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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. Cell culture and imaging data confirms the release of NO in this bimodular system. [ABSTRACT FROM AUTHOR]

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. This leads to more effective cytotoxicity in cancer cell cultures suggesting a potential utility in cancer therapy. [ABSTRACT FROM AUTHOR]

An imine-based nanoscale COF has been synthesized and functionalized with a pyridone-derived structure to create a singlet oxygen-storing nanoplatform, which can continuously produce and release singlet oxygen to realize "afterglow" photodynamic therapy. [Display omitted] Photodynamic therapy (PDT) is an emerging treatment but often restricted by the availability of oxygen. Enhancing the lifespan of singlet oxygen (1O 2) by fractionated generation is an effective approach to improve the efficacy of PDT. Herein, an imine-based nanoscale COF (TpDa-COF) has been synthesized and functionalized with a pyridone-derived structure (Py) to create a 1O 2 -storing nanoplatform TpDa-COF@Py, which can reversibly capture and release 1O 2. Under 660 nm laser exposure, Py interacts with 1O 2 produced by the porphyrin motif in COF backbones to generate 1O 2 -enriched COF (TpDa-COF@Py + hv), followed by the release of 1O 2 through retro -Diels-Alder reactions at physiological temperatures. The continuous producing and releasing of 1O 2 upon laser exposure leads to an "afterglow" effect and a prolonged 1O 2 lifespan. In vitro cytotoxicity assays demonstrates that TpDa-COF@Py + hv exhibits an extremely low half-maximal inhibitory concentration (IC 50) of 0.54 µg/mL on 4T1 cells. Remarkably, the Py-mediated TpDa-COF@Py nanoplatform demonstrates enhanced cell-killing capability under laser exposure, attributed to the sustained 1O 2 cycling, compared to TpDa-COF alone. Further in vivo assessment highlights the potential of TpDa-COF@Py + hv as a promising strategy to enhance phototheronostics and achieve effective tumor regression. Accordingly, the study supplies a generalized 1O 2 "afterglow" nanoplatform to improve the effectiveness of PDT. [ABSTRACT FROM AUTHOR]

The coastal region of the Caribbean is notable for the chemical diversity found in its sponge products, resulting in the biosynthesis of a range of natural marine products, including polyketides. The objective of this manuscript is to summarize the isolated polyketides from sponges of the genus Plakortis located around the Caribbean coasts. This review provides a comprehensive overview of specimen location, isolation procedures, characterization methods, and biological assay studies of about 95 polyketides isolated from 1978 to 2024 in the Caribbean coasts of The Bahamas, Cayman Islands, Belize, Dominica, Jamaica, Martinique, Panamá, Puerto Rico, and Tobago. The Caribbean polyketides have been isolated from different types of Plakortis sp., such as P. simplex, P. halichondroides, P. zyggompha, and P. angulospiculatus, which have demonstrated antimicrobial, anticancer, anti-inflammatory, antiparasitic, and antiviral activities. A variety of linear polyketides with different functionalities have been reported, including endoperoxides (1,2-dioxane), lactones, indane-type bicyclics (spiculane and zyggomphic), alcohols, alkenes, styryl groups, α,β-unsaturated carboxylic acids, and ketones, as well as related natural products of biosynthetic origin. The aim is to encourage further exploration by researchers in the Caribbean's coastal marine environments, promoting the discovery and investigation of novel polyketide cyclic peroxides and related secondary metabolites to identify additional bioactive medicinal natural products. [ABSTRACT FROM AUTHOR]

Abstract Metastable endoperoxides with beta‐amyloid fibrils targeting benzothiazole moieties were designed and synthesized. Singlet oxygen released from these endoperoxides by thermal cycloreversion reaction was shown to cause significant structural changes on the amyloid assemblies. Most importantly, the cytotoxicity of the beta‐amyloid fibrils on the PC12 cells were significantly reduced in the presence of endoperoxides. This observation, coupled with the fact that neither external oxygen, nor light is needed for this transformation, is very promising.

