- Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer
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The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.
- Wu, Chun-Feng,Wang, Qing-Chen,Chen, Rui,Zhou, Hai-Ling,Wu, Ting-Ting,Du, Yao,Zhang, Na-Na,Zhang, Hui-Min,Fan, Zu-Yan,Wang, Li-Li,Hu, Chu-Jiao,Sang, Zhi-Pei,Li, Hong-Liang,Wang, Ling,Tang, Lei,Zhang, Ji-Quan
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- Design, synthesis, docking, molecular dynamics and bioevaluation studies on novel N-methylpicolinamide and thienopyrimidine derivatives with inhibiting NF-κB and TAK1 activities: Cheminformatics tools RDKit applied in drug design
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Using cheminformatics tools RDKit and literature investigation, four series of 24 thienopyrimidine/N-methylpicolinamide derivatives substituted with pyrimidine were designed, synthesized and evaluated for activities against three cancer cell lines (MDA-MB-231, HCT116 and A549), TAK1 kinase and NF-κB signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-κB signaling pathway with the IC50 values of 0.58 and 0.84 μM. Moreover, 38 can induce cell cycle arrest of A549 cells at the G2/M checkpoint with 30.57% and induce apoptosis (34.94%) in a concentration-dependent manner. And western blot showed that compound 38 could inhibit TNF-α-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation and TAK1 phosphorylation, and reduce the expression of p65. What's more, the studies of docking, molecular dynamics, MM/PBSA and frequency analysis theoretically supported the conclusions of the bioevaluation.
- Wang, Linxiao,Zhang, Qian,Wang, Zhe,Zhu, Wufu,Tan, Ninghua
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- INHIBITORS OF CYCLIN-DEPENDENT KINASES
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Provided herein are inhibitors of cyclin-dependent kinases (CDKs), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.
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Paragraph 00314
(2020/01/24)
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- HFIP Promoted Low-Temperature SNAr of Chloroheteroarenes Using Thiols and Amines
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A highly efficient and an unprecedented hexafluoro-2-propanol, promoting low-temperature aromatic nucleophilic substitutions of chloroheteroarenes, has been performed using thiols and (secondary) amines under base-free and metal-free conditions. The developed protocol also provides excellent regio-control for the selective functionalization of dichloroheteroarenes, while the utility of the protocol was demonstrated by the modification of a commercially available drug ceritinib.
- Bhujabal, Yuvraj B.,Vadagaonkar, Kamlesh S.,Gholap, Aniket,Sanghvi, Yogesh S.,Dandela, Rambabu,Kapdi, Anant R.
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p. 15343 - 15354
(2019/12/04)
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- Discovery of 3-Oxabicyclo[4.1.0]heptane, a non-nitrogen containing morpholine isostere, and its application in novel inhibitors of the PI3K-AKT-mTOR Pathway
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4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine Π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).
- Hobbs, Heather,Bravi, Gianpaolo,Campbell, Ian,Convery, Maire,Davies, Hannah,Inglis, Graham,Pal, Sandeep,Peace, Simon,Redmond, Joanna,Summers, Declan
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p. 6972 - 6984
(2019/09/16)
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- Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-negative breast cancer cell line MDA-MB-468
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Triple-negative breast cancers (TNBCs) are characterized as an invasive and intractable subtype of breast cancers. Overexpression of epidermal growth factor receptor (EGFR) has been considered to be an important target for TNBC therapy, but efficacies of
- Jo, Jeyun,Kim, Sou Hyun,Kim, Heegyu,Jeong, Myeonggyo,Kwak, Jae-Hwan,Taek Han, Young,Jeong, Jee-Yeong,Jung, Young-Suk,Yun, Hwayoung
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supporting information
p. 62 - 65
(2018/11/23)
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- SAR optimization studies on a novel series of 2-anilinopyrimidines as selective inhibitors against triple-negative breast cancer cell line MDA-MB-468
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Triple-negative breast cancers (TNBCs) account for approximately 15% of breast cancer cases and exhibit an aggressive clinical behavior. In this study, we designed and synthesized two series of 2-anilinopyrimidines based on the structure of our previously
- Jo, Jeyun,Kim, Heegyu,Oh, Ji Youn,Kim, Soyeong,Park, Yeong Hye,Choi, Hyeonjin,Jeong, Jee-Yeong,Jung, Young-Suk,Yun, Hwayoung
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- Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes
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A mild and highly efficient catalytic amination procedure for chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is reported. The protocol is selective for the amination of chloroheteroarenes using secondary amines such as piperidine, pyrrolidine, and several others. The exceptional mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib intermediate as well as the formal synthesis of Alogliptin in competitive yields.
