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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 1.4 hours at 37 °C. Endoperoxide modification yields a significant improvement in cytotoxicity against MDR-cell lines, compared to both CPT and DM-CPT. It appears that the simultaneous action of singlet oxygen and CPT is highly effective due to the targeting of P-glycoprotein by singlet oxygen. [ABSTRACT FROM AUTHOR]

Cancer cells change their glucose metabolism towards lactic acid production for various defensive and proliferative advantages. Dichloroacetate (DCA) is an inhibitor of a key enzyme and thus, changes back the OX‐PHOS to glycolysis ratio. We designed and synthesized a singlet oxygen triggered source of dichloroacetate which releases this inhibitor during photodynamic singlet oxygen generation. Synergistic action of DCA and singlet oxygen results in significant enhancement of photocytotoxicity. The results suggest that this approach could offer significant improvement in the therapeutic outcome of PDT. [ABSTRACT FROM AUTHOR]

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. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3‐methyl‐N‐phenyl‐2‐pyridone for these two lung diseases, and triplet oxygen could downregulate HIF‐1α and relieve tumor hypoxia which is a critical issue in photodynamic therapy (PDT). Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases. [ABSTRACT FROM AUTHOR]

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. Here, we show that these compounds release singlet oxygen by thermal cycloreversion, and initiate cell death with IC50<10 μM in cancer cell cultures. The mouse 4T1 breast tumor model study, where the endoperoxide compound was introduced intraperitoneally, also showed highly promising results, with negligible systemic toxicity. Targeted delivery of singlet oxygen to cancer cell mitochondria could be the breakthrough needed to transform Photodynamic Therapy into a broadly applicable methodology for cancer treatment by keeping the central tenet and discarding problematic dependencies on oxygen or external light. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds. [ABSTRACT FROM AUTHOR]

Naphthalene endoperoxides are known as convenient sources of singlet oxygen (O2, 1Δg), which is the major product of endoperoxide cycloreversion reaction. However, their potential as carriers of ground‐state molecular oxygen (O2, 3Σg) similar to artificial oxygen carriers remains largely unexplored. This is due to the extreme reactivity and cytotoxic effects of the released singlet oxygen. We now report that a compound with a bimodular design, which incorporates an endoperoxide and an efficient physical quencher of singlet oxygen, 1,4‐diazabicyclo[2.2.2]octane (DABCO), produces exclusively ground‐state molecular oxygen. This result, coupled with the fact that oxygen release rates from endoperoxides are highly amenable to fine‐tuning in a very broad range, and open to targeting by ligand attachment, raises the potential of these compounds far above any comparable chemical, or even biochemical sources. In cell culture experiments, we showed that the addition of the endoperoxide‐quencher conjugate can enhance and sustain cell proliferation. [ABSTRACT FROM AUTHOR]

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. The endoperoxide form (BZTN-O2) of this compound, which releases singlet oxygen with a half-life of 77 minutes at 37 °C, successfully inhibited and/or reversed amyloid aggregation. The endoperoxide is capable of singlet oxygen release without any need for light, and its charge-neutral form could allow blood–brain barrier (BBB) permeability. The therapeutic potential of such endoperoxide compounds with amyloid binding affinity is exciting. [ABSTRACT FROM AUTHOR]

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. However, unlike typical photodynamic processes, there is no need for light or oxygen. The potential of the approach is exciting, considering the limitations on the availability of light and oxygen in deep-seated tumors. [ABSTRACT FROM AUTHOR]

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. The potential of this approach in advancing PDT beyond its current limits is exciting. [ABSTRACT FROM AUTHOR]

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. The potential utility of controlled singlet oxygen release was demonstrated in cell cultures. [ABSTRACT FROM AUTHOR]

The versatile chemistry of Bodipy dyes which facilitates the design and synthesis of multivalent-multitopic derivatives based on the selection of metal ion-ligand pairs to afford photoinduced electron transfer and internal charge transfer processes is reported. The different metal ions with careful design could selectively modulate diverse photophysical processes to result in a range of signals, useful in molecular logic design, and an interesting potential for multianalyte chemosensors.