Tumor hypoxia severely limits the therapeutic efficacy of photodynamic therapy (PDT) for solid tumors, which is highly dependent on tissue oxygen concentration. In this study, we developed a platinum(II)-acetylide-based metallacycle compound bearing six 1,4-dimethylnaphthalenes (DMN) groups, and controlled the photodynamic and photothermal effects of the compound by adjusting the power of 730 nm laser to achieve reversible sensitization, storage and release of 1O2 within a single molecule. The compound formed nanoparticles by self-assembly and exhibited good water solubility and biocompatibility. Under laser irradiation, the strong spin-orbit coupling of platinum atoms in the metallacycle facilitated 1O2 generation. The produced 1O2 was captured by the DMN carriers and transported into the hypoxic tumor, where 1O2 release was triggered owing to the good photothermal effect of the extended conjugation of the metallacycle. During therapy, the metallacycle serving as a photosensitizer, 1O2 carrier, and photothermal reagent, achieved the synergistic therapy of PDT/PTT, demonstrating the versatility of the metallacycle. This study proposes a new strategy to develop phototherapy agents that are suitable for hypoxic tumors. [ABSTRACT FROM AUTHOR]

The high‐resolution X‐ray crystal structure of the ternary complex FtmOx1 ⋅ 2OG ⋅ fumitremorgin B and the catalytic mechanism were recently reported by us (DOI 10.1002/anie.202112063). In their Correspondence, Zhang, Costello, Liu et al. criticize our work in several aspects. Herein, we address these questions one by one. These structural clarifications and new computational results further support the CarC‐like mechanistic model. [ABSTRACT FROM AUTHOR]

In their recent Angewandte Chemie publication (doi: 10.1002/anie.202112063), Cen, Wang, Zhou et al. reported the crystal structure of a ternary complex of the non‐heme iron endoperoxidase FtmOx1 (PDB entry 7ETK). The biochemical data assessed in this study were from a retracted study (doi: 10.1038/nature15519) by Zhang, Liu, Zhang et al.; no additional biochemical data were included, yet there was no discussion on the source of the biochemical data in the report by Cen, Wang, Zhou et al. Based on this new crystal structure and subsequent QM/MM‐MD calculations, Cen, Wang, Zhou et al. concluded that their work provided evidence supporting the CarC‐like mechanistic model for FtmOx1 catalysis. However, the authors did not accurately describe either the CarC‐like model or the COX‐like model, and they did not address the differences between them. Further, and contrary to their interpretations in the manuscript, the authors' data are consistent with the COX‐like model once the details of the CarC‐like and COX‐like models have been carefully analyzed. [ABSTRACT FROM AUTHOR]

Energy transfer to ground state triplet molecular oxygen results in the generation of singlet molecular oxygen (1O2), which has potent oxidizing ability. Irradiation of light, notably ultraviolet A, to a photosensitizing molecule results in the generation of 1O2, which is thought to play a role in causing skin damage and aging. It should also be noted that 1O2 is a dominant tumoricidal component that is generated during the photodynamic therapy (PDT). While type II photodynamic action generates not only 1O2 but also other reactive species, endoperoxides release pure 1O2 upon mild exposure to heat and, hence, are considered to be beneficial compounds for research purposes. Concerning target molecules, 1O2 preferentially reacts with unsaturated fatty acids to produce lipid peroxidation. Enzymes that contain a reactive cysteine group at the catalytic center are vulnerable to 1O2 exposure. Guanine base in nucleic acids is also susceptible to oxidative modification, and cells carrying DNA with oxidized guanine units may experience mutations. Since 1O2 is produced in various physiological reactions in addition to photodynamic reactions, overcoming technical challenges related to its detection and methods used for its generation would allow its potential functions in biological systems to be better understood. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) for cancer treatment has garnered tremendous attention with its promising non‐invasiveness, low side effects, and spatiotemporal selectivity. However, the hypoxic microenvironment in solid tumours remains a serious resistant factor to reducing the effects of PDT. Endoperoxides are successfully utilized as the chemical storage or supplier of singlet oxygen (1O2), the active substance for PDT in materials and other domains. Recent reports indicated that this type of compound could remarkably enhance the therapeutic effects of PDT under hypoxia. This concept mainly introduces a few representative endoperoxides and the outlook of their potent application for treating hypoxic cancer cells. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogPOW larger than 3.5 and a polar surface area smaller than 100 Å2. The most effective compounds (IC50 in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models. [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]

A major research topic consists of revealing the contribution of radical‐mediated reactions in dermatological diseases related to xenobiotic‐induced stress to succeed risk‐assessment procedures protecting producers and consumers. Allergic contact dermatitis is the clinically relevant consequence of skin sensitization, one of the most critical occupational and environmental health issues related to xenobiotics exposure. The first key event identified for the skin sensitization process to a chemical is its aptitude to react with epidermal proteins and form antigenic structures that will further trigger the immune response. Many chemical sensitizers are suspected to react through mechanisms involving radical intermediates. This review focuses on the recent progress we have accomplished over the last few years studying radical intermediates derived from skin‐sensitizing chemicals by electron paramagnetic resonance in combination with the spin‐trapping technique. Our work is carried out "from the molecule", performing studies in solution, "to the tissue", by the development of a methodology on a reconstructed human epidermis model, very close in terms of histology and metabolic/enzymatic activity to real human epidermis, that can be used as suitable biological tissue model. The benefits are to test chemicals under conditions close to human use and real‐life sensitization exposures and benefit from the three‐dimensional (3D) microenvironment. [ABSTRACT FROM AUTHOR]

