Fraix Aurore, Blangetti Marco, Guglielmo Stefano, Lazzarato Loretta, Marino Nino, Cardile Venera, Graziano Adriana C E, Manet Ilse, Fruttero Roberta, Gasco Alberto, Sortino Salvatore
Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, 95125, Catania, Italy.
Department of Science and Drug Technology, University of Torino, 10125, Torino, Italy.
ChemMedChem. 2016 Jun 20;11(12):1371-9. doi: 10.1002/cmdc.201500396. Epub 2015 Nov 5.
The design, synthesis, photochemical properties, and biological evaluation of a novel photoactivatable bichromophoric conjugate are reported. The compound 1, [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)butanamide] combines a 2,6-diiodo-1,3,5,7-tetramethyl BODIPY derivative as singlet oxygen ((1) O2 ) photosensitizer and 4-nitro-3-(trifluoromethyl)aniline (NOPD) as nitric oxide (NO) photodonor, joined by an alkyl spacer. These two chromogenic units absorb in distinct regions of the visible spectrum, and their individual photochemical properties are conserved in the molecular conjugate. Irradiation of the bichromophoric conjugate with green light afforded (1) O2 in high quantum yields, whereas (1) O2 production was negligible with the use of blue light; under this latter condition, NO was released. Photogeneration of NO and cytotoxic (1) O2 can therefore be regulated by appropriately tuning the excitation light wavelength and intensity. Tested on melanoma cancer cells, this resulted in amplified photomortality relative to that of a structurally correlated model compound 2 [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-(p-tolylamino)propyl)butanamide] deprived of the NO-release capacity. The cellular uptake of 1, evaluated by confocal fluorescence microscopy, showed that the product is localized in the cytoplasm.
报道了一种新型光可激活双发色团共轭物的设计、合成、光化学性质及生物学评价。化合物1，[4-(4,4-二氟-2,6-二碘-1,3,5,7-四甲基-4-硼-3a,4a-二氮杂-s-茚并-8-基)-N-(3-((4-硝基-3-(三氟甲基)苯基)氨基)丙基)丁酰胺]结合了一种2,6-二碘-1,3,5,7-四甲基BODIPY衍生物作为单线态氧（(1)O2）光敏剂和4-硝基-3-(三氟甲基)苯胺（NOPD）作为一氧化氮（NO）光供体，通过烷基间隔基连接。这两个发色单元在可见光谱的不同区域吸收，并且它们各自的光化学性质在分子共轭物中得以保留。用绿光照射双发色团共轭物可产生高量子产率的(1)O2，而使用蓝光时(1)O2的产生可忽略不计；在后者条件下，NO被释放。因此，通过适当调节激发光波长和强度，可以调控NO的光生成和细胞毒性(1)O2。在黑色素瘤癌细胞上进行测试，相对于缺乏NO释放能力的结构相关模型化合物2 [4-(4,4-二氟-2,6-二碘-1,3,5,7-四甲基-4-硼-3a,4a-二氮杂-s-茚并-8-基)-N-(3-(对甲苯氨基)丙基)丁酰胺]，这导致了放大的光致死亡率。通过共聚焦荧光显微镜评估，化合物1的细胞摄取显示该产物定位于细胞质中。
