The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform
Pär Nordlund - One of the best experts on this subject based on the ideXlab platform.
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pan pathway based interaction profiling of fda approved nucleoside and nucleobase Analogs with enzymes of the human nucleotide metabolism
PLOS ONE, 2012Co-Authors: Louise Egeblad, Liya Wang, Jan Balzarini, Staffan Eriksson, Pär Nordlund, M Welin, S Flodin, S GraslundAbstract:To identify interactions a nucleoside Analog Library (NAL) consisting of 45 FDA-approved nucleoside Analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of “off target effects.” However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA) and uridine phosphorylase 1 (UPP1). An acyclic guanosine prodrug Analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔTagg around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside Analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside Analogs, which could also serve as a starting point for future drug design.
Robert C. Reynolds - One of the best experts on this subject based on the ideXlab platform.
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Parallel Solution Phase Synthesis and Preliminary Biological Activity of a 5'-Substituted Cytidine Analog Library.
ACS combinatorial science, 2019Co-Authors: Omar Moukha-chafiq, Robert C. Reynolds, Jacob C. Wilson, Timothy S. SnowdenAbstract:A 109-membered Library of 5′-substituted cytidine Analogs was synthesized, via funding through the NIH Roadmap Initiative and the Pilot Scale Library (PSL) Program. Reaction core compounds contained −NH2 (2) and −COOH (44 and 93) groups that were coupled to a diversity of reactants in a parallel, solution phase format to produce the target Library. The assorted reactants included −NH2, −CHO, −SO2Cl, and −COOH functional groups, and condensation with the intermediate core materials 2 and 44 followed by acidic hydrolysis produced 3–91 in good yields and high purity. Linkage of the amino terminus of d-phenylalanine methyl ester to the free 5′-COOH of 44 and NaOH treatment led to core Library −COOH precursor 93. In a libraries from libraries approach, compound 93 served as the vital building block for our unique Library of dipeptidyl cytidine Analogs 94–114 through amide coupling of the −COOH group with numerous commercial amines followed by acidic deprotection. Initial screening of the complete final Library...
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Parallel Solution-Phase Synthesis and General Biological Activity of a Uridine Antibiotic Analog Library
2015Co-Authors: Omar Moukha-chafiq, Robert C. ReynoldsAbstract:A small Library of ninety four uridine antibiotic Analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3–32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34–75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid Analog 77. Hydrolysis of this material gave Analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine Analogs 79–99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program
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Parallel solution-phase synthesis and general biological activity of a uridine antibiotic Analog Library.
ACS combinatorial science, 2014Co-Authors: Omar Moukha-chafiq, Robert C. ReynoldsAbstract:A small Library of ninety four uridine antibiotic Analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3–32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34–75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid Analog 77. Hydrolysis of this material gave Analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine Analogs 79–99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of pro...
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Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library
ACS combinatorial science, 2013Co-Authors: Omar Moukha-chafiq, Robert C. ReynoldsAbstract:A Library of eighty one adenosine antibiotic Analogs was prepared under the Pilot Scale Library Program of the NIH Roadmap initiative from 5′-amino-5′-deoxy-2′,3′-O-isopropylidene-adenosine 3. Diverse aldehyde, sulfonyl chloride and carboxylic acid reactant sets were condensed to 3, in solution-phase fashion, leading after acid-mediated hydrolysis to the targeted compounds in good yields and high purity. No marked antituberculosis or anticancer activity was noted on preliminary cellular testing, but these nucleoside Analogs should be useful candidates for other types of biological activity.
Zhijian Zhao - One of the best experts on this subject based on the ideXlab platform.
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Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M1 positive allosteric modulators
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Feng V. Yang, Zhijian Zhao, William D. Shipe, Jaime Lynn Bunda, M. Brad Nolt, David D. Wisnoski, James C. Barrow, William J. Ray, Marion WittmannAbstract:An iterative Analog Library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M1 positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.
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Challenges in the development of mGluR5 positive allosteric modulators: The discovery of CPPHA
Bioorganic & medicinal chemistry letters, 2006Co-Authors: Zhijian Zhao, Julie A. O'brien, Wei Lemaire, David L. Williams, Marlene A. Jacobson, David D. Wisnoski, Marion Wittman, Hervé Schaffhauser, Cyrille SurAbstract:This Letter describes, for the first time, the synthesis and SAR, developed through an iterative Analog Library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.
