18 research outputs found
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><sup>2</sup>-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)Âsulfamoyl]Âadenosine (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)Âsulfamoyl]Âadenosine
(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><sub>a</sub> = 3) by a more stable sulfonamide linkage (p<i>K</i><sub>a</sub> = 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><sub>i</sub> = 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 ÎĽM).
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 Ă…) 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