Browsing by Subject "Distributed Drug Discovery (D3)"

Now showing 1 - 4 of 4
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    Solid-Phase Synthesis of Arylpiperazine Derivatives and Implementation of the Distributed Drug Discovery (D3) Project in the Search for CNS Agents
    (MDPI, 2011-05) Zajdel, Pawel; Król, Joanna; Grychowska, Katarzyna; Pawłowski, Maciej; Subra, Gilles; Nomezine, Gaël; Martinez, Jean; Satala, Grzegorz; Bojarski, Andrzej J.; Zhou, Ziniu; O'Donnell, Martin J.; Scott, William; Chemistry and Chemical Biology, School of Science
    We have successfully implemented the concept of Distributed Drug Discovery (D3) in the search for CNS agents. Herein, we demonstrate, for the first time, student engagement from different sites around the globe in the development of new biologically active compounds. As an outcome we have synthesized a 24-membered library of arylpiperazine derivatives targeted to 5-HT1A and 5-HT2A receptors. The synthesis was simultaneously performed on BAL-MBHA-PS resin in Poland and the United States, and on BAL-PS-SynPhase Lanterns in France. The D3 project strategy opens the possibility of obtaining potent 5-HT1A/5-HT2A agents in a distributed fashion. While the biological testing is still centralized, this combination of distributed synthesis with screening will enable a D3 network of students world-wide to participate, as part of their education, in the synthesis and testing of this class of biologically active compounds.
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    Solid-phase synthetic route to multiple derivatives of a fundamental peptide unit
    (MDPI, 2010-07-20) Scott, William L.; Zhou, Ziniu; Zajdel, Pawel; Pawlowski, Maciej; O'Donnell, Martin J.; Chemistry and Chemical Biology, School of Science
    Amino acids are Nature's combinatorial building blocks. When substituted on both the amino and carboxyl sides they become the basic scaffold present in all peptides and proteins. We report a solid-phase synthetic route to large combinatorial variations of this fundamental scaffold, extending the variety of substituted biomimetic molecules available to successfully implement the Distributed Drug Discovery (D3) project. In a single solid-phase sequence, compatible with basic amine substituents, three-point variation is performed at the amino acid a-carbon and the amino and carboxyl functionalities.
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    Successful Integration of Distributed Drug Discovery (D3) Components: Computational, Synthetic, and Biological Evaluation of Phenylalanine Derivatives as Potential Biofilm Inhibitors
    (Office of the Vice Chancellor for Research, 2013-04-05) Abraham, Milata M.; LaCombe, Jonathan M.; Carnahan, Jon M.; O'Donnell, Martin J. O.; Scott, William L.; Denton, Ryan E.; Samaritoni, J. Geno; Harper, Richard; Anderson, Gregory G.; Marrs, Kathleen A.; Coffey, Barbara M.
    Distributed Drug Discovery (D3) is a multidisciplinary approach to identifying molecules that exhibit activity in the treatment of neglected diseases such as malaria, leishmaniasis, and tuberculosis as well as recalcitrant cystic fibrosis (CF) airway infections. D3 seeks to accomplish this task by combining computational chemistry, synthetic chemistry, and biological screening all within an educational framework. Recent reports suggest that D-amino acids are effective in the disassembly and inhibition of bacterial biofilms, which are important for a number of bacterial infections, including those in the CF lung. Utilizing chemical drawing software, we constructed (enumerated) target phenylalanine derivatives from commercially available benzyl halides by substitution at the α position of an amino acid scaffold. A subset of these enumerated molecules was computationally selected for synthesis based on chemical properties. These compounds were synthesized using simple, solid-phase techniques in an undergraduate organic chemistry laboratory class. The resulting racemic unnatural amino acid derivatives were then screened for activity in a biofilm assay. The results show biofilm inhibition with synthesized phenylalanine derivatives. Analysis of the results reveals a trend between lipophilicity and the degree of biofilm inhibition. These new molecules may lead to an avenue for therapy for those CF individuals suffering with bacterial lung infection. As a part of the undergraduate curriculum, this work provides the first example of D3-linked undergraduate student computational analysis, synthesis, and biological evaluation.
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    The Synthesis and Biological Activity of N-Acylated Amino Acids. A Collaborative Effort of Distributed Drug Discovery (D3)
    (Office of the Vice Chancellor for Research, 2016-04-08) Scott, William L.; Popiołek, Łukasz; Biernasiuk, Anna; Hitchens, Jake R.; Samaritoni, J. Geno; O’Donnell, Martin J.
    As part of a Distributed Drug Discovery collaborative effort between students at IUPUI and Medical University of Lublin (Poland), the solid-phase combinatorial synthesis of a series of natural, acylated tyrosine (1) and phenylalanine (2) analogs was carried out in replicated fashion. The crude samples were purified and characterized by LC/MS, proton NMR, and in cases involving novel structures, by proton and carbon-13 NMR and high-resolution mass spectrometry. The samples were characterized in biological assays at the Medical University of Lublin against the Gram-positive bacteria Staphylococcus aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228, Bacillus cereus ATCC 10876, Bacillus subtilis ATCC 10876, and Micrococcus luteus ATCC 10240. Although activity of the 2-nitro and 3-nitro derivatives of phenylalanine was not reproduced by the IUPUI samples, the 5-chlorosalicylic acid derivative 1g demonstrated good activity against M. luteus (MIC = 62.5 g/mL) and moderate activity against S. aureus, S. epidermidis, and B. cereus. O Cl OH HN OH OH O O Ar HN X OH O 1 X = OH 2 X = H 1g