The 2‐oxoglutarate (2OG)‐dependent non‐heme enzyme FtmOx1 catalyzes the endoperoxide biosynthesis of verruculogen. Although several mechanistic studies have been carried out, the catalytic mechanism of FtmOx1 is not well determined owing to the lack of a reliable complex structure of FtmOx1 with fumitremorgin B. Herein we provide the X‐ray crystal structure of the ternary complex FtmOx1⋅2OG⋅fumitremorgin B at a resolution of 1.22 Å. Our structures show that the binding of fumitremorgin B induces significant compression of the active pocket and that Y68 is in close proximity to C26 of the substrate. Further MD simulation and QM/MM calculations support a CarC‐like mechanism, in which Y68 acts as the H atom donor for quenching the C26‐centered substrate radical. Our results are consistent with all available experimental data and highlight the importance of accurate complex structures in the mechanistic study of enzymatic catalysis. [ABSTRACT FROM AUTHOR]

Controlled release of singlet oxygen is of interest not only to chemists, but also to biologists and medics involved in cancer therapy. Two chiral polyaza macrocyclic compounds and their corresponding endoperoxides have been synthesized. These peroxides exhibit high temperature stability, up to 80 °C. Detailed studies on their structure, including X‐ray analysis as well as NMR, UV‐VIS ECD spectroscopy and theoretical calculations, combined with photochemical measurements indicate that their high stability is related to the arrangement of oxygen atoms in a conformationally stable macrocyclic ring. Despite the change of carbon hybridization from sp2 to sp3 at the 9 and 10 positions of the anthracene units, the macrocyclic skeleton of the obtained compounds does not change its conformation. The obtained endoperoxides can be formed and release singlet oxygen by irradiation with UV light of 365 and 275 nm, respectively. Release of the oxygen does not degrade the macrocyclic structure. [ABSTRACT FROM AUTHOR]

The discovery of artemisinin, an endoperoxide, encouraged the scientific community to explore endoperoxides as potential anti-parasitic molecules. Although artemisinin derivatives are rapidly evolving as potent anti-malarials, their potential as anti-leishmanials is emerging gradually. The treatment of leishmaniasis, a group of neglected tropical diseases is handicapped by lack of effective vaccines, drug toxicities and drug resistance. The weak antioxidant defense mechanism of the Leishmania parasites due to lack of catalase and a selenium dependent glutathione peroxidase system makes them vulnerable to oxidative stress, and this has been successful exploited by endoperoxides. The study aimed to review the available literature on the anti-leishmanial efficacy of natural endoperoxides with a view to achieve insights into their mode of actions. We reviewed more around 110 research and review articles restricted to the English language, sourced from electronic bibliographic databases including PubMed, Google, Web of Science, Google scholar etc. Natural endoperoxides could potentially augment the anti-leishmanial drug library, with artemisinin and ascaridole emerging as potential anti-leishmanial agents. Due to higher reactivity of the cyclic peroxide moiety, and exploiting the compromised antioxidant defense of Leishmania , endoperoxides like artemisinin and ascaridole potentiate their leishmanicidal efficacy by creating a redox imbalance. Furthermore, these molecules minimally impair oxidative phosphorylation; instead inhibit glycolytic functions, culminating in depolarization of the mitochondrial membrane and depletion of ATP. Additionally, the carbon-centered free radicals generated from endoperoxides, participate in chain reactions that can generate even more reactive organic radicals that are toxic to macromolecules, including lipids, proteins and DNA, leading to cell cycle arrest and apoptosis of Leishmania parasites. However, the precise target(s) of the toxic free radicals remains open-ended. In this overview, the spectrum of natural endoperoxide molecules as major anti-leishmanials and their mechanism of action has been delineated. In view of the substantial evidence that natural endoperoxides (e.g., artemisinin, ascaridole) exert a noxious effect on different species of Leishmania, identification and characterization of other natural endoperoxides is a promising therapeutic option worthy of further pharmacological consideration. [ABSTRACT FROM AUTHOR]

