Doubly Stimulated Corrole for Organelle-Selective Antitumor Cytotoxicity

Abstract

Balancing between safety and efficacy of cancer chemotherapeutics is achievable by relying on internal and/or external stimuli for selective and on-demand antitumor cytotoxicity. We now introduce the difluorophosphorus­(V) corrole PC-Im, a theranostic agent with a pH-sensitive N-methylimidazole moiety. Structure/activity relationships, via comparison with the permanently charged PC-ImM + and the lipophilic PC, uncovered the exceptional features of PC-Im: nanoparticular and monomeric at neutral and low pH, respectively, 10-fold increased light-induced singlet oxygen production at acidic pH, internalization into malignant cells within minutes, and selective accumulation within lysosomes. Submillimolar PC-Im concentrations are tolerable in the dark, while illumination induces nanomolar cytotoxic effects due to a multiplicity of cellular deleterious events: endoplasmic reticulum fragmentation, lysosome fusion and exocytosis, calcium leakage, mitochondrial fission, and swelling. PC-Im emerges as an antitumor agent, whose potency is triggered by endogenous and exogenous stimuli, assuring its cytotoxicity will occur selectively upon lysosomal accumulation and solely upon light activation.

Milestones in corrole chemistry: historical ligand syntheses and post-functionalization

“…18,62,63 Protonation, or rather the alkylation of the basic N atoms may also be used for inducing water-solubility, an approach exemplified by the ABA corrole, in which A stands for C 6 F 5 or CF 3 , and B stands for imidazolyl or N-methylimidazolyl, whose unique features are described later in this review (vide infra). 64,65 Recently, Caroleo and co-workers introduced the synthesis of compounds 13, 5,10,15-tris(4-trimethylsilylphenyl)dimethoxyl phosphorus corrole, as a precursor for the synthesis Scheme 9 Preparation of ABC corroles by the condensation of dipyrromethanedicarbinol with pyrroles.…”

“…18,62,63 Protonation, or rather the alkylation of the basic N atoms may also be used for inducing water-solubility, an approach exemplified by the ABA corrole, in which A stands for C 6 F 5 or CF 3 , and B stands for imidazolyl or N -methylimidazolyl, whose unique features are described later in this review ( vide infra ). 64,65…”

Oxido-Molybdenum(V) Corroles as Robust Catalysts for Oxidative Bromination and Selective Epoxidation Reactions in Aqueous Media under Mild Conditions

“…1−6 Metallocorroles are diverse in terms of structural and redox properties and exhibit enhanced chemical as well as thermal stability along with strong absorption in the visible spectral range. 7−11 Metallocorroles are very useful in dye-sensitized solar cells, 12,13 catalysis, 14 PDT, 15,16 chemical sensors, 17,18 and nonlinear optics 19,20 because of their customizable excitation and emission spectral features. 21−24 Epoxides are excellent synthons in organic synthesis and are useful as a fumigant to antifreeze compounds like ethylene glycol, assembling polymers (epoxies), adhesives in surface coatings, surfactants, detergents, structural materials, and stabilizers in PVC.…”

GaIIItriarylcorroles with push–pull substitutions: synthesis, electronic structure and biomedical applications

“…6 Corroles are porphyrin analogues that contain a direct pyrrole-pyrrole bond. [7][8][9][10] Their dye properties have attracted considerable interest in a wide variety of different fields, 10 including PDT 7,[11][12][13][14][15][16][17][18] and PACT. 19 Due to the smaller central cavity, the corrole ligand stabilizes higher valent central ions.…”

“…Pentafluorophenyldipyrromethane was reacted with 9-(4-formylphenyl)-3,6-ditert-butyl-9H-carbazole (C-1, G-1) and N-butyl-4-carbazole-3-carboxaldehyde (C-2, G-2), and the carbazole nitrogen atom of Ga III triarylcorrole G-2 was quaternized with methyl iodide to form a cationic species (G-2Q). The heavy atom effect of Ga III ion in the corrole cavity enhances the rate of intersystem crossing and hence the generation of singlet oxygen, 8,25 making the G-1 and G-2 dyes potentially suitable for use in biomedical applications such as PDT and PACT. The axial pyridine ligand and alkyl groups on the carbazole moieties are expected to limit aggregation effects.…”