Quinoline Endoperoxides for Mitochondria Targeted Singlet Oxygen Delivery.

Controlled release of singlet oxygen from chemical sources is becoming an interesting path for eliciting apoptotic death of cancer cells. In this work, we present the synthesis and characterization of hitherto unknown class of aromatic endoperoxides, namely quinoline endoperoxides. Quinolines, especially after quaternization, show significant targeting of mitochondria.

Overcoming multidrug resistance by a singlet oxygen releasing camptothecin-endoperoxide.

We made structural modifications on the A-ring of camptothecin (CPT) by incorporating methyl substituents on positions 9 and 12. This allows conversion of the camptothecin-derivative to an endoperoxide (ENDO-CPT). The endoperoxide obtained this way thermally releases singlet oxygen, reverting back to the original 9,12-dimethylcamptothecin (DM-CPT) with a half-life of 1.

Singlet Oxygen-Triggered Release of Nitric Oxide in an Endoperoxide-Arginine Conjugate.

Nitric oxide (NO) is an important signaling molecule in both healthy and pathological processes. In this work, we present the first example of a novel class of organic NO-donor compounds with minimal toxicity. The release is driven by the reaction of singlet oxygen spontaneously produced by the cycloreversion reaction of the endoperoxide.

Self-reporting intracellular delivery agent for singlet oxygen.

1,4-Dimethylphenazine endoperoxide releases singlet oxygen with a half-life of 89 hours at 37 °C. The thermal cycloreversion reaction is accompanied by a strong increase in the emission intensity with a peak at 490 nm, due to the formation of the phenazine core. The endoperoxide is effective against cancer cells in culture medium and tumor spheroids, with singlet oxygen-mediated cytotoxicity.

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits the transforming growth factor β1 (TGF-β1) induced fibrosis in vitro.

Targeted Endoperoxides Delivering Singlet Oxygen to Cancer Cell Mitochondria: Exploration of the Therapeutic Potential.

The clinical practice of photodynamic therapy of cancer (PDT) is mostly limited to superficial types of cancer. The major reason behind this limited applicability is the need for light in the photogeneration of ROS, and in particular singlet oxygen. In order to circumvent this major roadblock, we designed and synthesized naphthalene-derived endoperoxides with mitochondria targeting triphenylphosphonium moieties.

Upconverting Nanoparticle-Based Photoactive Probes for Highly Efficient Labeling and Isolation of Target Proteins.

Photoaffinity labeling (PAL) has blossomed into a powerful and versatile tool for capture and identification of biomolecular targets. However, low labeling efficiency for specific targets such as lectins, the tedious process for protein purification, inevitable cellular photodamage, and less tissue penetration of UV light are significant challenges. Herein, we reported a near-infrared (NIR) light-driven photoaffinity labeling approach using upconverting nanoparticle (UCNP)-based photoactive probes, which were constructed by assembling photoactive groups and ligands onto NaYF:Yb,Tm nanoparticles.

Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release.

Singlet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride-triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role.

Silyl-naphthalene endoperoxides as switchable sources of singlet oxygen for bactericidal activity.

Singlet oxygen is a short half-life cytotoxic agent which can be generated by chemical and photochemical methods. In order to make use of its antibacterial action at a selected location, it is desirable to have singlet oxygen in a relatively stable, "caged" structure, in the form of an endoperoxide. Here, the trimethylsilyl (TMS) group supplies the steric bulk, inhibiting the cycloreversion reaction to produce very little singlet oxygen under ambient conditions.

Anticoagulant activity of singlet oxygen released from a water soluble endoperoxide by thermal cycloreversion.

Singlet oxygen generated by photosensitization has limited potential due to light attenuation in tissues. However, controlled chemical generation of this reactive oxygen species is likely to open new therapeutic spaces to explore. The fact that its activity is limited by the rate of cycloreversion reaction and the diffusion distance of the excited state molecular oxygen species, is a clear advantage, considering the serious side effects of off-target anticoagulants.

Taming of Singlet Oxygen: Towards Artificial Oxygen Carriers Based on 1,4-Dialkylnaphthalenes.

Naphthalene endoperoxides are known as convenient sources of singlet oxygen (O , Δ ), which is the major product of endoperoxide cycloreversion reaction. However, their potential as carriers of ground-state molecular oxygen (O , Σ ) similar to artificial oxygen carriers remains largely unexplored. This is due to the extreme reactivity and cytotoxic effects of the released singlet oxygen.

Degradation of amyloid peptide aggregates by targeted singlet oxygen delivery from a benzothiazole functionalized naphthalene endoperoxide.

Aggregate structures formed by amyloid-β (Aβ) are correlated with the progression of pathogenesis in Alzheimer's disease. Previous works have shown that photodynamic photosensitizers were effective in oxidatively degrading amyloid-β aggregates and thus decreasing their cytotoxicity under various conditions. In this work, we designed and synthesized a benzothiazole-naphthalene conjugate, with high level of structural analogy to Thioflavin T which is known to have high affinities for the amyloid peptide aggregates.

Prostate-specific membrane antigen (PSMA) targeted singlet oxygen delivery endoperoxide tethered ligands.

