The hydroxyl functionality and a rigid proximal N are required for forming a novel non-covalent quinine-heme complex

• Published in: Journal of inorganic biochemistry Vol. 105; no. 3; pp. 467 - 475
• Main Authors: Alumasa, John N., Gorka, Alexander P., Casabianca, Leah B., Comstock, Erica, de Dios, Angel C., Roepe, Paul D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2011
• Subjects: Amodiaquine - chemistry; Antimalarial drugs; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Chloroquine - chemistry; Dimerization; Dose-Response Relationship, Drug; Ferriprotoporphyrin IX; Hemeproteins - chemistry; Hemin - chemistry; Hemozoin; Hydroxyl Radical - chemistry; Hydroxyl Radical - pharmacology; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Malaria, Falciparum - drug therapy; Malaria, Falciparum - metabolism; Malaria, Falciparum - pathology; Nitrogen - chemistry; Nitrogen - pharmacology; Plasmodium falciparum - drug effects; Quinine - analogs & derivatives; Quinine - chemical synthesis; Quinine - chemistry; Quinine - pharmacology; Hemozoin; Ferriprotoporphyrin IX; Antimalarial drugs
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2010.08.011

Quinoline antimalarial drugs bind both monomeric and dimeric forms of free heme, with distinct preferences depending on the chemical environment. Under biological conditions, chloroquine (CQ) appears to prefer to bind to μ-oxo dimeric heme, while quinine (QN) preferentially binds monomer. To further explore this important distinction, we study three newly synthesized and several commercially available QN analogues lacking various functional groups. We find that removal of the QN hydroxyl lowers heme affinity, hemozoin (Hz) inhibition efficiency, and antiplasmodial activity. Elimination of the rigid quinuclidyl ring has similar effects, but elimination of either the vinyl or methoxy group does not. Replacing the quinuclidyl N with a less rigid tertiary aliphatic N only partially restores activity. To further study these trends, we probe drug-heme interactions via NMR studies with both Fe and Zn protoporphyrin IX (FPIX, ZnPIX) for QN, dehydroxyQN (DHQN), dequinuclidylQN (DQQN), and deamino-dequinuclidylQN (DADQQN). Magnetic susceptibility measurements in the presence of FPIX demonstrate that these compounds differentially perturb FPIX monomer-dimer equilibrium. We also isolate the QN-FPIX complex formed under mild aqueous conditions and analyze it by mass spectrometry, as well as fluorescence, vibrational, and solid-state NMR spectroscopies. The data elucidate key features of QN pharmacology and allow us to propose a refined model for the preferred binding of QN to monomeric FPIX under biologically relevant conditions. With this model in hand, we also propose how QN, CQ, and amodiaquine (AQ) differ in their ability to inhibit Hz formation. Proposed QN-FPIX adduct structure involving coordination between the –OH group of QN and Fe of FPIX, aided by the formation of a five-membered ring containing a strong hydrogen bond between the –OH proton and the quinuclidyl nitrogen. [Display omitted]