- Murthy Bandaru, Siva Sankar,Bhilare, Shatrughn,Chrysochos, Nicolas,Gayakhe, Vijay,Trentin, Ivan,Schulzke, Carola,Kapdi, Anant R.
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supporting information
p. 473 - 476
(2018/01/28)
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- Novel Derivatives of 2-Anilinopyrimidine and Composition Comprising the Same
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The present invention relates to a 2-anilinopyrimidine derivative represented by chemical formula 1 and a composition containing the 2-anilinopyrimidine derivative as an active ingredient for preventing or treating cancer. According to the present inventi
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Paragraph 0064; 0070-0071; 0084-0085
(2018/09/08)
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- BICYCLIC COMPOUND AND USE THEREOF FOR INHIBITING SUV39H2
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The present invention directs to a compound represented by formula (I).
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Page/Page column 419-421
(2017/08/01)
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- NOVEL OXAZOLE DERIVATIVES THAT INHIBIT SYK
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The present invention is concerned with substituted oxazole derivatives that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant protein kinases implicated in a variety of human and animal diseases s
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Paragraph 0108
(2017/04/04)
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- Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation
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Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. We previously reported the discovery of 2 (NEU-617), a small molecule with activity against T. brucei bloodstream prol
- Woodring, Jennifer L.,Bachovchin, Kelly A.,Brady, Kimberly G.,Gallerstein, Mitchell F.,Erath, Jessey,Tanghe, Scott,Leed, Susan E.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Sciotti, Richard J.,Pollastri, Michael P.
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p. 446 - 459
(2017/10/24)
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- Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis
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Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against c
- Wu, Xiaoai,Fang, Zhen,Yang, Bo,Zhong, Lei,Yang, Qiuyuan,Zhang, Chunhui,Huang, Shenzhen,Xiang, Rong,Suzuki, Takayoshi,Li, Lin-Li,Yang, Sheng-Yong
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supporting information
p. 2284 - 2288
(2016/04/20)
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- Selective mono-amination of dichlorodiazines
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A mild, easy-to-perform, and versatile method for the formation of aminochlorodiazines from reaction of several types of dichlorodiazines (i.e., pyridazines, pyrimidines, and pyrazines) with primary or secondary amines in ethanol in the presence of trieth
- Sengmany, Stéphane,Lebre, Julie,Le Gall, Ewan,Léonel, Eric
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p. 4859 - 4867
(2015/08/03)
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- DIAZASPIROALKANEONE-SUBSTITUTED OXAZOLE DERIVATIVES AS SPLEEN TYROSINE KINASE INHIBITORS
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The present invention is concerned with diazaspiroalkanone- substituted oxazole derivatives that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant protein kinases implicated in a variety of human a
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Page/Page column 40
(2015/12/08)
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- Triazine-pyrimidine based molecular hybrids: Synthesis, docking studies and evaluation of antimalarial activity
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A series of novel triazine-pyrimidine hybrids have been synthesized and evaluated for their in vitro antimalarial activity. Some of the compounds showed promising antimalarial activity against both CQ-sensitive and CQ-resistant strains at micromolar level with a high selectivity index. All the compounds displayed better activity (IC50 = 1.32-10.70 μM) than the standard drug pyrimethamine (>19 μM) against the chloroquine-resistant strain W2. All the tested compounds were nontoxic against mammalian cell lines. Further, docking studies of the most active compounds were performed on both wild type and quadruple mutant (N51I, C59R, S108N, I164L) PfDHFR-TS using Glide to analyse the interaction of the compounds with the binding site of the protein. The binding poses of compounds 14 and 19, having a high Glide XP score and the lowest Glide energies, show an efficient binding pattern similar to that of the DHFR substrate (dihydrofolate) in the wild type and mutant DHFR active site. The analysis of the pharmacokinetic properties of the most active compounds using ADMET prediction attests to the possibility of developing compound 14 as a potent antimalarial lead. This journal is
- Kumar, Deepak,Khan, Shabana I.,Ponnan, Prija,Rawat, Diwan S.
