- Fsp3-rich and diverse fragments inspired by natural products as a collection to enhance fragment-based drug discovery
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Herein, we describe the natural product inspired synthesis of 38 complex small molecules based upon 20 unique frameworks suitable for fragment-based screening. Utilising an efficient strategy, two key building block diastereomers were harnessed to generate novel, three-dimensional fragments which each possess numerous synthetically accessible fragment growth positions.
- Hanby, Abigail R.,Kidd, Sarah L.,Mortensen, Kim T.,Osberger, Thomas J.,Spring, David R.,Troelsen, Nikolaj S.
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supporting information
p. 2280 - 2283
(2020/03/04)
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- THE USE OF N-(4-IODOBENZOYLAMINO)-5-ETHYL-1,2,3,6-TETRAHYDROPYRIDINE AS A TREATMENT FOR CANCER
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Disclosed herein is the use of N-(4-iodobenzoylamino)-5-ethyl-1,2,3,6-tetra-hydropyridine as a treatment for cancer.
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Paragraph 0023
(2020/04/24)
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- SUBSTITUTED TETRAHYDROISOQUINOLINE ETHYLBENZAMIDE ANTI-CANCER AGENTS
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The compounds herein disclosed are N-substituted tetrahydroisoquinoline ethylbenzamide compounds that have modifications on the phenyl rings by introducing groups with various electronic properties. These derivatives of N-substituted tetrahydroisoquinoline ethylbenzamide compounds have been shown to have anti-proliferative activity against cells. In particular, the compounds have been found to be effective in inhibiting the proliferation of cancer cells, such as cancer cells that originated in breast tissue. Additionally, it has been shown that the novel compounds have IC50 values against the breast cancer cells that are 6- to 10-fold less than the IC50 of Tamoxifen.
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Paragraph 031
(2019/04/18)
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- Novel catenated N6 energetic compounds based on substituted 1,2,4-triazoles: Synthesis, structures and properties
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1-Amino-3,5-dinitro-1,2,4-triazole (ADNT) was prepared using an efficient N-amination process. Three novel catenated N6 energetic derivatives of ADNT, which contain 1,1′-azobis(3,5-dinitro-1,2,4-triazole) (ABDNT), 1,1′-azobis(3-chloro-5-nitro-1,2,4-triazole) (ABCNT) and 1,1′-azobis(3,5-diazido-1,2,4-triazole) (ABDAT), were synthesized from N-amino oxidative-coupling reactions of ADNT. All compounds were fully characterized by 1H and 13C nuclear magnetic resonance spectroscopies, infrared spectroscopy, elemental analysis, mass spectrum, as well as differential scanning calorimetry (DSC). The crystal structure of compound ABCNT was confirmed by single-crystal X-ray diffraction showing an extensive conjugated structure. The densities of energetic derivatives ranged from 1.71 to 1.93 g cm-3, and all compounds have positive heats of formation in the range of 774.8 to 2150.8 kJ mol-1. Based on the measured densities and calculated heats of formation, theoretical performance calculations, including detonation pressures (29.6-42.4 GPa) and detonation velocities (8.22-9.49 km s-1) were carried out using the Gaussian 09 program and Kamlet-Jacobs equations, and they compared favorably with those of TNT and RDX. These properties make them potentially competitive as new high energy-density compounds.
- Li, Yanan,Wang, Bin,Chang, Pei,Hu, Jianjian,Chen, Tao,Wang, Yinglei,Wang, Bozhou
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p. 13755 - 13763
(2018/04/25)
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- Ammonia-free synthesis of 3-trifluoromethyl-3-phenyldiaziridine
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An ammonia-free synthesis of 3-trifluoromethyl-3-phenyldiaziridine, an important intermediate in the synthesis of a widely used photolabel 3-trifluoromethyl-3-phenyldiazirine, is described. By avoiding the use of volatile, corrosive, and toxic anhydrous ammonia, the major hazard involved in the synthesis of this widely used photolabel is eliminated. Furthermore, this synthesis is convenient compared to the conventional route, since it is significantly less time consuming and, due to the absence of liquid ammonia, this method does not require the maintenance of low temperature for prolonged periods.
