生物活性化合物的光反应性。第十九部分：抗疟药伯氨喹的激发态和自由基
Photoreactivity of biologically active compounds. XIX: excited states and free radicals from the antimalarial drug primaquine.
作者信息
Kristensen Solveig, Edge Ruth, Tønnesen Hanne Hjorth, Bisby Roger Hugh, Navaratnam Suppiah
机构信息
University of Oslo, School of Pharmacy, Department of Pharmacy, P.O. Box 1068 Blindern, NO-0316 Oslo, Norway.
出版信息
J Photochem Photobiol B. 2009 Mar 3;94(3):147-57. doi: 10.1016/j.jphotobiol.2008.11.006. Epub 2008 Dec 3.
The formation and reactivity of excited states and free radicals from primaquine, a drug used in the treatment of malaria, 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 (1)O(2) by laser flash photolysis ((PQ)Phi(Delta)=0.025). Primaquine (PQ) exists as the monocation (PQH(+)) in aqueous solution at physiological pH. PQH(+) photoionises by a biphotonic process and also forms the monoprotonated cation radical (PQH(2+)) by one electron oxidation by HO (k(q)=6.6 x 10(9) M(-1) s(-1)) and Br*(2)(-) (k(q)=4.7 x 10(9) M(-1) s(-1)) at physiological pH, detected as a long-lived transient decaying essentially by a second order process (k(2)=7.4 x 10(8) M(-1) s(-1)). PQH(2+)* is scavenged by O(2), although at a limited rate (k(q)=1.0 x 10(6) M(-1) s(-1)). The reduction potential (E degrees) of PQH(2+)/PQH(+) is < +1015 mV, as measured versus tryptophan (TRP/TRPH). Primaquine also forms PQH(2+)* at pH 2.4, by one electron oxidation by Br*(2)(-) and proton loss (k(q)=2.7 x 10(9) M(-1) s(-1)). The non-protonated cation radical (PQ(+)) is formed during one electron oxidation with Br(2)(-) at alkaline conditions (k(q)=4.2 x 10(9) M(-1) s(-1) at pH 10.8). The estimated pK(a)-value of PQH(2+)/PQ(+) is pK(a) approximately 7-8. Primaquine is not a scavenger of O*(2)(-) at physiological pH. Thus self-sensitization by O*(2)(-) 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+)* is expected to play an essential part in the photochemical degradation process in a neutral, aqueous medium.
为了评估主要的光化学反应机制，对用于治疗疟疾的药物伯氨喹激发态和自由基的形成及反应活性进行了研究。未检测到激发态伯氨喹三线态，但由于该药物是联苯丁酯三线态和联苯三线态的有效猝灭剂，并通过激光闪光光解形成单线态氧（(PQ)Φ(Δ)=0.025），所以其可能以短寿命（<50 ns）和三线态能量<250 kJ/mol的形式形成。在生理pH值下，伯氨喹（PQ）在水溶液中以单阳离子（PQH⁺）形式存在。PQH⁺通过双光子过程发生光离子化，并且在生理pH值下通过HO*（k(q)=6.6×10⁹ M⁻¹ s⁻¹）和Br₂⁻（k(q)=4.7×10⁹ M⁻¹ s⁻¹）的单电子氧化形成单质子化阳离子自由基（PQH₂⁺），检测到其作为长寿命瞬态，基本上通过二级过程衰减（k(2)=7.4×10⁸ M⁻¹ s⁻¹）。PQH₂⁺被O₂清除，尽管速率有限（k(q)=1.0×10⁶ M⁻¹ s⁻¹）。相对于色氨酸（TRP/TRPH）测量，PQH₂⁺/PQH⁺的还原电位（E°）< +¹⁰¹⁵ mV。在pH 2.4时，伯氨喹也通过Br₂⁻的单电子氧化和质子损失形成PQH₂⁺（k(q)=2.7×10⁹ M⁻¹ s⁻¹）。在碱性条件下，用Br₂⁻进行单电子氧化时形成非质子化阳离子自由基（PQ⁺）（在pH 10.8时k(q)=4.2×10⁹ M⁻¹ s⁻¹）。PQH₂⁺*/PQ⁺*的估计pK(a)值约为7 - 8。在生理pH值下，伯氨喹不是O₂⁻*的清除剂。因此，在光化学反应中，O₂⁻*的自敏化作为一种降解途径被排除。原料中的杂质和光化学降解产物引发重水中伯氨喹的光敏降解，通过添加单线态氧猝灭剂叠氮化钠可防止这种情况。因此，通过形成单线态氧的光敏降解对于伯氨喹的初始光化学分解很重要，其也通过自由基反应进行。预计PQH₂⁺*的形成在中性水介质中的光化学降解过程中起重要作用。
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