Photophysical Studies on Antimalarial Drugs

Motten, Ann G.; Martínez, Lydia J.; Holt, Nathan; Sik, Robert H.; Reszka, Krzysztof J.; Chignell, Colin F.; Tønnesen, Hanne; Roberts, Joan E.

doi:10.1562/0031-8655(1999)069<0282:psoad>2.3.co;2

Cited by 58 publications

(44 citation statements)

References 26 publications

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“…This hypothesis is supported by the fact that the formation of adducts via Z^Z bonds with the porphyrin ring is essential for the activity of quinoline antimalarials [3], and that the quinoline ring, as well as the side chain, of chloroquine can host radicals [15]. We thus propose the occurrence of an electron transfer between the redox couple Fe[II]PPIX/Fe[III]PPIX and the quinoline ring [16,17], to generate highly reactive radicals.…”

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confidence: 93%

Does chloroquine really act through oxidative stress?

et al. 2002

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To assess whether molecular oxygen and oxidative stress contribute to chloroquine activity, we cultivated strains of Plasmodium falciparum in erythrocytes with carboxyhemoglobin and an atmosphere containing 2% CO, 5% CO 2 and 93% N 2 . Results indicate that, contrary to common belief, oxygen is not involved in the activity of chloroquine. Reactive radicals formation is suggested. ß 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.Key words: Carboxyhemoglobin; Chloroquine; Carbon monoxide ; Oxygen; Malaria; Plasmodium falciparum Malaria continues to be a major health problem in tropical countries. Some 300^500 million clinical cases occur annually and result in 700 000^2.7 million deaths [1]. Chloroquine, a 4-amino 7-chloro quinoline, has been the mainstay of malaria control for decades. Despite years of use, its mode of action and the mechanism by which malaria parasites become resistant are only partly known. We know, however, that they are unrelated and independent [2]. Resistance of Plasmodium falciparum to chloroquine is multigenic and concerns drug accumulation in the parasite. In contrast, chloroquine and other quinoline drugs target a unique, essential metabolic pathway of the parasite, the ingestion and degradation of host cell hemoglobin (Hb) within the parasite's food vacuole. While globin-derived amino acids are used by the parasite, the remaining free heme moiety must be disposed: iron(II)protoporphyrin IX (Fe[II]PPIX) is oxidized to iron(III)protoporphyrin IX (Fe[III]PPIX) and, for the most part, converted into a crystalline pigment called hemozoin [3]. So, although chloroquine resistance is nowadays widely spread, knowing how chloroquine works is important in order to design newer and more e¡ective drugs.It is generally accepted that chloroquine prevents heme disposal through the formation of complexes with Fe[III]PPIX. Nuclear magnetic resonance, UV-visible and Mo « ssbauer spectroscopy data concur to show that Z^Z interaction between the drug and the electronic system of hematin governs the formation of these adducts. The accumulation of free heme and/or of chloroquine^Fe(III)PPIX adducts is thought to generate oxidative stress, leading to peroxidation of parasite membrane lipids and parasitic death [3^5]. However, uncertainties still exist.If the peroxidative damage hypothesis were correct, molecular oxygen would be important and play a key role in the initiation and ampli¢cation of the oxidative reactions. However, our ¢ndings are not supportive of this view. We found no signi¢cant variation in the activity of chloroquine when the oxygen tension in the culture was increased [6]. Also the presence of preformed peroxides was necessary for membranes to react with the drug^Fe[III]PPIX complexes and for lipid peroxidation to occur [7]. To further clarify if molecular oxygen and oxidative stress had a role in the mechanism of action of chloroquine, we compared P. falciparum (chloroquine resistant and susceptible clones) cultured in sta...

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confidence: 93%

Does chloroquine really act through oxidative stress?

et al. 2002

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“…Noscapine shares some pharmacophores with berberine and sanguinarine, but lacks the aromatic heterocyclic ring systems of those compounds. Chloroquine is photodynamic but does not produce detectable singlet oxygen under physiological conditions [65, 66]. We were unable to find reports of photodynamic activity for m -AMSA, which has been suggested to damage proteins by a light independent mechanism [67].…”

Section: Discussionmentioning

confidence: 99%

PCNA damage caused by antineoplastic drugs

Bae

Zhao

Snapka

2008

Biochemical Pharmacology

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Structurally diverse chemotherapeutic and chemopreventive drugs, including camptothecin, doxorubicin, sanguinarine, and others, were found to cause covalent crosslinking of proliferating cell nuclear antigen (PCNA) trimers in mammalian cells exposed to fluorescent light. This PCNA damage was caused by both nuclear and cytoplasmically localizing drugs. For some drugs, the PCNA crosslinking was evident even with very brief exposures to laboratory room lighting. In the absence of drugs, there was no detectable covalent crosslinking of PCNA trimers. Other proteins were photocrosslinked to PCNA at much lower levels, including crosslinking of additional PCNA to the PCNA trimer. The proteins photo-crosslinked to PCNA did not vary with cell type or drug. PCNA was not crosslinked to itself or to other proteins by superoxide, hydrogen peroxide or hydroxyl radicals, but hydrogen peroxide caused mono-ubiquitination of PCNA. Quenching of PCNA photo-crosslinking by histidine, and enhancement by deuterium oxide, suggest a role for singlet oxygen in the crosslinking. SV40 large T antigen hexamers were also efficiently covalently photo-crosslinked by drugs and light. Photodynamic crosslinking of nuclear proteins by cytoplasmically localizing drugs, together with other evidence, argues that these drugs may reach the nucleoplasm in amounts sufficient to photodamage important chromosomal enzymes. The covalent crosslinking of PCNA trimers provides an extremely sensitive biomarker for photodynamic damage. The damage to PCNA and large T antigen raises the possibility that DNA damage signaling and repair mechanisms may be compromised when cells treated with antineoplastic drugs are exposed to visible light.

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“…exposure. [27]. The first absorption band of ground state primaquine at 350 nm is decreased during photodegradation parallel to growth of a new maximum at 455 nm (i.e.…”

Section: Photosensitized Degradation Of Primaquinementioning

confidence: 99%

Photoreactivity of biologically active compounds. XIX: Excited states and free radicals from the antimalarial drug primaquine

Kristensen

Edge

Tønnesen

et al. 2009

Journal of Photochemistry and Photobiology B: Biology

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The formation and reactivity of excited states and free radicals from primaquine was studied in order to evaluate the primary photochemical reaction mechanisms. The excited primaquine triplet was not detected, but is likely to be formed with a short lifetime (< 50 ns) and with a triplet energy < 250 kJ/mol as the drug is an efficient quencher of the fenbufen triplet and the biphenyl triplet, and forms -is eliminated as a degradation pathway in the photochemical reactions. Impurities in the raw material and photochemical degradation products initiate photosensitized degradation of primaquine in deuterium oxide, prevented by addition of the 1 O 2 quencher sodium azide. Photosensitized degradation by formation of 1 O 2 is thus important for the initial photochemical decomposition of primaquine, which also proceeds by free radical reactions. Formation of PQH 2+

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Photophysical Studies on Antimalarial Drugs

Cited by 58 publications

References 26 publications

Does chloroquine really act through oxidative stress?

Does chloroquine really act through oxidative stress?

PCNA damage caused by antineoplastic drugs

Photoreactivity of biologically active compounds. XIX: Excited states and free radicals from the antimalarial drug primaquine

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