- Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor
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A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC50 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity. This journal is
- England, Katherine S.,Tumber, Anthony,Krojer, Tobias,Scozzafava, Giuseppe,Ng, Stanley S.,Daniel, Michelle,Szykowska, Aleksandra,Che, Kahing,Von Delft, Frank,Burgess-Brown, Nicola A.,Kawamura, Akane,Schofield, Christopher J.,Brennan, Paul E.
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Read Online
- Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds
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Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5–197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between ?9.375 and ?14.55 units, compared to ?9.137 for lapachol and ?12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.
- Brand?o, Geraldo Célio,Rocha Missias, Franciele C.,Pereira, Guilherme Rocha,Arantes, Lucas Miquéias,Soares, Luciana Ferreira,Braga de Oliveira, Alaide,Roy, Kuldeep K.,Doerksen, Robert J.
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- Novel histone deacetylase inhibitors bearing a 4-piperidin-4-yl-triazole scaffold as antitumor agents
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Histone deacetylases have proven to be promising targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of 20 novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core structure. Five newly obtained compounds displayed excellent HDAC6 inhibitory activities. Among them, compounds WY-12 and WY-15 also exhibited excellent antiproliferative activities against six human tumor cell lines. WY-15 could increase the level of acetylated histone H3 in a dose-dependent manner. Furthermore, WY-15 remarkably induced cell cycle arrest of Sy5y cancer cells in G0/G1 phase. Finally, the high potency of compound WY-15 toward HDAC6 was rationalized by molecular docking study.
- Wang, Yan,Su, Li,Wang, Qiang,Zhang, Li,Luan, Yepeng
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Read Online
- INDOLE DERIVATIVES AND USES THEREOF FOR TREATING A CANCER
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The present invention relates to indole derivatives of formula (I') as CK2 inhibitor and pharmaceutical compositions comprising the same. The present invention further relates to the use of such compounds of formula (I) for use for preventing and/or treating a cancer.
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Page/Page column 71; 85; 88; 113; 115
(2022/02/06)
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- Covalent Allosteric Inhibitors of Akt Generated Using a Click Fragment Approach
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Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties.
- Green, Ivan R.,Landel, Ina,Lindemann, Marius,Müller, Matthias P.,Pelly, Stephen C.,Quambusch, Lena,Rauh, Daniel,Taher, Abu,Uhlenbrock, Niklas,Weisner, J?rn,van Otterlo, Willem A. L.,van der Westhuizen, Leandi
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- TRICYCLIC DEGRADERS OF IKAROS AND AIOLOS
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Tricyclic cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic applications are described.
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Page/Page column 254-255; 480
(2020/10/21)
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- 1, 2, 4-OXADIAZOLE DERIVATIVES AND USES THEREOF
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The disclosure provides 1, 2, 4-oxadiazole derivatives useful for stemming bleeding and for treating cancer.
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Paragraph 0095
(2020/04/25)
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- 1, 3, 4-OXADIAZOLE DERIVATIVES AND USES THEREOF
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The disclosure provides 1, 3, 4-oxadiazole derivatives useful for stemming bleeding and for treating cancer.
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Paragraph 0083
(2020/04/25)
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- Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor
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As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-?-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
- Divakaran, Anand,Talluri, Siva K.,Ayoub, Alex M.,Mishra, Neeraj K.,Cui, Huarui,Widen, John C.,Berndt, Norbert,Zhu, Jin-Yi,Carlson, Angela S.,Topczewski, Joseph J.,Schonbrunn, Ernst K.,Harki, Daniel A.,Pomerantz, William C. K.
