Jakeman, David
Permanent URI for this collectionhttps://hdl.handle.net/10222/27724
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Item Embargo A novel bis-phosphonyl C-glycoside: First synthesis of C-(1,6-deoxy-β-D-glucopyranosyl)dimethylphosphonate, a stable bisphosphonate to probe the mechanism of β-phosphoglucomutase(Royal Society of Chemistry (UK), 2024) Ghosh, Rampersad; Jakeman, David L.β-Phosphoglucomutase (β-PGM) catayzes the interconversion of β-D-glucose-1-phosphate and β-D-glucose-6-phosphate sequentially utilizing a transient aspartyl-phospho enzyme and a β-D-glucose-1,6—bisphosphate intermediate. Herein, we report the first synthesis of the isosteric, cleavage resistant, phosphonate analogue C-(1,6-deoxy-β-D-glucopyranosyl)dimethylphosphonate, to aid in mechanistic and structural investigations of β-PGM and its phosphate tranfer process. Introduction of the of the ‘pseudo anomeric’ phosphonate was accomplished through methylenephosphonate anion addition to gluconolactone whilst the second phosphonate was installed at C-6 of β-D-glucopyranosyl moiety using a Horner–Wadsworth–Emmons (HWE) reaction on the C-6 aldehyde. The synthesis was completed in 10 steps and 8 % overall yield.Item Embargo Introductory Medicinal Chemistry for Pharmacy Students: An Assignment-Based Online Assessment Strategy (Postprint)(ACS Publications, 2024-06-22) Jakeman, David L.New assessment approaches for medicinal chemistry in an introductory course within the pharmacy curriculum are presented. A required introductory pharmaceutical sciences course specific for first year entry-to-practice pharmacy (PharmD) students was developed concurrently within the mandated online learning environment of COVID19. Instead of in-person or online examinations for the medicinal chemistry section, students were required to complete online assignments over the semester. The first series of assignments involved interpretation of a series of specific drug-target PDB structures, using molecular viewing software, to devise new drug analogues, and to rationalize the structural modifications based on proposing specific molecular interactions with the target, with structures being submitted to an online portal as SMILES codes. The final assignment required students to create an online 3 min video describing a specific drug−target interaction, the mechanism of action, structure−activity and additional considerations (adsorption, distribution, metabolism, excretion, toxicity) relevant to the specific drug. In subsequent academic years, the same course was delivered in-person to the first year pharmacy students and quantitative feedback collected. Specific questions were posed in addition to those evaluating the instructor, to better understand the student perspective on the assignments. Initial qualitative feedback was highly supportive of the assignment-based assessment strategy. In subsequent years the student feedback was quantified, and the data indicated that the students preferred the assignments over multiple choice or short answer examination assessment.Item Open Access Synthesis of a novel fluorinated phosphonyl C-glycoside, (3-deoxy-3-fluoro- F β-d-glucopyranosyl)methylphosphonate, a potential inhibitor of β- phosphoglucomutase Postprint(Elsevier, 2023) Carroll-Poehls, Madison; Jakeman, David L.β-phosphoglucomutase (βPGM) catalyzes the conversion of β-glucose 1-phosphate (βG1P) to glucose-6-phosphate (G6P), a universal source of cellular energy, in a two-step process. Transition state analogue (TSA) complexes formed from substrate analogues and a metal fluoride (MgF3 and AlF4-) enable analysis of each of these enzymatic steps independently. Novel substrate analogues incorporating fluorine offer opportunities to interrogate the enzyme mechanism using 19F NMR spectroscopy. Herein, the synthesis of a novel fluorinated phosphonyl C-glycoside (3-deoxy-3-fluoro-β-D-glucopyranosyl)methylphosphonate (1), in 12 steps (0.85 % overall yield) is disclosed. A four-stage synthetic strategy was employed, involving: 1) fluorine addition to the monosaccharide, 2) selective anomeric deprotection, 3) phosphonylation of the anomeric centre, and 4) global deprotection. Analysis of βPGM and 1 will be reported in due course.Item Open Access A Method for Structure-Activity Analysis of Quorum-Sensing Signaling Peptides from Naturally Transformable