Singlet oxygen is the primary agent responsible for the therapeutic effects of photodynamic therapy (PDT). In this work, we demonstrate that singlet oxygen release due to thermal endoperoxide cycloreversion can be targeted towards specific features of selected cancer cells, and this targeted singlet oxygen delivery can serve as an effective therapeutic tool. Thus, cytotoxic singlet oxygen can be delivered regioselectively into prostate specific membrane antigen (PSMA) overexpressing lymph node carcinoma (LNCaP) cells.

Naphthalene Endoperoxide Heterodimer Designed for Sustained Singlet Oxygen Release.

Naphthalene endoperoxides undergo thermal cycloreversion reactions to produce singlet oxygen and their parent naphthalene compounds. The rate of the reaction is dependent on the structural features, such as steric and electronic modulators. We believe that achieving a sustained release rate of singlet oxygen is important in potential biological applications.

Proof-of-principle for two-stage photodynamic therapy: hypoxia triggered release of singlet oxygen.

We propose to overcome oxygen deficiency and light attenuation problems in photodynamic therapy (PDT), by separating photoexcitation and singlet oxygen delivery of the PDT process into two distinct operations to be carried out sequentially, at different locations. We now demonstrate the viability of this approach, using 2-pyridone derivative which yields a relatively stable endoperoxide. The initial storage endoperoxide obtained is transformed enzymatically into a more labile compound when placed in hypoxic cell cultures, and releases singlet oxygen significantly faster.

Mechanochemical generation of singlet oxygen.

Controlled generation of singlet oxygen is very important due to its involvement in scheduled cellular maintenance processes and therapeutic potential. As a consequence, precise manipulation of singlet oxygen release rates under mild conditions, is crucial. In this work, a cross-linked polyacrylate, and a polydimethylsiloxane elastomer incorporating anthracene-endoperoxide modules with chain extensions at the 9,10-positions were synthesized.

"Off-on" switching of intracellular singlet oxygen release under biocompatible conditions.

Precise spatiotemporal control of singlet oxygen generation is of immense importance considering its involvement in photodynamic therapy. In this work, we present a rational design for an endoperoxide which is highly stable at ambient temperatures yet, can rapidly be converted into a highly labile endoperoxide, thus releasing the "stored" singlet oxygen on demand. The "off-on" chemical switching from the stable to the labile form is accomplished by the reaction with fluoride ions.

Energy Harvesting in a Bodipy-Functionalized Rotaxane.

A rotaxane composed of two separate Bodipy-functionalized units can be synthesized with a high yield. The resulting structure shows a very efficient through-space energy transfer (FRET), acting as an energy funnel. Thus, maximum solar output in the visible region can be collected and converted into red light, which can be transformed efficiently with a fine-tuned photovoltaic device.

Molecular logic gates: the past, present and future.

The field of molecular logic gates originated 25 years ago, when A. P. de Silva published a seminal article in Nature.

Molecular demultiplexer as a terminator automaton.

Molecular logic gates are expected to play an important role on the way to information processing therapeutic agents, especially considering the wide variety of physical and chemical responses that they can elicit in response to the inputs applied. Here, we show that a 1:2 demultiplexer based on a Zn-terpyridine-Bodipy conjugate with a quenched fluorescent emission, is efficient in photosensitized singlet oxygen generation as inferred from trap compound experiments and cell culture data. However, once the singlet oxygen generated by photosensitization triggers apoptotic response, the Zn complex then interacts with the exposed phosphatidylserine lipids in the external leaflet of the membrane bilayer, autonomously switching off singlet oxygen generation, and simultaneously switching on a bright emission response.

Fluorescent chemosensors: the past, present and future.

Fluorescent chemosensors for ions and neutral analytes have been widely applied in many diverse fields such as biology, physiology, pharmacology, and environmental sciences. The field of fluorescent chemosensors has been in existence for about 150 years. In this time, a large range of fluorescent chemosensors have been established for the detection of biologically and/or environmentally important species.

Amplified Chemiluminescence Signal for Sensing Fluoride Ions.

Bringing together the concepts of self-immolative linkers and chemiluminogen dioxetane modules, a chemiluminescence-based sensor for fluoride with signal amplification is presented. Signal amplification is obtained by triggering two chemiluminescence events for each reacting fluoride ion that in turn releases two fluoride ions for each ion. As expected, the chemiluminescence signal starts to rise following an induction period.

Singlet Oxygen Generation with Chemical Excitation of an Erythrosine-Luminol Conjugate.

Chemical generation of singlet oxygen under biologically relevant conditions is very important, considering the role played by singlet oxygen in cancer therapeutics. We now demonstrate that a luminol derivative can be chemically excited and transfer the excitation energy to the covalently attached photosensitizer derived from erythrosin. A photosensitizer module, when excited in this manner, can generate singlet oxygen in solution.

Catalytic Conversion of Lipophilic Substrates by Phase constrained Enzymes in the Aqueous or in the Membrane Phase.

Both soluble and membrane-bound enzymes can catalyze the conversion of lipophilic substrates. The precise substrate access path, with regard to phase, has however, until now relied on conjecture from enzyme structural data only (certainly giving credible and valuable hypotheses). Alternative methods have been missing.