Portland State University. Department of Chemistry
David H. Peyton
Term of Graduation
Date of Publication
Master of Science (M.S.) in Chemistry
Antimalarials, Xanthone, Heme
1 online resource (x, 101 pages)
Human falciparum malaria is caused by Plasmodium falciparum parasite, which digests host hemoglobin within its food vacuole, releasing toxic heme. P. falciparum detoxifies free heme to hemozoin by polymerization. This process is believed to be the target of most successful antimalarial drugs, chloroquine and quinine, which are now losing their effectiveness due to the spread of multi-drug resistant strains. Xanthones were recognized in the laboratory of Dr. M. Riscoe (Portland VA Medical Center) to bind to heme, preventing heme polymerization [Ignatushchenko, M., Winter R., and Riscoe, M. (1997) FEBS Letters 409, 67].
This thesis reports a study of the interactions of a potential antimalarial agent, 4,5-dihydroxyxanthone (X2), with heme and tin (IV) protoporphyrin IX (SnPP), as well as with other heme analogues, by NMR and optical spectroscopies. It was found that X2 binds to heme with a stoichiometry of two heme molecules to one X2 molecule, exhibiting an apparent dissociation equilibrium constant (Kd) of 5xI0-6 at pH 5.8. This stoichiometry is identical to that previously found for complexes between heme and chloroquine or quinine. Kd is close to those of chloroquine, 5xl0-6 and of quinine, 6xl0-6. X2 primarily binds to dimeric SnPP, with the stoichiometry of two X2 molecules to one dimer of SnPP and Kd is close to those of chloroquine, IxI0-5 and of quinine, IxI0-5. The binding was found to be noncooperative in all of the above cases. Axial coordination between the keto of X2 and metal Fe or Sn, π π interaction between aromatic ring of X2 and porphyrin plane, and hydrogen bonding between 4(5) hydroxy group of X2 with carboxylate side chain of the metalloporphyrin are likely contributions to binding enengetics. X2 binds to both sides of monomeric SnPP but to each side of the μ-oxo bridged dimeric SnPP, while X2 binds to β-hematin dimer through coordination between the keto of X2 and the unbound iron with a 1:1 stoichiometry. Structural confirmation and characterization of 29 xanthone derivatives by 1H NMR is presented.
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Kelly, Jane Xu, "Xanthones as Antimalarial Agents : Binding Interactions Between Heme Analogues and Xanthones" (1998). Dissertations and Theses. Paper 6375.