Molecular structural effects involved in the interaction of quinolinemethanolamines with DNA. Implications for antimalarial action.
Molecular structural effects involved in the interaction of quinolinemethanolamines with DNA. Implications for antimalarial action.
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喹啉甲醇胺与 DNA 相互作用中涉及的分子结构效应。
DOI：
10.1021/jm00219a002
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发表时间：
1977
影响因子：
7.3
通讯作者：
W. Wilson
中科院分区：
文献类型：
--
作者：
M. Davidson;B. G. Griggs;D. Boykin;W. Wilson
用差示光谱、DNA存在下的光谱漂移、超声小牛胸腺DNA和胶体超螺旋DNA粘度法滴定等方法研究了甲氟喹(4)及其类似物5、6、奎宁(2)、氯喹(1)和奎宁(3)与DNA的相互作用。这些实验的结果表明，如果甲醇胺侧链位于第4位的喹啉在第2位有另一个大的取代基(如三氟甲基)，则它们不能与DNA嵌合。甲氟喹(4)已被发现在临床上对抗氯喹的恶性疟原虫有效，单次给药即可完全清除寄生虫血症。这种药物在喹啉核团的第2位和第8位含有三氟甲基取代基，在低离子强度下仅通过静电吸引与DNA结合。类似的化合物，如5和奎宁(3)，在位置2上没有大的取代基，可以与DNA嵌入，但这种相互作用与抗疟疾活性没有任何明显的联系。即使是插层的喹啉甲醇胺与DNA的结合也很弱，而不是像喹卡林(2)、乙锭和柔红霉素这样的化合物，这些化合物被认为是通过在体内插入DNA而发挥药效的。综上所述，这些结果强烈表明，在这些实验中分析的喹啉甲醇胺类药物的抗疟疾作用并不涉及与DNA的相互作用。脱氧核糖核酸被认为是抗肿瘤药物的体内受体，如芳香类药物、1“3放线菌素、4，5和Coralyne、6、7抗锥虫药物如菲啶类、8、9和结构相当不同的抗疟疾药物。10”13 Haandhn的同事做了大量关于抗疟疾药物与DNA结合的早期工作。12他们提出的证据表明，氯喹(1)、奎宁(2)和奎宁(3)等化合物可以通过德国的经典模型嵌入DNA 11，并表明嵌入是其抗疟疾作用机制的一部分。这个模型的证据、它的简单性以及替代模型14、15缺乏明确的生物感受器，帮助它获得了广泛的接受。合成化学家已经使用该模型设计了新的抗疟疾药物，16并假设其他芳基甲醇胺和类似结构的相关化合物在其作用机制中涉及DNA结合。
The interaction of mefloquine (4), two of its analogues, 5 and 6, quinacrine (2), chloroquine (1), and quinine (3) with DNA has been investigated using difference spectroscopy, spectral shifts in the presence of DNA, viscometric titrations with sonicated calf thymus DNA and Col Ei plasmid superhelical DNA, and Tm measurements. The results from these experimentsindicate that quinolines with the methanolamine side chain atposition 4 cannot intercalate with DNA if they have another bulky substituent (such as trifluoromethyl) at position 2. Mefloquine (4), which has been found to be clinically effectiveagainst chloroquine-resistant Plasmodium falciparum, completelyclears parasitemia in a single dose. This drug contains trifluoromethyl substituentsat positions 2 and 8 of the quinoline nucleus and binds to DNA only weaklyby electrostatic attraction at low ionic strength. Similar compounds such as 5 and quinine (3) without bulky substituentsat position 2 can intercalate with DNA, but this interaction is not correlated in any apparent manner with antimalarial activity. Even intercalating quinolinemethanolamines bind weakly to DNA relative to compounds such as quinacrine (2), ethidium, and daunorubicin which are thought to exert their medicinal effects through in vivo intercalationwith DNA. These results, taken collectively, strongly suggest that interaction with DNA is not involved in the antimalarial action of the quinolinemethanolamines analyzed in these experiments.Deoxyribonucleic acid has been implicated as the in vivo receptor for antineoplastic drugs such as the anthracy-clines, 1" 3 actinomycin, 4, 5and coralyne, 6, 7 antitrypanosomal drugs such as the phenanthridines, 8, 9 and antimalarial drugs of quite varied structure. 10" 13 A considerable amount of the early work on the binding of antimalarials to DNA was done by Hahn andco-workers. 12 They presented evidence that compounds such as chloroquine (1), quinacrine (2), and quinine (3) can intercalate with DNA by the classical model of German11 and suggested that intercalation was a part of their mechanism of antimalarial action. The evidence for this model, its simplicity, and the lack of a definite bioreceptor for alternative models14, 15 have helped it gain widespread acceptance. Synthetic chemists have used the model to design new antimalarial drugs, 16 and the assumption has been made that other arylmethanolamines and related compounds of similar structure involve DNA binding in their mechanism of