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p. 9316 - 9334
(2018/10/24)
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- JANUS KINASES INHIBITORS, COMPOSITIONS THEREOF AND USE THEREOF
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Compounds of Formula (00A) and salts thereof, wherein R1, R2 R3, R4 and n are defined herein, are useful as inhibitors of one or more Janus kinases. Also provided are pharmaceutical compositions that include a compound of Formula (00A) and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient. ( 00A)
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Page/Page column 107
(2017/07/04)
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- Synthesis of diaziridines and diazirines via resin-bound sulfonyl oximes
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Diazirines are one of the most prominent functionalities in labeling experiments in vivo and in vitro because they allow photochemical generation of carbenes. The strategy presented herein describes the formation of diaziridines, being essential precursors in diazirine syntheses, using solid-supported procedures with immobilized sulfonyl oximes. The solid-supported building blocks have been shown to be valuable intermediates for CuAAC and amidation reactions, offering the possibility to build complex compounds with diverse functionalities.
- Protasova, Irina,Bulat, Bekir,Jung, Nicole,Br?se, Stefan
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supporting information
p. 34 - 37
(2017/11/28)
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- FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
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The disclosure provides novel chemical compounds represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. The compounds can be used as an inhibitor of Trk and are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases. In some compounds of Formula I, Q is —CH═CR3C(O)NR4R5, —C≡CC(O)NR4R5, or
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- KINASE INHIBITORS AND THEIR USE IN CANCER THERAPY
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The present invention relates to a 2,3-diphenyl-1,6-naphthyridine-5-one derivative according to general formula (I), and the use of the 2,3-diphenyl-1,6-naphthyridine-5-one derivative in the diagnosis or treatment of cancer.
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Page/Page column 23-24
(2016/11/21)
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- 5-CHLORO-2-DIFLUOROMETHOXYPHENYL PYRAZOLOPYRIMIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF
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Compounds of Formula (00A) and methods of use as Janus kinase inhibitors are described herein.
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Paragraph 0999
(2015/12/05)
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- Covalent-Allosteric Kinase Inhibitors
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Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-depende
- Weisner, J?rn,Gontla, Rajesh,Van der westhuizen, Leandi,Oeck, Sebastian,Ketzer, Julia,Janning, Petra,Richters, Andr,Mühlenberg, Thomas,Fang, Zhizhou,Taher, Abu,Jendrossek, Verena,Pelly, Stephen C.,Bauer, Sebastian,Van otterlo, Willem A. L.,Rauh, Daniel
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supporting information
p. 10313 - 10316
(2015/09/01)
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- Aminoheteroaryl compounds and preparation method and use thereof
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The present invention refers to aminoheteroaryl compounds of the following formula (I) as well as the preparation method and use thereof, wherein R1 and R3 are defined in the Description in details. The aminoheteroaryl compounds of t
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Paragraph 0110; 0111
(2014/12/09)
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- AMINO HETEROARYL COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF
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The present invention refers to aminoheteroaryl compounds of the following formula (I) as well as the preparation method and use thereof, wherein R1 and R3 are defined in the Description in details. The aminoheteroaryl compounds of t
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Paragraph 0082; 0083
(2014/12/09)
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- A novel amalgamation of 1,2,3-triazoles, piperidines and thieno pyridine rings and evaluation of their antifungal activity
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It is the first report of the novel amalgamation of 1,2,3-triazoles, piperidines, thieno pyridine rings and evaluation of their antifungal activity. The synthesized compounds showed interesting moderate to good antifungal activity, wherein they were able to discriminate between the two species Aspergillus flavus and Aspergillus niger of the same genus. In addition, the main highlight of this series is the sensitivity of the fungal strain Cryptococcus neoformans to the compounds having p-chlorobenzoyl (9h), methane sulfonyl (9i) and p-methylbenzene sulfonyl (9j) attached to the piperazine nitrogen.
- Darandale, Sunil N.,Mulla, Nayeem A.,Pansare, Dattatraya N.,Sangshetti, Jaiprakash N.,Shinde, Devanand B.