A covalent organic polymer (COP) is prepared by crosslinking the photosensitizer 4,4′,4′′,4′′′‐(porphyrin‐5,10,15,20‐tetrayl)tetraaniline (TAPP) with 4,4′‐(anthracene‐9,10‐diyl)dibenzoic acid (ADDA) via 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide/4‐dimethylaminopyridine coupling. The COP is further modified with a hydrophilic polymer, poly(poly(ethylene glycol) methyl ether methacrylate) by grafting‐from reversible‐addition‐fragmentation chain transfer (RAFT) polymerization to enhance its solubility in various solvents. The modified COP can bind singlet oxygen through the formation of endoperoxide by ADDA upon the exposure to red light irradiation. Singlet oxygen can be then released via the photodynamic mechanism or the cycloreversion by endoperoxide when heated at 110 °C. These results open new possibilities for simultaneous generation of singlet oxygen by the photodynamic route and singlet oxygen carriers, demonstrating promise for treating hypoxic tumors. [ABSTRACT FROM AUTHOR]

Several 1,8,10-functionalised anthracene derivatives and a couple of 1,8,9-functionalised anthracene analogous, bearing alkynyl substituents at positions 1 and 8 were synthesised and their photochemistry investigated in UV irradiation experiments. Almost all compounds could be converted into their 9,10:10′,9′- head -to- tail photodimers completely excluding the formation of the corresponding head -to- head isomers. Working under non-inert conditions led to formation of endoperoxides in some cases. Furthermore, a non-classical [4π+2π] photodimer was obtained from 1,8,10-tris[(trimethylsilyl)ethynyl]anthracene with one of the alkynyl substituents involved in the photoreaction. The1 H and13 C NMR spectra of all classical and non-classical photodimers were compared with those of the endoperoxides identifying characteristic shifts for the atoms at positions 9 and 10. Moreover, solid-state structures were determined for one or more of each representative. [ABSTRACT FROM AUTHOR]

Endoperoxides kill malaria parasites via cleavage of their endoperoxide bridge by haem or iron, leading to generation of cytotoxic oxygen-centred radicals. In view of the Leishmania parasites having a relatively compromised anti-oxidant defense and high iron content, this study aims to establish the underlying mechanism(s) accounting for the apoptotic-like death of Leishmania promastigotes by artemisinin, an endoperoxide. The formation of reactive oxygen species was confirmed by flow cytometry and was accompanied by inhibition of mitochondrial complexes I–III and II–III. However, this did not translate into a generation of mitochondrial superoxide or decrease in oxygen consumption, indicating minimal impairment of the electron transport chain. Artemisinin caused depolarization of the mitochondrial membrane along with a substantial depletion of adenosine triphosphatase (ATP), but it was not accompanied by enhancement of ATP hydrolysis. Collectively, the endoperoxide-mediated radical formation by artemisinin in Leishmania promastigotes was the key step for triggering its antileishmanial activity, leading secondarily to mitochondrial dysfunction indicating that endoperoxides represent a promising therapeutic strategy against Leishmania worthy of pharmacological consideration. [ABSTRACT FROM AUTHOR]

The mechanism of aniline oxidation by singlet oxygen was studied by the DFT-PBE/L2 method. According to the calculations, aniline endoperoxide cannot participate in the reaction because of its energy instability. The addition of 1O2 to aniline proceeds with the simultaneous proton transfer to the oxygen molecule from the NH2 group (for the syn-approach of oxygen) or from the aromatic ring (for the anti-approach). For the syn-approach of the 1O2 molecule, the HNC6H4(H)OOH intermediate is formed, whose decomposition leads to aniline p-hydroperoxide (predominantly) or p-iminoquinone. In the case of the anti-approach, the 1O2 molecule is inserted at the C-H bond to form aniline p-hydroperoxide (H2NC6H4OOH). The decomposition of aniline p-hydroperoxide with the formation of p-aminophenol and H2O2 molecule proceeds via concerted mechanism. [ABSTRACT FROM AUTHOR]

The mechanism of aniline oxidation by singlet oxygen was studied by the DFT-PBE/L2 method. According to the calculations, aniline endoperoxide cannot participate in the reaction because of its energy instability. The addition of 1O2 to aniline proceeds with the simultaneous proton transfer to the oxygen molecule from the NH2 group (for the syn-approach of oxygen) or from the aromatic ring (for the anti-approach). For the syn-approach of the 1O2 molecule, the HNC6H4(H)OOH intermediate is formed, whose decomposition leads to aniline p-hydroperoxide (predominantly) or p-iminoquinone. In the case of the anti-approach, the 1O2 molecule is inserted at the C-H bond to form aniline p-hydroperoxide (H2NC6H4OOH). The decomposition of aniline p-hydroperoxide with the formation of p-aminophenol and H2O2 molecule proceeds via concerted mechanism. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs’ reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon-centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action. [ABSTRACT FROM AUTHOR]

