Seth Sourav Kanti, Acquah Chris, Levi Liraz, Jockusch Steffen, Crespo-Hernández Carlos E
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.
ACS Appl Bio Mater. 2025 Aug 18;8(8):7357-7369. doi: 10.1021/acsabm.5c01035. Epub 2025 Jul 24.
Nucleoside analogs simultaneously exhibiting high fluorescence quantum yields and efficient triplet state population are rare. Such multifunctional nucleosides represent a crucial advancement for cell imaging-assisted photodynamic therapy relying on heavy-atom-free photosensitizers and hold additional promises as inhibitors of cancer cell proliferation. This study investigates the photophysical, electronic structure, excited state dynamics, and skin cancer cell photodynamic and inhibitory properties of 5-(5-phenylthiophen-2-yl)-6-azauridine (PTAU). PTAU absorbs up to 425 nm and demonstrates dual photophysical characteristics, with fluorescence and singlet oxygen quantum yields of 43 ± 1% and 52 ± 2% in acetonitrile and 12 ± 1% and 33 ± 2% in aqueous buffer, respectively. Time-resolved absorption and fluorescence spectroscopy, complemented by quantum chemical calculations, reveal the existence of two rotameric species of PTAU in solution. Both rotamers exhibit nanosecond-scale fluorescence and intersystem crossing lifetimes, as well as microsecond-scale triplet decay lifetimes. When applied to B16F10 murine melanoma cells, PTAU localizes mostly in the cytoplasm, primarily in mitochondria, and demonstrates moderate photodynamic activity, achieving IC values of 125 ± 5 μM and 80 ± 3 μM at photoactivation doses of 7.5 J cm and 25 J cm, respectively, while exhibiting no cytotoxicity in the dark. Notably, PTAU also inhibits the cell proliferation of B16F10 murine melanoma and A431 human epidermoid carcinoma by more than 95% at a concentration of 250 μM in the dark. Therefore, this proof-of-concept study reveals PTAU as the first example of a nucleoside analog with potential multifunctional applications, including photodynamic action, bioimaging, and the inhibition of skin cancer cell proliferation. These findings pave the way for further developing next-generation modified 6-azauridine analogs absorbing visible to near-infrared light for their use as cell imaging-assisted PDT agents and cancer cell inhibitors, targeting potential deep-tissue cancer treatment.
同时具有高荧光量子产率和高效三线态布居的核苷类似物很少见。这类多功能核苷对于依赖无重原子光敏剂的细胞成像辅助光动力疗法而言是一项关键进展，并且作为癌细胞增殖抑制剂还有更多前景。本研究考察了5-(5-苯基噻吩-2-基)-6-氮杂尿苷（PTAU）的光物理性质、电子结构、激发态动力学以及对皮肤癌细胞的光动力和抑制特性。PTAU吸收波长可达425 nm，并表现出双重光物理特性，在乙腈中的荧光和单线态氧量子产率分别为43±1%和52±2%，在水性缓冲液中分别为12±1%和33±2%。时间分辨吸收和荧光光谱结合量子化学计算，揭示了溶液中PTAU存在两种旋转异构体。两种旋转异构体均表现出纳秒级的荧光和系间窜越寿命，以及微秒级的三线态衰减寿命。当应用于B16F10小鼠黑色素瘤细胞时，PTAU主要定位于细胞质中，主要在线粒体中，并表现出适度的光动力活性，在光激活剂量分别为7.5 J/cm²和25 J/cm²时，IC值分别为125±5 μM和80±3 μM，而在黑暗中无细胞毒性。值得注意的是，在黑暗中，PTAU在250 μM浓度下也能抑制B16F10小鼠黑色素瘤和A431人表皮样癌细胞的增殖超过95%。因此，这项概念验证研究揭示了PTAU是首个具有潜在多功能应用的核苷类似物实例，包括光动力作用、生物成像以及抑制皮肤癌细胞增殖。这些发现为进一步开发吸收可见光至近红外光的下一代修饰6-氮杂尿苷类似物铺平了道路，这些类似物可作为细胞成像辅助光动力疗法药物和癌细胞抑制剂，用于潜在的深部组织癌症治疗。