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p. 527 - 532
(2013/10/01)
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- Microwave assisted one pot synthesis of some novel 2,5-disubstituted 1,3,4-oxadiazoles as antifungal agents
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Sodium bisulfite has been reported first time for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole using microwave and conventional method in ethanol-water. The yields obtained are in the range of 90-95% using microwave and 87-91% using conventional method. All the synthesized compounds (8a-8s) are novel and were evaluated for their in vitro antifungal activity. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Some of the compounds from the series like 8k was equipotent with miconazole against Candida albicans and Fusarium oxysporum. Also compound 8n was equipotent with miconazole against F. oxysporum.
- Sangshetti, Jaiprakash N.,Chabukswar, Aniruddha R.,Shinde, Devanand B.
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p. 444 - 448
(2011/02/25)
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- Synthesis of some novel 3-(1-(1-substitutedpiperidin-4-yl)-1H-1,2,3- triazol-4-yl)-5-substituted phenyl-1,2,4-oxadiazoles as antifungal agents
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A novel series of 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4- yl)-5-substituted phenyl-1,2,4-oxadiazoles bearing 1,2,3-triazole and piperidine ring has been synthesized in one step from amidoxime using Carbonyl diimidazole (CDI) and K2CO3. All the synthesized compounds (4a-4r) are novel and evaluated for their in vitro antifungal activities. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Some of the compounds from the series like 4j was equipotent with miconazole against Cryptococcus neoformans whereas activities of compound 4m against Aspergillus niger and Aspergillus flavus were comparable to miconazole. Also compound 4r shows activity comparable to miconazole against Candida albicans, A. niger and A. flavus.
- Sangshetti, Jaiprakash N.,Shinde, Devanand B.
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p. 1040 - 1044
(2011/04/17)
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- 4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents
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A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the cor
- Huang, Xiaoguang,Zhang, Aiqin,Chen, Dongliang,Jia, Zhenhua,Li, Xingshu
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scheme or table
p. 2859 - 2863
(2010/08/19)
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- Synthesis and SAR of some new 4 substituted 3H-1,2,3,5-oxathiadiazole 2-oxides as antifungal agents
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A new series of 4-substituted 3H-1,2,3,5-oxathiadiazole 2-oxides bearing 1,2,3 triazole and piperidine ring has been synthesized in one step from amidoxime using thionyl chloride (SOCl2) and Triethylamine (TEA). All the synthesized compounds (10a-10l) are new and evaluated for their in vitro antifungal activities using standard agar plate method. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Compound 10j from the series was equipotent with miconazole against C. albicans and F. oxysporum whereas activity of compound 10i was comparable to miconazole against F. oxysporum and C. neoformans (MIC-30 μg/mL).
- Sangshetti, Jaiprakash N.,Shinde, Devanand B.
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scheme or table
p. 171 - 175
(2011/02/23)
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- Synthesis of novel 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-5(4H)-one as antifungal agents
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A novel series of 1,2,3 triazole compounds possessing 1,2,4 oxadiazole ring were efficiently synthesized. Synthesized compounds were evaluated for their in vitro antifungal activities using standard cup plate method. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Compound 11a from the series was more potent than miconazole against Candida albicans (MIC-20) and Aspergillus flavus (MIC-10) whereas equipotent with miconazole against Fusarium oxysporum (MIC-25) and Aspergillus niger (MIC-12.5). Also compound 11h was more potent than miconazole against Candida albicans (MIC-20) and Aspergillus niger (MIC-10) and equipotent with miconazole against Fusarium oxysporum. Compound 11h was equipotent with fluconazole against Aspergillus niger (MIC-10).
- Sangshetti, Jaiprakash N.,Nagawade, Rahul R.,Shinde, Devanand B.
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supporting information; experimental part
p. 3564 - 3567
(2010/03/31)
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- N-LINKED HETEROCYCLIC RECEPTOR AGONISTS FOR THE TREATMENT OF DIABETES AND METABOLIC DISORDERS
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Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control.
