We report corroles as good agents for utilizing the otherwise harmless sonication of aqueous solutions as a tool for creating highly cytotoxic singlet oxygen, and demonstrate cancer cell killing via this approach.
Chlorophyll
special pairs in photosynthetic reaction centers function
as both exciton acceptors and primary electron donors. Although the
macrocyclic natural pigments contain Mg(II), the central metal in
most synthetic analogs is Zn(II). Here we report that insertion of
either Al(III) or Ga(III) into an imidazole-substituted corrole affords
an exceptionally robust photoactive dimer. Notably, attractive electronic
interactions between dimer subunits are relatively strong, as documented
by signature changes in NMR and electronic absorption spectra, as
well as by cyclic voltammetry, where two well-separated reversible
redox couples were observed. EPR spectra of one-electron oxidized
dimers closely mimic those of native special pairs, and strong through-space
interactions between corrole subunits inferred from spectroscopic
and electrochemical data are further supported by crystal structure
analyses (3 Å interplanar distances, 5 Å lateral shifts,
and 6 Å metal to metal distances).
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.
Heme-like metal-chelating macrocycles, including expanded and contracted porphyrins, are of everlasting interest as drug candidates for numerous diseases. Still, all reported corrole derivatives (and most other heme analogues) do not fulfill the most basic standards expected for oral drug administration: a combination of low molecular weight and reasonable water solubility. We now disclose a very straightforward synthetic method that relies on surprisingly facile trifluoromethyl hydrolysis for gaining access to a new class of corroles that do satisfy all druglikeness criteria. The relevance is briefly exemplified for the iron corroles by demonstrating the ability to affect their association with plasma proteins and their performance for catalase-like decomposition of hydrogen peroxide.
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