- Kumar, Arun Babu,Manetsch, Roman
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supporting information
p. 626 - 631
(2018/02/26)
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- O - substituted hydroxylamine hydrochloride and its preparation method (by machine translation)
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The present invention provides a O - substituted hydroxylamine hydrochloride and its preparation, wherein the preparation method comprises the following steps: step S1, to the acetyl hydroximic acid ethyl ester in ethanol solution of adding sodium hydroxide, in addition at the same time instillment halohydrocarbon, chloride or acyl chloride substitution reaction to take place, then added to the water in order to separate out the O - substituted [...]; step S2, the said O - substituted [...] adding hydrochloric acid solution in order to produce reflux reaction O - substituted hydroxylamine hydrochloride. According to the embodiment of the invention of the O - substituted hydroxylamine hydrochloride of the preparation method, high purity of the product can be obtained, and the method is safe, easy to process, the process is simple, and is suitable for industrial production. (by machine translation)
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Paragraph 0100-0102
(2018/10/11)
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- Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus
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As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
- Hamdouchi, Chafiq,Maiti, Pranab,Warshawsky, Alan M.,Debaillie, Amy C.,Otto, Keith A.,Wilbur, Kelly L.,Kahl, Steven D.,Patel Lewis, Anjana,Cardona, Guemalli R.,Zink, Richard W.,Chen, Keyue,Cr, Siddaramaiah,Lineswala, Jayana P.,Neathery, Grace L.,Bouaichi, Cecilia,Diseroad, Benjamin A.,Campbell, Alison N.,Sweetana, Stephanie A.,Adams, Lisa A.,Cabrera, Over,Ma, Xiaosu,Yumibe, Nathan P.,Montrose-Rafizadeh, Chahrzad,Chen, Yanyun,Miller, Anne Reifel
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p. 934 - 945
(2018/02/17)
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- Oxidative activation of C-S bonds with an electropositive nitrogen promoter enables orthogonal glycosylation of alkyl over phenyl thioglycosides
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A method for the selective activation of thioglycosides that uses the N+-thiophilic reagent Omesitylenesulfonylhydroxylamine (MSH) as a promoter is presented. The reaction proceeds via anomeric mesitylensulfonate intermediates, which could be isolated and fully characterized by placing a fluorine atom at the C2 position. In the presence of a soft Lewis acid, glycosylation reaction proceeds at ambient temperature with good yields. It is further demonstrated that it is possible to orthogonally activate S-ethyl in the presence of S-phenyl donors, enabling the design of sequential glycosylation strategies.
- Kitowski, Annabel,Jiménez-Moreno, Ester,Salvadó, Míriam,Mestre, Jordi,Castillón, Sergio,Jiménez-Osés, Gonzalo,Boutureira, Omar,Bernardes, Gon?alo J.L.
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supporting information
p. 5490 - 5493
(2017/11/07)
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- Synthesis and biological evaluation of substituted N-[3-(1H-pyrrol-1-yl) methyl]-1,2,5,6-tetrahydropyridin-1-yl]benzamide/benzene Sulfonamides as anti-inflammatory agents
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The pharmacological activities of tetrahydropyridine (THP) derivatives are dependent on the substituent ring moiety. In this study, we investigate the anti-inflammatory activities of 12 newly synthesized substituted N-[3-(1H-pyrrol-1-yl)methyl]-1,2,5,6-tetrahydrobenzamide/benzene sulfonamides (9a-l) in murine BV-2 microglial cells. All compounds were initially screened for attenuation of nitric oxide (NO) production in lipopolysaccharide (LPS) (1 μg/mL)-activated microglial cells. The data show that only SO 2-substituted THPs were effective at sub-lethal concentrations (IC50 values of 12.92 μM (9i), 14.64 μM (9j), 19.63 μM (9k)) relative to L-N6-(1-iminoethyl)lysine positive control (IC50 = 3.1 μM). The most potent SO2-substituted compound (9i) also blocked the LPS-inducible nitric oxide synthase (iNOS) and attenuated the release of several cytokines including IL-1α, IL-10, and IL-6. These findings establish the moderate immuno-modulating effects of SO2-substituted THP derivatives.
- Gangapuram, Madhavi,Mazzio, Elizabeth,Eyunni, Suresh,Soliman, Karam F. A.,Redda, Kinfe K.
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p. 360 - 369
(2014/05/20)
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- OLEFIN METATHESIS REACTIONS OF AMINO ACIDS, PEPTIDES AND PROTEINS CONTAINING ALLYL SULFIDE GROUPS
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A method for the modification of an amino acid, protein or peptide is disclosed. The method comprises reacting a carbon-carbon double bond-containing compound with an amino acid, a protein or a peptide containing an allyl sulfide group in the presence of a catalyst which promotes olefin metathesis, to form a modified amino acid, protein or peptide. Preferred carbon-carbon double bond-containing compounds include carbohydrates.