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(2009/03/07)
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- Divergent synthesis of three classes of aryl N-glycosides by solvent control
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Aryl glycosides represent a group of molecules with immense biological applications and implications. While the syntheses of aryl C-glycosides and O-glycosides have been studied extensively, the preparation for aryl N-glycosides is relatively unexplored. By employing 1,4-naphthoquinone and glycosyl azides undergoing a [3 + 2] cycloaddition, we have developed a convenient method for constructing three different classes of aryl N-glycosides that include N-glycosylated 2-aminomethylene-1,3-indanedione, benzazepine-1,5-dione, and 9,10-anthraquinone derivatives via solvent control. It was found that conducting cycloaddition in DMF formed exclusively 9,10-anthraquinone derivatives, while less polar solvent such as toluene offered all three aryl N-glycosides. The synthesis of N-glycosylated 9,10-anthraquinone derivatives is of particular interest since no known example has been documented. The synthesis of these N-glycosylated heterocyclic compounds using traditional glycosylation methods could be challenging. Therefore, our diversity-oriented protocols can be viewed as an alternative and practical glycosylation approach. In addition, we have also demonstrated that alkyl azides can also undergo the same cycloaddition, further expanding the structural repertoire available for a broader interest. Initial anticancer assays have revealed that 19f and 19k exert mean growth percent of 17.58 and-5.95, respectively.
- Zhang, Jianjun,Chang, Cheng-Wei Tom
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supporting information; experimental part
p. 685 - 695
(2009/06/28)
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- Synthesis and in vitro antibacterial activity of novel methylamino piperidinyl oxazolidinones
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Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N-{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperid in-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2-4 μg/mL against linezolid resistant Staphylococcus aureus (linezolid ≥16 μg/mL).
- Srivastava, Brijesh Kumar,Soni, Rina,Patel, Jayendra Z.,Solanki, Manish,Valani, Darshan,Gupta, Sunil,Mishra, Bhupendra,Takale, Vijay,Pandya, Purvi,Jain, Mukul R.,Patel, Pankaj R.
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p. 5227 - 5232
(2008/03/13)
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- Nicotinoyl azide (NCA)-mediated Mitsunobu reaction: An expedient one-pot transformation of alcohols into azides
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A practical and simple method that allows preparation of azides from alcohols is described. The process involves oxyphosphonium-type activation and it is based upon the use of nicotinoyl azide (NCA), a cheap and easily accessible azide ion source.
- Papeo, Gianluca,Posteri, Helena,Vianello, Paola,Varasi, Mario
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p. 2886 - 2892
(2007/10/03)
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- Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: Synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N- (benzyloxycarbonyl)amino)piperidin-1-yl)butanes
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(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro (2,3-dihydrobenzthiophene-3,4′-piperidin-1′-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50 = 10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
- Finke, Paul E.,Oates, Bryan,Mills, Sander G.,MacCoss, Malcolm,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael,Schleif, William A.,Emini, Emilio A.
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p. 2475 - 2479
(2007/10/03)
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- CYCLIC AMINE MODULATIONS OF CHEMOKINE RECEPTOR ACTIVITY
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The present invention is directed to cyclic amines of the formula I: STR1 (wherein R 1, R 2, R 3, m and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
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- Cyclic amine modulators of chemokine receptor activity
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The present invention is directed to cyclic amines of the formula I: (wherein R1, R2, R3, m and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
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- 4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors
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The syntheses of a number of different N-linked heterocyclic pyrazole replacements based on the structure 1 are described (compounds 3-12) as hD4 ligands. After further optimisation the best compound identified was 13 which has high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over hD2 and hD3 receptors.
- Moore, Kevin W.,Bonner, Katrine,Jones, Elizabeth A.,Emms, Frances,Leeson, Paul D.,Marwood, Rosemary,Patel, Shil,Patel, Smita,Rowley, Michael,Thomas, Steven,Carling, Robert W.
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p. 1285 - 1290
(2007/10/03)
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