Browsing by Author "Samaritoni, J. Geno"
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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 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 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.Item 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 1gItem 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 ScienceRemote 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.Item 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.