The consequences of the modulation of energy transfer efficiency at the energy donor site are explored in a molecular design that has an ICT type metal ion-sensitive chromophore placed as the energy donor in the dyad. The studies have shown unaltered emission wavelength in the red end of the visible spectrum, while keeping a large Stokes shift and the ratiometric character.

The process of designing of ratiometric chemosensors requires magnitude of the range of signal ratios of emission intensities at two different wavelengths for the analyte free and analyte bound chemosensor. The feasibility of this approach is demonstrated by synthesizing a series of boradiazaindacene dyads with increasing interchromophoric distance and the specific dithiazacrown selected shows selectivity for Hg(II) ions in a range of solvents.

A general strategy for large pseudo-Stokes' shift, ratiometric chemosensors, utilizing efficient energy transfer is introduced. However, the synthesis is highly straightforward due to the symmetry of the precursor and in only one step, this symmetric precursor can be transformed into an efficient RET system where the choice of the ligand carrying aldehyde would determine the selectivity of the resulting chemosensor.

Among the pathways for improving the practice of photodynamic therapy of cancer, increasing the selectivity of photodynamic action is an obvious choice. Considering the different characteristics of mitochondria in normal cells and cancer cells, we designed mitochondria‐targeting photosensitizers. We now demonstrate for the first time that mitochondria‐targeted photosensitizers by triphenylphosphonium (TPP) derivatization are more selective for cancer cells compared to normal cells, presumably due to the larger membrane potential of cancer‐cell mitochondria allowing more efficient accumulation of the photosensitizer. Not all the same: A series of photosensitizers were synthesized in order to investigate the effectiveness of mitochondrial targeting. The results show not only that the photosensitizers are more effective against cancer cells compared to normal cells, but also that mitochondrial targeting results in an enhanced selectivity at low concentrations, suggesting a higher activity of mitochondria generated singlet oxygen. [ABSTRACT FROM AUTHOR]

The field of molecular logic gates originated 25 years ago, when A. P. de Silva published a seminal article in Nature. Stimulated by this ground breaking research, scientists were inspired to join the race to simulate the workings of the fundamental components of integrated circuits using molecules. The rules of this game of mimicry were flexible, and have evolved and morphed over the years. This tutorial review takes a look back on and provides an overview of the birth and growth of the field of molecular logics. Spinning-off from chemosensor research, molecular logic gates quickly proved themselves to be more than intellectual exercises and are now poised for many potential practical applications. The ultimate goal of this vein of research became clearer only recently – to “boldly go where no silicon-based logic gate has gone before” and seek out a new deeper understanding of life inside tissues and cells. [ABSTRACT FROM AUTHOR]

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 Zn2+-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 Zn2+ 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. This is the confirmatory signal of the cancer cell death by the action of molecular automaton and the confinement of unintended damage by excessive singlet oxygen production. [ABSTRACT FROM AUTHOR]

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. Despite the progress made in this field, several problems and challenges still exist. This tutorial review introduces the history and provides a general overview of the development in the research of fluorescent sensors, often referred to as chemosensors. This will be achieved by highlighting some pioneering and representative works from about 40 groups in the world that have made substantial contributions to this field. The basic principles involved in the design of chemosensors for specific analytes, problems and challenges in the field as well as possible future research directions are covered. The application of chemosensors in various established and emerging biotechnologies, is very bright. [ABSTRACT FROM AUTHOR]

Recent developments in the design of bifunctional and activatable photosensitizers rejuvenate the aging field of photodynamic sensitization and photodynamic therapy. While systematic studies have uncovered new dyes that can serve as potential photosensitizers, the most promising results have come from studies aimed at gaining precise control over the location and rate of cytotoxic singlet oxygen generation. As a consequence, higher selectivities and efficiencies in photodynamic treatment protocols are now within reach. This feature article highlights the variety of approaches that have been pursued to improve photodynamic therapy and to transform simple photosensitizers into smarter theranostic agents. [ABSTRACT FROM AUTHOR]

Results show that the fluorescent molecular sensor boradiazaindacene-appended calix[4]arene signals pH changes near neutral pH and two-thirds of its fluorescence enhancement occurs within the pH range of 8.2-5.6. Ten-fold or more pH change occurs at 509 nanometer emission intensity.