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supporting information
p. 5087 - 5095
(2015/02/19)
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- Antibacterial Compounds
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The present invention provides a compound of the following formula, salts, racemates, diastereomers, enantiomers, esters, carbamates, phosphates, sulfates, deuterated forms and prodrugs thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
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Paragraph 0500; 0501
(2013/10/07)
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- An automated continuous-flow platform for the estimation of multistep reaction kinetics
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Automated continuous flow systems coupled with online analysis and feedback have been previously demonstrated to model and optimize chemical syntheses with little a priori reaction information. However, these methods have yet to address the challenge of modeling and optimizing for product yield or selectivity in a multistep reaction network, where low selectivity toward desired product formation can be encountered. Here we demonstrate an automated system capable of rapidly estimating accurate kinetic parameters for a given reaction network using maximum likelihood estimation and a D-optimal design of experiments. The network studied is the series-parallel nucleophilic aromatic substitution of morpholine onto 2,4-dichloropyrimidine. To improve the precision of the estimated parameters, we demonstrate the use of the automated platform first in optimization of the yield of the less kinetically favorable 2-substituted product. Then, upon isolation of the intermediates, we use the automated system with maximum a posteriori estimation to minimize uncertainties in the network parameters. From considering the steps of the reaction network in isolation, the kinetic parameter uncertainties are reduced by 50%, with less than 5 g of the dichloropyrimidine substrate consumed over all experiments. We conclude that isolating pathways in the multistep reaction network is important to minimizing uncertainty for low sensitivity rate parameters.
- Reizman, Brandon J.,Jensen, Klavs F.
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p. 1770 - 1782
(2013/01/15)
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- Compounds
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Compounds of formula I: [in-line-formulae]A-B-C??(I)[/in-line-formulae] and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: B is selected from the group consisting of: ?where RN is H or Me; or B is a divalent C5 heterocyclic residue containing one or two ring heteroatoms; A is: RA3 and RA5 are independently selected from halo, ORO and RAC, where RO is H or Me, and RAC is H or C1-4 alkyl; XA is selected from N and CRA4, where RA4 is selected from H, ORO, CH2OH, CO2H, NHSO2Me and NHCOMe; RA2 and RA6 are independently selected from H, halo and ORO; or RA3 and RA4 together with the carbon atoms to which they are attached, or RA2 and RA3 together with the carbon atoms to which they are attached, may form a C5-6 heterocylic or heteroaromatic ring, containing at least one nitrogen ring atom; where if X is not N, 1, 2, or 3 of RA2 to RA6 are not H; C is: ?where X is selected from N and CH, Y is selected from N and CH, and Z is selected from N and CRC6; RC3 is selected from H, halo and an optionally substituted N-containing C5-7 heterocyclic group; RC5 is a group selected from: ?which group may be selected by one or two C1-4 alkyl groups or a carboxy group; RC6 is H; or, when X and Y are N, RC5 and RC6 (when Z is CRC6) together with the carbon atoms to which they are attached may form a fused C6 aromatic ring selected from the group consisting of:
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Page/Page column 27
(2008/06/13)
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- Synthesis and in vitro study of platelet antiaggregant activity of 2(4)-imidazol-1-yl-4(2)-cycloalkylamino pyrimidines
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The synthesis of some 2(4)-imidazol-1-yl-4(2)-cycloalkylaminopyrimidines are reported. The compounds demonstrated a marked antiaggregating activity superior to dipyridamole, ASA, ticlopidine and similar to that of indobufen.
- Del Corona,Signorelli,Manzardo,Pinzetta,Coppi
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p. 729 - 733
(2007/10/02)
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