Browsing by Author "Scott, William L."
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Item 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.Item Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics(Elsevier, 2019-01) Méndez, Yanira; De Armas, German; Pérez, Idalia; Rojas, Tamara; Valdés-Tresanco, Mario E.; Izquierdo, Maikel; del Rivero, Maday Alonso; Álvarez-Ginarte, Yoanna María; Valiente, Pedro A.; Soto, Carmen; de León, Lena; Vasco, Aldrin V.; Scott, William L.; Westermann, Bernhard; González-Bacerio, Jorge; Rivera, Daniel G.; Chemistry and Chemical Biology, School of ScienceThe Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.Item Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs(Wiley, 2017-11) Abraham, Milata M.; Denton, Ryan E.; Harper, Richard W.; Scott, William L.; O'Donnell, Martin J.; Durrant, Jacob D.; Chemistry and Chemical Biology, School of ScienceVirtual molecular catalogs have limited utility if member compounds are (i) difficult to synthesize or (ii) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays. The results provide insight into the broad range of drug-target classes amenable to inhibition and/or agonism by D3-accessible molecules. To encourage computer-aided drug discovery centered on these compounds, a publicly available virtual database of D3 molecules prepared for use with popular computer docking programs is also presented.Item Elimination of TFA-Mediated Cleavage in Distributed Drug Discovery(Office of the Vice Chancellor for Research, 2014-04-11) Carnahan, Jon M.; Scott, William L.; Samaritoni, J. Geno; O'Donnell, Martin J. O.Distributed Drug Discovery (D3) is a multi-disciplinary approach to the discovery of new drugs, which target neglected diseases or conditions common to developing-world countries. As part of a continuing effort to improve D3 methodology, two approaches for eliminating the final step TFA-mediated resin cleavage are proposed for investigation. Cleavage under basic conditions (saponification) and mild acid conditions (dilute HCl/hexafluoroisopropanol or dilute HCl/trifluoroethanol) represent improvements in safety and convenience to the undergraduate student researcher. Previous studies have shown that saponification provides yields comparable to the traditional TFA cleavage but recovery is not as convenient. Further improvements in the saponification workup will be evaluated by analyzing the effectiveness of simple trituration with acetone compared to use of a strong anion-exchange resin or drying reagents to isolate the free acid from the salt. Different trituration procedural modifications have been made and are being tested. Results have shown that in the presence of methanol, esterification will occur when the acid is liberated from the salt using HCl. To counter this problem, the samples are first evaporated to remove methanol and then the pH is adjusted with HCl. It was shown that using acetic acid did not result in pH levels low enough to guarantee complete protonation of the carboxylate. Through the use of a Bill-Board, an apparatus that holds six reaction vessels, several procedural modifications can be carried out simultaneously. Analysis is conducted by liquid chromatography coupled with a mass spectrometer and with nuclear magnetic resonance spectroscopy. Further studies will be carried out to assess the efficiency and practicality of using mild acidic conditions for cleavage using HCl/hexafluoroisopropanol or dilute HCl/trifluoroethanol. Both saponification and mild acid cleavage would represent improvements in safety and convenience to the undergraduate student researcher.Item Globally Distributed Drug Discovery of New Antibiotics: Design and Combinatorial Synthesis of Amino Acid Derivatives in the Organic Chemistry Laboratory(ACS, 2019-06) Dounay, Amy B.; O'Donnell, Martin J.; Samaritoni, J. Geno; Popiolek, Lukasz; Schirch, Douglas; Biernasiuk, Anna; Malm, Anna; Lamb, Isaac W.; Mudrack, Kristen; Rivera, Daniel G.; Ojeda, Gerardo M.; Scott, William L.; Chemistry and Chemical Biology, School of ScienceAn experiment for the synthesis of N-acyl derivatives of natural amino acids has been developed as part of the Distributed Drug Discovery (D3) program. Students use solid-phase synthesis techniques to complete a three-step, combinatorial synthesis of six products, which are analyzed using LC–MS and NMR spectroscopy. This protocol is suitable for introductory organic laboratory students and has been successfully implemented at multiple academic sites internationally. Accompanying prelab activities introduce students to SciFinder and to medicinal chemistry design principles. Pairing of these activities with the laboratory work provides students an authentic and cohesive research project experience.Item 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 ScienceNew 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.Item 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 ScienceThe 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.Item Saponification of N-Acylated L-Phenylalanine Wang and Merrifield Resins. Assessment of Cleavage Efficiency and Epimerization(Office of the Vice Chancellor for Research, 2013-04-05) Carnahan, Jon M.; O'Donnell, Martin J. O.; Samaritoni, J. Geno; Crews, DeMarcus K.; Lawrence, Brian M.; Scott, William L.As part of a continuing effort to modify Distributed Drug Discovery (D3) synthetic procedures to enhance safety and accommodate the limited resources available to students in developing-world countries, we have recently begun to examine alternatives to trifluoroacetic acid (TFA)-cleavage of amino acid derivatives from polystyrene-based resins. Cleavage of a representative example, N-(4-chlorobenzoyl)-L-phenylalanine, from both Wang and Merrifield resins was accomplished in thirty minutes at room temperature using 0.5M sodium hydroxide in methanol/tetrahydrofuran. In a side-by-side comparison with cleavage using TFA, results indicated that saponification from Wang resin was incomplete after thirty minutes. Experiments designed to examine separately the effect of reaction time, temperature, and concentration were performed and results will be presented. Additionally, investigations were performed to assess the degree of epimerization which had occurred during cleavage of Merrifield-bound L-phenylalanine acylated with both (R)- and (S)-mandelic acid. Results revealed a small but significant amount of epimerization (15:1 to 31:1 diastereomeric ratios) after a thirty-minute cleavage time at room temperature.Item Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations(MDPI, 2016-03) Zhou, Ziniu; Scott, William L.; O'Donnell, Martin J.; Department of Chemistry & Chemical Biology, School of ScienceA solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields.Item 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 ScienceWe 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.