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Synthesis and SAR of GlyT1 inhibitors derived from a series of N-((4-(morpholine-4-carbonyl)-1-(propylsulfonyl)piperidin-4-yl)methyl)benzamides.
Bioorganic & medicinal chemistry letters, 2006Co-Authors: Zhijian Zhao, Julie A. O'brien, Wei Lemaire, David L. Williams, Marlene A. Jacobson, Cyrille Sur, Doug J. Pettibone, Philip R. Tiller, Sheri Smith, George D. HartmanAbstract:This Letter describes the synthesis and SAR, developed through an iterative Analog Library approach, of potent and selective non-sarcosine-derived GlyT1 inhibitors.
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allosteric akt pkb inhibitors discovery and sar of isozyme selective inhibitors
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Craig W Lindsley, Zhijian Zhao, George D. Hartman, William H Leister, Ronald G Robinson, Stanley F Barnett, Deborah Defeojones, Raymond E Jones, Joel R Huff, Hans E HuberAbstract:This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative Analog Library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.
Omar Moukha-chafiq - One of the best experts on this subject based on the ideXlab platform.
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Parallel Solution Phase Synthesis and Preliminary Biological Activity of a 5'-Substituted Cytidine Analog Library.
ACS combinatorial science, 2019Co-Authors: Omar Moukha-chafiq, Robert C. Reynolds, Jacob C. Wilson, Timothy S. SnowdenAbstract:A 109-membered Library of 5′-substituted cytidine Analogs was synthesized, via funding through the NIH Roadmap Initiative and the Pilot Scale Library (PSL) Program. Reaction core compounds contained −NH2 (2) and −COOH (44 and 93) groups that were coupled to a diversity of reactants in a parallel, solution phase format to produce the target Library. The assorted reactants included −NH2, −CHO, −SO2Cl, and −COOH functional groups, and condensation with the intermediate core materials 2 and 44 followed by acidic hydrolysis produced 3–91 in good yields and high purity. Linkage of the amino terminus of d-phenylalanine methyl ester to the free 5′-COOH of 44 and NaOH treatment led to core Library −COOH precursor 93. In a libraries from libraries approach, compound 93 served as the vital building block for our unique Library of dipeptidyl cytidine Analogs 94–114 through amide coupling of the −COOH group with numerous commercial amines followed by acidic deprotection. Initial screening of the complete final Library...
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Parallel Solution-Phase Synthesis and General Biological Activity of a Uridine Antibiotic Analog Library
2015Co-Authors: Omar Moukha-chafiq, Robert C. ReynoldsAbstract:A small Library of ninety four uridine antibiotic Analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3–32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34–75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid Analog 77. Hydrolysis of this material gave Analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine Analogs 79–99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program
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Parallel solution-phase synthesis and general biological activity of a uridine antibiotic Analog Library.
ACS combinatorial science, 2014Co-Authors: Omar Moukha-chafiq, Robert C. ReynoldsAbstract:A small Library of ninety four uridine antibiotic Analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3–32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34–75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid Analog 77. Hydrolysis of this material gave Analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine Analogs 79–99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of pro...
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Parallel Solution-Phase Synthesis of an Adenosine Antibiotic Analog Library
ACS combinatorial science, 2013Co-Authors: Omar Moukha-chafiq, Robert C. ReynoldsAbstract:A Library of eighty one adenosine antibiotic Analogs was prepared under the Pilot Scale Library Program of the NIH Roadmap initiative from 5′-amino-5′-deoxy-2′,3′-O-isopropylidene-adenosine 3. Diverse aldehyde, sulfonyl chloride and carboxylic acid reactant sets were condensed to 3, in solution-phase fashion, leading after acid-mediated hydrolysis to the targeted compounds in good yields and high purity. No marked antituberculosis or anticancer activity was noted on preliminary cellular testing, but these nucleoside Analogs should be useful candidates for other types of biological activity.
Craig W Lindsley - One of the best experts on this subject based on the ideXlab platform.
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Abstract B197: Understanding the mechanism of action of small molecules that restore E-cadherin expression.
