Modulating Photostability and Mitochondria Selectivity in Far-Red/NIR Emitting Coumarin Fluorophores through Replacement of Pyridinium by Pyrimidinium

Abstract

Mitochondrial dysfunction has been associated with several human pathologies, including cancer, aging and neurodegenerative diseases. Thus, the availability of selective fluorescent probes for mitochondria could play an important role in the future for monitoring cellular function and disease progression. In this work, we have studied how the photophysical properties and subcellular accumulation of nonconventional coumarin-based COUPY fluorophores can be fine-tuned through replacement of the para-pyridinium moiety with several heterocycles. Among them, ortho,para-pyrimidinium substitution provided novel fluorophores with suitable photophysical properties for bioimaging applications, including emission in the far-red to NIR region, large Stokes' shifts and high photostability.Furthermore, the compounds exhibited excellent cell membrane permeability in living cells and a higher selectivity for mitochondria compared with the parent COUPY fluorophores.Overall, these results provide useful insights for the development of novel mitochondriatargeted fluorescent probes based on small organic molecules, since higher selectivity for this organelle can be achieved through the replacement of conventional N-alkylated pyridinium moieties by the corresponding N-alkylated-ortho,para-pyrimidinium counterparts.

Fluorescently Labeled Ceramides and 1-Deoxyceramides: Synthesis, Characterization, and Cellular Distribution Studies

“…As detailed in Table , COUPY-labeled probes exhibited excellent fluorescent quantum yields (Φ F ) both in nonpolar solvents (∼0.7 in CH 2 Cl 2 ) and in polar solvents (∼0.4 in CH 3 CN and ∼0.5 in CH 3 OH), comparable to those of the parental N -methylpyridinium COUPY dye (Φ F = 0.70 in CH 2 Cl 2 , Φ F = 0.18 in CH 3 CN, Φ F = 0.45 in EtOH) . The two BODIPY-labeled derivatives also exhibited excellent Φ F values, albeit slightly lower than their COUPY-labeled counterparts, irrespective of solvent polarity (0.47–0.65).…”

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

“…Coumarins 1–14 were synthesized following previously reported procedures − Coumarin 15. 1-Bromohexane (600 μL, 4.3 mmol) was added to a solution of coumarin 8 (150 mg, 0.45 mmol) in anhydrous ACN (15 mL).…”

“…Hence, mitochondria-targeted theranostic agents are highly attractive compounds for both cancer diagnosis and therapy. − Recently, we have developed a new family of low-molecular-weight coumarins (COUPYs) in which the carbonyl group of the lactone function of the classical coumarin scaffold was replaced by the cyano­(4-pyridine/pyrimidine)­methylene moieties (Figure ). − In addition to having attractive photophysical and physicochemical properties for bioimaging and caging applications (e.g., emission in the far-red/NIR region, large Stokes’ shifts, brightness and high photostability, and aqueous solubility), N-alkylated COUPY coumarins exhibit excellent cell membrane permeability in living cells and accumulate preferentially in mitochondria and, to a lesser extent, in nucleoli and in intracellular vesicles. Mitochondria selectivity can be attributed to the lipophilic positively charged N-alkyl pyridinium/pyrimidinium moieties in the coumarin scaffold, which exploit the negative potential across the outer and inner mitochondrial membrane.…”

Tunable Naphthalimide/Cinnoline‐Fused (CinNapht) Hybrid Dyes for Fluorescence Imaging in Living Cells

“…[7] In this context, combining a stokes shift enhancement with a redshift of the absorption and emission wavelengths is one of the most addressed topics. [8] Multiple approaches have been implemented for this purpose, as clearly explains by Yuan's group. [9] Possible approaches consist of either introducing alternating vibronic structures or extending the polyaromatic system's conjugation of existing structures, for example, by elaborating fused hybrid fluorophores.…”