Development of 5-(5-Phenylthiophen-2-yl)-6-Azauridine as a Three-Prong Agent for Photodynamic Therapy, Cell Imaging, and Cancer Cell Inhibition

The development of DNA and RNA nucleobase analogs as potential photodynamic therapy and cell imaging agents represents a significant breakthrough for prospective clinical applications relying on metal-free photosensitizers. The ability of these nucleobase analogs to inhibit cancer cell growth would add another dimension of sophistication and versatility. This study investigates the photophysical, electronic-structure, excited state dynamics, and cancer cell photodynamic and inhibitory properties of 5-(5-phenylthiophen-2-yl)-6-azauridine (PTAU). PTAU absorbs up to 425 nm and exhibits an intersystem crossing lifetime of 2.6 ± 0.2 ns in acetonitrile. Intersystem crossing leads to the population of a long-lived triplet state, which decays in 2.4 ± 0.3 µs. Furthermore, PTAU has fluorescence and singlet oxygen quantum yields of 43 ± 1% and 52 ± 2% in acetonitrile, and 12 ± 1% and 33 ± 2% in aqueous phosphate buffer solution, respectively. When applied to B16F10 murine melanoma cell lines, PTAU localizes primarily in mitochondria and exhibits excellent photodynamic efficacy with an IC50 of 125 ± 5 µM at a low dose of 5 J cm-2 of photoactivation. No dark toxicity is observed. Notably, PTAU also inhibits cell proliferation of B16F10 murine melanoma and A431 human epidermoid carcinoma by more than 95% at a concentration of 250 µM in the absence of light. Therefore, PTAU stands out as the first DNA/RNA nucleobase derivative capable of acting as a multipurpose agent for photodynamic therapy, bioimaging, and inhibition of cancer cell proliferation. These findings pave the way for developing modified 6-azauridine analogs absorbing visible to infrared light for their use as cell imaging-assisted PDT agents and cancer cell inhibitors.