Streptococci(2009-12) Tian, XiaoLin; Syvitski, Raymond T.; Liu, TianLei; Livingstone, Nadine; Jakeman, David L.; Li, Yung-HuaMany species of streptococci secrete and use a competence-stimulating peptide (CSP) to initiate quorum sensing for induction of genetic competence, bacteriocin production, and other activities. These signaling molecules are small, unmodified peptides that induce powerful strain-specific activity at nano-molar concentrations. This feature has provided an excellent opportunity to explore their structure-function relationships. However, CSP variants have also been identified in many species, and each specifically activates its cognate receptor. How such minor changes dramatically affect the specificity of these peptides remains unclear. Structure-activity analysis of these peptides may provide clues for understanding the specificity of signaling peptide-receptor interactions. Here, we use the Streptococcus mutans CSP as an example to describe methods of analyzing its structure-activity relationship. The methods described here may provide a platform for studying quorum-sensing signaling peptides of other naturally transformable streptococci.Item Open Access Structure-activity analysis of quorum-sensing signaling peptides from Streptococcus mutans(2007-02) Syvitski, Raymond T.; Tian, Xiao-Lin; Sampara, Kamal; Salman, Alan; Lee, Song F.; Jakeman, David L.; Li, Yung-HuaStreptococcus mutans secretes and utilizes a 21-amino-acid signaling peptide pheromone to initiate quorum sensing for genetic competence, biofilm formation, stress responses, and bacteriocin production. In this study, we designed and synthesized a series of truncated peptides and peptides with amino acid substitutions to investigate their structure-activity relationships based on the three-dimensional structures of S. mutans wild-type signaling peptide UA159sp and C-terminally truncated peptide TPC3 from mutant JH1005 defective in genetic competence. By analyzing these peptides, we demonstrated that the signaling peptide of S. mutans has at least two functional domains. The C-terminal structural motif consisting of a sequence of polar hydrophobic charged residues is crucial for activation of the signal transduction pathway, while the core a-helical structure extending from residue 5 to the end of the peptide is required for receptor binding. Peptides in which three or more residues were deleted from the C terminus did not induce genetic competence but competitively inhibited quorum sensing activated by UA159sp. Disruption of the amphipathic a-helix by replacing the Phe-7, Phe-11, or Phe-15 residue with a hydrophilic residue resulted in a significant reduction in or complete loss of the activity of the peptide. In contrast to the C-terminally truncated peptides, these peptides with amino acid substitutions did not compete with UA159sp to activate quorum sensing, suggesting that disruption of the hydrophobic face of the a-helical structure results in a peptide that is not able to bind to the receptor. This study is the first study to recognize the importance of the signaling peptide C-terminal residues in streptococcal quorum sensing.Item Open Access Lipophilic sugar nucleotide synthesis by structure-based design of nucleotidylyltransferase substrates(2008-02) Huestis, Malcolm P.; Aish, Gaia A.; Hui, Joseph P. M.; Soo, Evelyn C.; Jakeman, David L.Structure-based design of alkyl sugar-1-phosphates provides an efficient nucleotidylyltransferase-catalyzed synthesis of a series of new lipophilic sugar nucleotides possessing long or branched alkyl chains, thereby demonstrating the utility of nucleotidylyltransferases to catalyze the synthesis of sugar nucleotides with potential applications in lipopolysaccharide and lipoglycopeptide biosynthesis.Item Open Access Antimicrobial Activities of Jadomycin B and Structurally Related Analogues(2009-03) Jakeman, David L.; Bandi, Srinivasulu; Graham, Cathy L.; Reid, Taryn R.; Wentzell, Jason R.; Douglas, Susan E.Natural products are leads for new antibiotics as a result of their structural complexity and diversity. We have isolated a series of structurally related polyketide-derived natural products from Streptomyces venezuelae ISP5230. The most active of these jadomycin analogues showed good activity against a variety of staphylococci, including methicillin-resistant Staphylococcus aureus.