Research was conducted to examine a novel one-pot synthesis of squaraine fluoroionophores that provides an entry to derivatized squaraines using simple commercially available synthons. The general reactivity of phloroglucinol with secondary amines was used as the basis for the reaction through its keto tautomer. NMR spectroscopy provides evidence of the highly symmetrical nature of the squaraines and the existence of strong internal hydrogen bonding between the squaryl oxygens and ArOH.

Wie Lei Wang, Engin U. Akkaya et al. in ihrer Zuschrift berichten (e202210249), erweitert dieser Ansatz nicht nur das Spektrum der intrazellulären bioorthogonalen Reaktionen, sondern zeigt gleichzeitig einen neuen Weg auf, der zu selektiven therapeutischen Wirkstoffen mit präziser räumlich-zeitliche Zielansteuerung von Singulett-Sauerstoff führt. Apoptosis, Bioorthogonal, Endoperoxide, Hypoxia, Singlet Oxygen Keywords: Apoptosis; Bioorthogonal; Endoperoxide; Hypoxia; Singlet Oxygen EN Apoptosis Bioorthogonal Endoperoxide Hypoxia Singlet Oxygen 1 1 1 11/16/22 20221121 NES 221121 B Ein intrazellulärer bioorthogonaler b metabolischer Shunt verknüpft die reduzierte Sauerstoffkonzentration erfolgreich mit der Erzeugung von Singulett-Sauerstoff, wobei in einem Zwischenschritt Fluorid freigesetzt wird. [Extracted from the article]

Keywords: Apoptosis; Bioorthogonal; Endoperoxide; Hypoxia; Singlet Oxygen EN Apoptosis Bioorthogonal Endoperoxide Hypoxia Singlet Oxygen 1 1 1 11/16/22 20221121 NES 221121 B An intracellular bioorthogonal b metabolic shunt has been shown to successfully link reduced oxygen concentration to singlet oxygen generation with an intermediate fluoride releasing step. Back Cover: Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release (Angew. Apoptosis, Bioorthogonal, Endoperoxide, Hypoxia, Singlet Oxygen. [Extracted from the article]

The photodynamic therapy of cancer is contingent upon the sustained generation of singlet oxygen in the tumor region. However, tumors of the most metastatic cancer types develop a region of severe hypoxia, which puts them beyond the reach of most therapeutic protocols. More troublesome, photodynamic action generates acute hypoxia as the process itself diminishes cellular oxygen reserves, which makes it a self-limiting method. Herein, we describe a new concept that could eventually lead to a change in the 100 year old paradigm of photodynamic therapy and potentially offer solutions to some of the lingering problems. When gold nanorods with tethered endoperoxides are irradiated at 808 nm, the endoperoxides undergo thermal cycloreversion, resulting in the generation of singlet oxygen. We demonstrate that the amount of singlet oxygen produced in this way is sufficient for triggering apoptosis in cell cultures. [ABSTRACT FROM AUTHOR]

The photosensitized generation of singlet oxygen within tumor tissues during photodynamic therapy (PDT) is self-limiting, as the already low oxygen concentrations within tumors is further diminished during the process. In certain applications, to minimize photoinduced hypoxia the light is introduced intermittently (fractional PDT) to allow time for the replenishment of cellular oxygen. This condition extends the time required for effective therapy. Herein, we demonstrated that a photosensitizer with an additional 2-pyridone module for trapping singlet oxygen would be useful in fractional PDT. Thus, in the light cycle, the endoperoxide of 2-pyridone is generated along with singlet oxygen. In the dark cycle, the endoperoxide undergoes thermal cycloreversion to produce singlet oxygen, regenerating the 2-pyridone module. As a result, the photodynamic process can continue in the dark as well as in the light cycles. Cell-culture studies validated this working principle in vitro. [ABSTRACT FROM AUTHOR]

A series of pH and GSH responsive photosensitizers were designed and synthesized. pKa values were optimized by adjusting the inductive contribution of substituents to reach a pH range (6.0–7.4) relevant to the tumour microenvironment. pH-Activatable behaviour and redox mediated release of the quencher from the PS by GSH allow the construction of an AND logic operator for selective photodynamic action in aqueous solutions. [ABSTRACT FROM AUTHOR]