The Novel Antimalarial Compound Dioncophylline C Forms a Complex with Heme in Solution

Schwedhelm, Kai F.; Horstmann, Martin; Faber, Johan H.; Reichert, Yana; Bringmann, Gerhard; Faber, Cornelius

doi:10.1002/cmdc.200600263

Cited by 21 publications

(13 citation statements)

References 47 publications

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“…[27] Very recently, structure determination by NMR spectroscopy showed CQ sitting in a central position over the outermost porphyrin rings of a FPIX-CQ 4:2 complex. [28] Furthermore, CQ inhibits the glutathione-mediated and hydrogen peroxide-mediated destruction of FPIX. [24,29] Most researchers assume that the buildup of noncrystalline FPIX, either in its free form or as a FPIX-CQ complex, finally kills the parasite.…”

Section: Chloroquinementioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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Section: Chloroquinementioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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“…The spin state S is accessible using the "Evans method". A detailed description of the entire process can be found in [7,8].…”

Section: Methodsmentioning

confidence: 99%

“…The first atomic resolution structures of FPIX in complex with several antimalarial drugs as determined by NMR were presented by De Dios and co-workers [7]. The technique was further refined in our group [8] to additionally include the determination of effective correlation times of the complexes.…”

Section: Introductionmentioning

confidence: 99%

Spin State of Chloroquine-Heme Complexes: Formation of a Hemin Tetramer Adduct

Schwedhelm¹,

Horstmann²,

Faber³

et al. 2008

TOSPECJ

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Complex formation between the antimalarial drug chloroquine and its presumed target ferriprotoporphyrin IX in three different solutions (pH 6.5, pH 9, and in a water methanol mixture) is characterized by nuclear magnetic resonance, UV spectroscopy, and mass spectrometry. NMR paramagnetic relaxation measurements are used to derive intermolecular distances between the molecules and model structures of the complexes are calculated by molecular dynamics simulations. Observation of an unusual spin state in NMR measurements leads to the postulation of a novel 4:2 stoichiometry of the complex, which is supported by mass spectrometry and UV spectroscopy.

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“…Another interesting work involving correlation times from paramagnetic relaxation, determined from measurements at three different magnetic fields, has shown that the antimalarial compound dioncophylline C binds with heme in solution in a chloroquine-like manner, indicating its mechanism of antimalarial activity and giving fundamental information for optimization of this type of drugs [44].…”

Section: Spin-lattice Relaxationmentioning

confidence: 99%

Spin-Lattice Relaxation Time in Drug Discovery and Design

Figueroa‐Villar

Tinoco²

2009

CTMC

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NMR is one of the most powerful techniques for ligand-biomolecule interaction studies and drug screening and design. There are several methods that are strongly used, including chemical shift perturbation (CSP), saturation transfer difference (STD) and diffusion coefficients. However, one of the most useful and easy to apply NMR parameters in medicinal chemistry studies is the spin-lattice relaxation data, which can be employed to investigate the strength and topology of intermolecular interactions, such as drug-drug, drug-protein, drug-DNA, drug-micelle (or vesicle) and biomolecule-biomolecule interactions. This review deals with the newest applications of T(1) in different studies of interest for drug design and evaluation.

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The Novel Antimalarial Compound Dioncophylline C Forms a Complex with Heme in Solution

Cited by 21 publications

References 47 publications

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Spin State of Chloroquine-Heme Complexes: Formation of a Hemin Tetramer Adduct

Spin-Lattice Relaxation Time in Drug Discovery and Design

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