Browsing by Author "O’Donnell, Martin J."

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    Aminolytic Cleavage from Wang Resin. A New Distributed Drug Discovery Laboratory for the Undergraduate Curriculum
    (Office of the Vice Chancellor for Research, 2016-04-08) Scott, William L.; Burris, Sarah D.; Hitchens, Jake R.; Samaritoni, J. Geno; O’Donnell, Martin J.
    When treated with ammonia or methylamine, unnatural amino acids bound to Wang resin (1) are released as their corresponding amides 2 in good yield and purity. When carried out at room temperature, aminolytic cleavage proceeds slowly with a four-day exposure to ammonia in methanol representing an optimal reaction time. Aminolytic cleavage proceeds well with unhindered primary amines, however, the hindered amine isopropylamine and benzylamines are unacceptably slow to effect cleavage. Use of the secondary amine pyrrolidine led to a complex mixture. Due to the large stoichiometric amine excess required, the scope is currently limited to unhindered, volatile, primary amines. The overall synthesis of 2 from BPI-Gly-Wang resin represents a new Distributed Drug Discovery Laboratory (D3-7) and was rolled out to the spring 2016 Organic II laboratory.
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    Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds
    (American Chemical Society, 2020-12-18) Fuller, Amelia A.; Dounay, Amy B.; Schirch, Douglas; Rivera, Daniel G.; Hansford, Karl A.; Elliott, Alysha G.; Zuegg, Johannes; Cooper, Matthew A.; Blaskovich, Mark A.T.; Hitchens, Jacob R.; Burris-Hiday, Sarah; Tenorio, Kristiana; Mendez, Yanira; Samaritoni, J. Geno; O’Donnell, Martin J.; Scott, William L.; Chemistry and Chemical Biology, School of Science
    New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.
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    Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations
    (MDPI, 2018-07-08) Samaritoni, J. Geno; Martynow, Jacek G.; O’Donnell, Martin J.; Scott, William L.; Chemistry and Chemical Biology, School of Science
    The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step.
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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, 2011-05-19) Zajdel, Paweł; Król, Joanna; Grychowska, Katarzyna; Pawłowski, Maciej; Subra, Gilles; Nomezine, Gaël; Martinez, Jean; Satała, Grzegorz; Bojarski, Andrzej J.; Zhou, Ziniu; O’Donnell, Martin J.; Scott, William L.; 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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    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
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    Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides
    (American Chemical Society, 2014-04-04) Samaritoni, J. Geno; Copes, Alexus T.; Crews, DeMarcus K.; Glos, Courtney; Thompson, Andre L.; Wilson, Corydon; O’Donnell, Martin J.; Scott, William L.; Department of Chemistry & Chemical Biology, School of Science
    Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R2CO, four bonds away from the site of hydrolysis. Electron-rich acyl R2 groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent’s Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.
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    VERSATILE FMOC-ACETAL MERRIFIELD RESINS: SYNTHESES OF BICYCLIC LACTAMS & LACTONES
    (Office of the Vice Chancellor for Research, 2012-04-13) Samaritoni, J. Geno; O’Donnell, Martin J.; Scott, William L.
    The preparation of Merrifield resins 5, which represent versatile intermediates in the syntheses of lactones, lactams, and bicyclic, tricyclic, and tetracyclic scaffolds, is described. The presence of Fmoc and acetal protecting groups allows for the eventual incorporation of ozone-labile groups at R2 (as in III) such as alkenes, alkynes, electron-rich aromatics and pi-excessive heterocycles whereas the previously reported route can only accommodate ozone-compatible groups. An extension of the current methodology to include bicyclic lactams, which features elaboration at each of R1, R2, and R3 of III including fragment condensation examples 10a-c, is described. In all cases separation and characterization of two of the four possible diastereomers was achieved. Using 2-D NMR methods the relative configuration of the two diastereomers is being established. Structures such as III are of interest since the thiazabicycloalkane ring system is a known bioactive scaffold that mimics the beta-turn (reverse turn) in polypeptides and proteins.