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Page/Page column 8
(2012/07/27)
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- COMPOUNDS FOR THE TREATMENT OF HEPATITIS C
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The disclosure provides ten specific compounds with a basic structure of pyrazolo [1, 5-a] pyridine, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.
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Page/Page column 202
(2011/10/05)
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- A coordinated synthesis and conjugation strategy for the preparation of homogeneous glycoconjugate vaccine candidates
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A sweet solution: A strategy for the synthesis of well-defined carbohydrate-based vaccines is presented. The approach couples complex oligosaccharide synthesis to site-specific conjugation methodology to provide pure glycoprotein vaccine candidates (see scheme). Copyright
- Grayson, Elizabeth J.,Bernardes, Goncalo J. L.,Chalker, Justin M.,Boutureira, Omar,Koeppe, Julia R.,Davis, Benjamin G.
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supporting information; experimental part
p. 4127 - 4132
(2011/07/07)
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- COMPOUNDS FOR THE TREATMENT OF HEPATITIS C
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The disclosure provides compounds of formula I, II, III, IV, and V, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.
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Page/Page column 203
(2010/04/06)
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- Synthesis of substituted N-[4(5-Methyl/phenyl-1,3,4-oxadiazol-2- Yl)-3,6-dihydropyridin-1(2H)-yl]benzamide/benzene sulfonamides as anti-inflammatory and anti-cancer agents
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Fourteen novel substituted N-[4(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)-3,6- dihydropyridin-1(2H)-yl] benzamide/benzene sulfonamides (11a-n) were synthesized in fair to good yields via sodium borohy-dride reduction of the corresponding substituted N-(benzoylimino)-4-(5-methyl/5-phenyl-1,3,4-oxadia- zol-2yl) pyridinium ylide (10a-n) in absolute ethanol.
- Gangapuram, Madhavi,Redda, Kinfe K.
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scheme or table
p. 309 - 316
(2009/07/19)
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- HETEROBICYCLIC CARBOXAMIDES AS INHIBITORS FOR KINASES
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The invention relates to novel organic compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula (I) and to the use of a compound of formula (I) for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in particular tumour diseases.
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Page/Page column 68
(2008/06/13)
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- Allyl sulfides are privileged substrates in aqueous cross-metathesis: Application to site-selective protein modification
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Allyl sulfides undergo efficient cross-metathesis in aqueous media with Hoveyda-Grubbs second generation catalyst 1. The high reactivity of allyl sulfides in cross-metathesis was exploited in the first examples of cross-metathesis on a protein surface. S-Allylcysteine was incorporated chemically into the protein, providing the requisite allyl sulfide handle. Preliminary efforts to genetically incorporate S-allylcysteine into proteins are also reported. Copyright
- Lin, Yuya A.,Chalker, Justin M.,Floyd, Nicola,Bernardes, Goncalo J. L.,Davis, Benjamin G.
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supporting information; experimental part
p. 9642 - 9643
(2009/02/04)
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- Synthesis of N-benzoylamino-1,2,3,6-tetrahydropyridine derivatives as potential anti-inflammatory agents
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(Chemical Equation Presented) N-Benzoylamino-1,2,3,6-tetrahydropyridines 9a-q were synthesized from 4-substituted pyridines in four steps. Amination of pyridines was carried out to prepare intermediate N-aminopyridinium mesylates using mesytelenesulfonyl hydroxmate (MSH) as aminating agent. N-aminopyridinium mestylates reacted with appropriately substituted acyl chlorides to form N-ylides as stable crystalline solids. Partial reduction of N-ylides with mild reducing agent afforded N-benzoylamino-1,2,3,6-tetrahydropyridines in fair to good yields.
- Mochona, Bereket,Redda, Kinfe K.
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p. 1383 - 1387
(2008/09/18)
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- Synthesis and antifungal activity of 2-aryl-1,2,4-triazolo[1,5-a]pyridine derivatives
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A series of novel antifungal triazole derivatives 2-aryl-1,2,4-triazolo[1, 5-a]pyridine 9a-m were synthesized and tested in vitro for their growth inhibitory activities against C. albicans and T. rubrum. The MIC values indicate that the activities of three compounds were superior or comparable to fluconazole against both tested fungi, worthy of further investigation of its antifungal activities.
- Luo, Yun,Hu, Yongzhou
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p. 262 - 266
(2007/10/03)
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