatives were synthesized from the corresponding amines, applying optimized Buchwald-Hartwig amination conditions using dichlorobis(triphenylphosphine)Pd(II), xantphos and sodium tert-butoxide in refluxing toluene under a nitrogen atmosphere. The target N-aryl derivatives were obtained in moderate to good yields ranging from 27% to 82%. The procedure described could be widely employed for the preparation of new heterocyclic compounds. The structures of the new compounds were confirmed by FT-NMR, FT-IR and elemental analysis.
- El-Deeb, Ibrahim Mustafa,Jae, Chun Ryu,So, Ha Lee
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p. 818 - 830
(2008/09/18)
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- An efficient synthesis of nilotinib (AMN107)
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A concise synthesis of AMN107, a compound currently undergoing several phase II/III clinical trials for chronic myelogenous leukemia is described. The new procedure reduces the number of synthetic steps from eight to four, with an overall yield of 65%. Georg Thieme Verlag Stuttgart.
- Huang, Wei-Sheng,Shakespeare, William C.
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p. 2121 - 2124
(2008/03/28)
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