DESIGN AND SYNTHESIS OF CHELATING COMPOUNDS AND SOLID-SUPPORTED CHELATORS FOR METAL DEPLETED SOLUTIONS

Metals are essential to life, yet they can be toxic for biological systems when present in excessive amounts. The major source of metal overload in humans is diet; and in some cases, intravenous feeding. Thus the removal of toxic metal ions from contaminated clinical products such as total parenteral nutrition (TPN) solutions, and drinking and waste water is extremely important. The use of chelating resins, which are polymeric solids containing covalently immobilized chelating compounds, for the selective removal of metal ions from contaminated solutions has been conceptualized long ago. Herein, the design and synthesis of metal specific chelating compounds and chelating resins will be presented, along with the application of these materials to remove toxic metals from aqueous solutions. Solution phase hydroxamate based chelating compounds have been synthesized for the selective binding of trivalent metals such as iron and aluminum in the presence of divalent metals such as calcium. Iron complexation behavior of these solution phase chelating compounds has been studied by UV-Vis Spectrophotometric methods. These hydroxamate chelators have potential applications as chelating agents in the treatment of iron and aluminum overload. A set of the strongly binding chelators have been immobilized on solid support via various linkages. These solid supported chelators have been employed to selectively remove aluminum from contaminated TPN components such as a solution of calcium gluconate. Our resins are able to remove more than 90% of aluminum from commercial calcium gluconate solutions. This technology of employing hydroxamate functionalized resins for the removal of aluminum from calcium gluconate solution will be available in hospitals soon and will greatly benefit premature neonates who receive TPN solutions for life support. Additionally, citramide functionalized chelating resins have been prepared for the removal of trivalent metals from contaminated solutions at low pH, and dithiolate based chelating resins were prepared for the removal of high priority environmental metal toxins such as lead, cadmium, mercury, and arsenic. Overall, this dissertation embodies the design, synthesis, and metal binding studies of novel chelators and chelating resins and the applications of these resins for the selective removal of metal ions from contaminated solutions

Chelating Compounds and Immobilized Tethered Chelators

Novel compounds useful as chelators, intermediates for their production and methods for removing trivalent and tetravalent metal ions from solution are presented.https://irl.umsl.edu/patents/1063/thumbnail.jp

Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors

Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic tuberculosis (TB), remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with KDs ≤ 2 nM. Additionally, we obtained high-resolution cocrystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 μM. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-α analogue over the corresponding C-2'-β analogue, consistent with their differential whole-cell activity

Synthesis and Analysis of Bacterial Folate Metabolism Intermediates and Antifolates

The mechanism of action of <i>para</i>-aminosalicylic acid (PAS), a drug used to treat drug-resistant tuberculosis (TB), has been confirmed through the first synthesis and biochemical characterization of its active metabolite <b>7</b>. The synthesis features the coupling of <i>N</i>²-acetyl-6-formylpterin obtained from the degradation of folic acid and appropriately functionalized arylamines to form Schiff bases. The sequential chemoselective reduction of the imine and pterin ring led to the formation of dihydrofolate analogue <b>7</b> and two other dihydropteroate species

Investigation and Conformational Analysis of Fluorinated Nucleoside Antibiotics Targeting Siderophore Biosynthesis

Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5′-<i>O</i>-[<i>N</i>-(salicyl)­sulfamoyl]­adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against <i>Mycobacterium tuberculosis</i>, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2′ and 3′ positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2′-<i>endo</i>, 3′-<i>exo</i> (South), or a 3′-<i>endo</i>,2′-<i>exo</i> (North) conformation. The structure–activity relationships revealed a strong conformational bias for the C3′-<i>endo</i> conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2′-<i>endo</i> conformation

Conformationally Constrained Cinnolinone Nucleoside Analogues as Siderophore Biosynthesis Inhibitors for Tuberculosis

5′-<i>O</i>-[<i>N</i>-(Salicyl)­sulfamoyl]­adenosine (Sal-AMS, <b>1</b>) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Cinnolone analogues exemplified by <b>5</b> were designed to replace the acidic acyl-sulfamate functional group of <b>1</b> (p<i>K</i>_a = 3) by a more stable sulfonamide linkage (p<i>K</i>_a = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability. We showed <b>5</b> potently inhibited the mycobacterial salicylate ligase MbtA (apparent <i>K</i>_i = 12 nM), blocked production of the salicylate-capped siderophores in whole-cell <i>Mtb</i>, and exhibited excellent antimycobacterial activity under iron-deficient conditions (minimum inhibitor concentration, MIC = 2.3 μM). To provide additional confirmation of the mechanism of action, we demonstrated the whole-cell activity of <b>5</b> could be fully antagonized by the addition of exogenous salicylate to the growth medium. Although the total polar surface area (tPSA) of <b>5</b> still exceeds the nominal threshold value (140 Å) typically required for oral bioavailability, we were pleasantly surprised to observe introduction of the less acidic and conformationally constrained cinnolone moiety conferred improved drug disposition properties as evidenced by the 7-fold increase in volume of distribution in Sprague–Dawley rats

Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma

The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester. We have employed this ProTide strategy for intracellular delivery of a nucleotide antagonist of eIF4E in mantle cell lymphoma (MCL) cells. Furthermore, we demonstrated that chemical inhibition of cap-dependent translation results in suppression of c-Myc expression, increased p27 expression, and enhanced chemosensitization to doxorubicin, dexamethasone, and ibrutinib. In addition, the new ProTide strategy was shown to enhance oral bioavailability of the corresponding monoester phosphoramidate