Barraja Paola, Diana Patrizia, Montalbano Alessandra, Dattolo Gaetano, Cirrincione Girolamo, Viola Giampietro, Vedaldi Daniela, Dall'Acqua Francesco
Dipartimento Farmacochimico, Tossicologico e Biologico Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
Bioorg Med Chem. 2006 Dec 15;14(24):8712-28. doi: 10.1016/j.bmc.2006.07.061. Epub 2006 Sep 20.
A new class of compounds, the pyrrolo[2,3-h]quinolin-2-ones, nitrogen isosters of the angular furocoumarin Angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects than the lead compound. Two synthetic pathways were approached to allow the isolation both of the dihydroderivatives 10-17 and of the aromatic ring system 23. Compounds 10-17 showed a remarkable phototoxicity and a great UVA dose dependence reaching IC(50) values at submicromolar level. Intracellular localization of these compounds has been evaluated by means of fluorescence microscopy using tetramethylrhodamine methyl ester and acridine orange, which are specific fluorescent probes for mitochondria and lysosomes, respectively. A weak co-staining was observed with mitochondrial stain, whereas a specific localization in lysosomes was observed. Studies directed to elucidate the mode of action of this series of compounds revealed that they do not intercalate with DNA and do not induce photodamage to the macromolecule. On the contrary, they induce significative photodamage to lipids and proteins.
一类新的化合物，即吡咯并[2,3 - h]喹啉 - 2 - 酮，角型呋喃香豆素白芷素的氮类似物，被合成出来，目的是获得比先导化合物具有更高抗增殖活性和更低不良毒性作用的新型光化学治疗剂。研究了两条合成途径以分离二氢衍生物10 - 17和芳香环系统23。化合物10 - 17表现出显著的光毒性和对UVA剂量的高度依赖性，在亚微摩尔水平达到IC(50)值。已通过荧光显微镜使用四甲基罗丹明甲酯和吖啶橙评估了这些化合物的细胞内定位，它们分别是线粒体和溶酶体的特异性荧光探针。观察到与线粒体染色有较弱的共染色，而在溶酶体中观察到特异性定位。旨在阐明这一系列化合物作用方式的研究表明，它们不会插入DNA，也不会对大分子诱导光损伤。相反，它们会对脂质和蛋白质诱导显著的光损伤。
