COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

Abstract

Photodynamic therapy (PDT) for cancer treatment has drawn increased attention over the last decades. Herein, we introduce a novel family of low-molecular-weight coumarins as potential PDT anticancer tools. Through a systematic study with a library of 15 compounds, we have established a detailed structure–activity relationship rationale, which allowed the selection of three lead compounds exhibiting effective in vitro anticancer activities upon visible-light irradiation in both normoxia and hypoxia (phototherapeutic indexes up to 71) and minimal toxicity toward normal cells. Acting as excellent theranostic agents targeting mitochondria, the mechanism of action of the photosensitizers has been investigated in detail in HeLa cells. The generation of cytotoxic reactive oxygen species, which has been found to be a major contributor of the coumarins’ phototoxicity, and the induction of apoptosis and/or autophagy have been identified as the cell death modes triggered after irradiation with low doses of visible light.

Improving Photodynamic Therapy Anticancer Activity of a Mitochondria-Targeted Coumarin Photosensitizer Using a Polyurethane–Polyurea Hybrid Nanocarrier

“…Similarly, Manders’ coefficients were quite high in both compounds ( M 1, M 2 = 0.89 for COUPY 2 ; M 1 = 0.83, M 2 = 0.95 for NC-COUPY-2 ). As previously found with COUPY 2 alone, 31 the mitochondria of HeLa cells after incubation with NC-COUPY-2 showed a characteristic donut-shaped morphology after excitation with the laser beam of the microscope ( Figure S19 ), which point out to the mitochondria stress and could be related with ROS generation upon light irradiation. 42 …”

“…The fact that this process was slightly more efficient when the coumarin was encapsulated (Φ Δ = 0.04 for NC-COUPY 2 vs Φ Δ = 0.02 for COUPY 2 ) suggests that nanoencapsulation in a hydrophobic environment has a positive effect on type II PDT photochemical reactions, leading to the generation of singlet oxygen. This conclusion is supported by the fact that the singlet oxygen production for the free coumarin 2 was much more efficient in DCM (Φ Δ = 0.11) 31 than in EtOH/H 2 O 1:1 (v/v) (Φ Δ = 0.02).…”

“…A detailed setup for hypoxia experiments has been previously described. 31 Serial dilutions of the compounds (final DMSO % below 0.4) or nanoparticles (water-diluted) were added at the final concentrations in the range of 0 to 200 μM in a final volume of 100 μL per well. The treatment schedule was performed as follows: 0.5 h incubation in the dark followed by 1 h incubation under irradiation conditions by placing the photoreactor EXPO-LED from LuzChem (Canada) fitted with white lamps (final light intensity applied of 3 mW/cm 2 at λ max = 520 nm; 2.6 mW/cm 2 at λ max = 595 nm) inside the CO 2 incubator.…”

“… 30 Recently, we have investigated structure–activity relationships (SAR) within the COUPY scaffold and identified several PS candidates whose phototoxicity was related with ROS generation, even under hypoxia. 31 Among them, COUPY derivatives 1 and 2 ( Figure 1 ) were able to promote cell death both by apoptosis and autophagy induction after visible light irradiation and showed good phototherapeutic indexes. In this work, we have successfully encapsulated coumarin 2 in polyurethane-polyurea hybrid NCs and demonstrated that key parameters for bioimaging applications and photostability were significantly improved.…”

Photocaged Activity-Based Probes for Spatiotemporal Detection of Protein S-sulfenylation in Living Cells

“…As mentioned above, the poor solubility of DYn-2-Cou can be one reason. Phototoxicity might be another reason for its low labelling ability in living cells, since multiple studies have shown coumarin-containing reagents are toxic under irradiation [31], [32]. We evaluated cell viability with MTT assay.…”