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Post-synthetic Functionalization of Bioactive Compounds for Rapid Anticancer Library Expansion and Mechanistic Probe Development for Antimicrobial Resistance

Hambira, Chido M
http://orcid.org/0000-0002-8119-9538
http://rave.ohiolink.edu/etdc/view?acc_num=osu1543423373480923

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Within the realm of medicinal chemistry, not only is it important to optimize for target potency and physicochemical properties of bioactive compounds, but development of enabling technologies that aid in elucidation of biochemical pathways is of equal importance. The body of work contained within this dissertation is a summary of my efforts toward the development of a new C-H functionalization method to facilitate late-stage derivatization of complex bioactive molecules, and post-synthetic modifications of known bioactive compounds of pharmaceutical agents for the development of mechanistic probes. By taking advantage of the versatile reactivity of hypervalent iodine, aided by the labile nature of the ligands, we have harnessed the mild yet enhanced reactivity of iodosobenzene chloroacetate for the chlorination of (hetero)arenes. My key contributions to this project were the discovery of methods amenable to the halogenation of challenging substrates of the (iso)quinoline class of compounds, and the cytotoxic natural product derivate 2”-acetyl phyllanthusmin D, in addition to conducting mechanistic investigations. A significant portion of my doctoral research has been spent developing tool compounds targeting two aspects contributing to the looming public health issue of antimicrobial resistance. The first effort was aimed at the investigation of small molecules transport across Gram-negative bacterial membranes. This work was conducted during a 12-month co-op at GlaxoSmithKline. We explored the feasibility of hijacking a native nutrient uptake system, the FadL/FadD-mediated uptake of long chain fatty acids to enable uptake of antimicrobial agents across the Gram-negative membranes. These investigations demonstrated the first proof-of-principle that a post-synthetic attachment of a long fatty acid chain to an antimicrobial agent could facilitate its uptake and cellular accumulation in a FadD-dependent manner. The potential impact of this work lies in conferring broad spectrum activity to Gram-positive only agents by simply attaching a long chain fatty acid recognition element. In addition to the significant drug development challenge imposed by the Gram-negative membranes, resistance mechanisms can develop and propagate within persistent bacterial biofilms impervious to therapeutic intervention. One example of an infection that relies very heavily on the biofilm lifestyle is that caused by S. Typhi, the causative agent of typhoid fever. In an attempt to find new ways to prevent formation of biofilms caused by S. Typhi, structurally distinct compounds, JK-1 and T315, were identified from compound libraries as antibiofilm agents. Several analogues to JK-1 were synthesized in an attempt to build initial structure activity relationships and improve the potency. In addition to analogue development of this class, two T315 mechanistic probes bearing a biotin tag were synthesized and subjected to affinity-based proteomics. These investigations led to the identification of a NADH-dependent oxidoreductase, WrbA as one of the protein targets implicated in the biofilm lifestyle of S. Typhi. This discovery is expected to inform rational analogue design to transform these initial hit compounds into viable drug development leads for the eradication of biofilm-related chronic infections.
James Fuchs (Advisor)
David Nagib (Advisor)
Karl Werbovetz (Committee Member)
Mark Mitton-Fry (Committee Member)
283 p.
Chemistry; Pharmaceuticals; Pharmacy Sciences

Recommended Citations

Citations

  • Hambira, C. M. (2018). Post-synthetic Functionalization of Bioactive Compounds for Rapid Anticancer Library Expansion and Mechanistic Probe Development for Antimicrobial Resistance [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543423373480923

    APA Style (7th edition)

  • Hambira, Chido. Post-synthetic Functionalization of Bioactive Compounds for Rapid Anticancer Library Expansion and Mechanistic Probe Development for Antimicrobial Resistance. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1543423373480923.

    MLA Style (8th edition)

  • Hambira, Chido. "Post-synthetic Functionalization of Bioactive Compounds for Rapid Anticancer Library Expansion and Mechanistic Probe Development for Antimicrobial Resistance." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543423373480923

    Chicago Manual of Style (17th edition)

osu1543423373480923
211
© 2018, some rights reserved.Creative Commons License Post-synthetic Functionalization of Bioactive Compounds for Rapid Anticancer Library Expansion and Mechanistic Probe Development for Antimicrobial Resistance by Chido M Hambira is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.