Target Identification and Validation, 2011Co-Authors: Sydney L. Stoops, R. Daniel Beauchamp, Craig W LindsleyAbstract:E-cadherin is a transmembrane protein that maintains intercellular contacts and cellular polarity in epithelial tissues. The down-regulation of E-cadherin is thought to aid in the induction of an epithelial-to-mesenchymal transition (EMT) resulting in an increased potential for invasion into surrounding tissues and entry into the bloodstream. Loss of E-cadherin has been observed in a variety of human tumors resulting from somatic mutations, chromosomal deletions, proteolytic cleavage of E-cadherin, and most commonly silencing of the CDH1 gene promoter. A novel High Throughput Screen was developed to identify small molecules that restored E-cadherin expression in the SW620 cell line followed by medicinal chemistry employing iterative Analog Library synthesis to better identify the structure-activity relationship (SAR). Preliminary optimization of the screening hit has shown it is possible to synthesize small molecules that have an improved ability to restore E-cadherin expression compared to the initial screening hits. This restoration of protein has been confirmed by visualization of E-cadherin at the membrane via immunofluorescent microscopy. Further biological analysis of profiled Analogs has shown a minimal effect on cell proliferation, but a decrease in cellular invasion. Recent endeavors have been taken to elucidate the mechanism of action of these small molecules to restore E-cadherin expression. Quantitative PCR analysis has shown that treatment with selected small molecules increases mRNA expression ∼50 fold after 16 hours suggesting the small molecules are altering transcription of the CDH1 gene. This was supported by experiments conducted using a plasmid construct containing a 1400bp fragment of the E-cadherin promoter and luciferase reporter. After transfection, the cells were treated with selected compounds, lysed, and luciferase activity was measured. It was shown that selected active small molecules had a significant increase in luciferase activity as compared to DMSO or a dead small molecule, which were used as controls. More specifically, this suggests that the small molecules are specifically effecting transcription within the 1400bp promoter region of the CDH1 gene. Future work will include truncating the promoter region within the plasmid to narrow down the portion of the promoter region targeted by these small molecules, in hopes that specific transcription binding sites will be present within the region. Elucidation of the mechanism of action will aid in identifying the novel molecular target. Such information would allow for further development of more efficacious and potent small molecules as well as further research to understand the importance of this interaction in the role of EMT and as a potential therapeutic target. In addition, combinatorial treatments with sub-therapeutic doses of standard of care chemotherapeutics in the clinic and our small molecules will be screened for synergistic effects in proliferation and apoptosis assays. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B197.
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Synthesis and SAR of N-(4-(4-alklylpiperazin-1-yl)phenyl)benzamides as muscarinic acetylcholine receptor subtype 1 (M1) anatgonists.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Nicole R. Miller, R. Nathan Daniels, P. Jeffrey Conn, David Lee, Craig W LindsleyAbstract:Abstract This Letter describes the synthesis and SAR, developed through an iterative Analog Library approach, of a novel series of selective M1 mAChR antagonists, based on an N-(4-(4-alkylpiperazin-1-yl)phenyl)benzamide scaffold for the potential treatment of Parkinson’s disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC50s in the 350 nM to >10 μM range with varying degrees of functional selectivity versus M2–M5.
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maos protocols for the general synthesis and lead optimization of 3 6 disubstituted 1 2 4 triazolo 4 3 b pyridazines
Tetrahedron Letters, 2009Co-Authors: Leslie N Aldrich, Evan P Lebois, Michelle L Lewis, Natalia T Nalywajko, Colleen M Niswender, David C Weaver, Jeffrey P Conn, Craig W LindsleyAbstract:General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative Analog Library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.
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Synthesis and SAR of Analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas--the effect of capping the distal basic piperidine nitrogen.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Nicole R. Miller, R. Nathan Daniels, Thomas M. Bridges, Ashley E. Brady, P. Jeffrey Conn, Craig W LindsleyAbstract:This letter describes the further synthesis and SAR, developed through an iterative Analog Library approach, of Analogs of the highly selective M1 allosteric agonist TBPB by deletion of the distal basic piperidine nitrogen by the formation of amides, sulfonamides and ureas. Despite the large change in basicity and topology, M1 selectivity was maintained.
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allosteric akt pkb inhibitors discovery and sar of isozyme selective inhibitors
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Craig W Lindsley, Zhijian Zhao, George D. Hartman, William H Leister, Ronald G Robinson, Stanley F Barnett, Deborah Defeojones, Raymond E Jones, Joel R Huff, Hans E HuberAbstract:This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative Analog Library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.