Endoperoxides (EP) are an emerging class of drugs which have potential in antiparasitic therapy, but also in other fields. For malaria therapy the EP artemisinin (Art) and its derivatives are successfully used. We have shown in the past that the EP ascaridole (Asc) is useful for the treatment of cutaneous leishmaniasis in a mouse model. Biomimetic experiments suggested that these drugs need activation in the respective target pathogens to exert their function. In spite of this idea, direct activation of EP to radicals inside cells has never been demonstrated. Therefore, this study was initiated to explore the activation of Asc in biomimetic systems and inside Leishmania in comparison to Art. Using electron paramagnetic resonance spectroscopy (EPR) in combination with spin-trapping we identified the secondary alkyl radical intermediates arising from reduction by Fe 2+ in cell-free systems. Combined GC/NMR analysis confirmed the loss of isopropyl residues from Asc during this process as intermediates. This activation of Asc was stimulated by low molecular Fe 2+ complexes or alternatively by hemin in conjunction with thiol reductants, such as cysteine (Cys). In Leishmania tarentolae promastigotes (LtP) as model for pathogenic forms of Leishmania carbon-centered radicals were identified in the presence of Asc by EPR spin-trapping. Both Asc and Art inhibited the viability in LtP with IC 50 values in the low micromolar range while IC 50 values for J774 macrophages were considerably higher. A similar structure without EP bridge (1,4-cineole) resulted in no detectable radicals and possessed much less cytotoxicity in LtP and no selectivity for LtP compared to J774 cells. The Asc-derived radical formation in LtP was inhibited by the iron chelator deferoxamine (DFO), and stimulated by Cys (a suitable reductant for hemin). The IC 50 values for LtP viability in the presence of Asc or Art were increased significantly by the spin trap DMPO, while Cys and DFO increased only IC 50 values for Art. In a heme association assay Asc demonstrated a lower binding affinity to heme than Art. ICP-OES measurements revealed that in LtP the total iron concentrations were twice as high as values in J774 macrophages. Since low molecular iron was important in Asc activation we studied the influence of Asc on the labile iron pool (LIP) in LtP. Low temperature EPR experiments demonstrated that Asc shifts the redox balance of iron in the LIP to its oxidized state. These data demonstrate that univalent cleavage of Asc/Art in LtP is an essential part of their pharmacological mechanism. The structure of the EP determines whether activation by low molecular iron or heme is favored and the availability of these intracellular activators modulates their cytotoxicity. These findings may be helpful for synthesis of new Asc derivatives and understanding the action of EP in other cell types. [ABSTRACT FROM AUTHOR]

Malaria is an infectious disease causing at least 1 million deaths per year, and, unfortunately, the chemical entities available to treat malaria are still too limited. In this review we highlight the contribution of marine chemistry in the field of antimalarial research by reporting the most important results obtained until the beginning of 2009, with particular emphasis on recent discoveries. About 60 secondary metabolites produced by marine organisms have been grouped into three structural types and discussed in terms of their reported antimalarial activities. The major groups of metabolites include isonitrile derivatives, alkaloids and endoperoxide derivatives. The following discussion evidences that antimalarial marine molecules can efficiently integrate the panel of lead compounds isolated from terrestrial sources with new chemical backbones and, sometimes, with unique functional groups.

Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure–activity relationship of this kind of antimalarials. The tetraoxanes 2–5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand) strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure-activity relationship of this kind of antimalarials. The tetraoxanes 2-5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand) strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

The thermal decomposition of 9,10 diphenylanthracene peroxide (DPAO 2 ) generates DPA and a mix of triplet and singlet molecular oxygen. For DPAO 2 the efficiency to produce singlet molecular oxygen is 0.35. On the other hand, it has shown that many thermal reactions can be carried out through the interaction of molecules with ultrasound. Ultrasound irradiation can create hydrodynamic stress (sonomechanical process), inertial cavitation (pyrolitic process) and long range effects mediated by radicals or ROS. Sonochemical reactions can be originated by pyrolytic like process, shock mechanical waves, thermal reactions and radical and ROS mediated reactions. Sonolysis of pure water can yield hydrogen or hydroxyl radicals and hydrogen peroxide (ROS). When DPAO 2 in 1,4 dioxane solution is treated with 20 or 24 kHz and different power intensity the production of molecular singlet oxygen is observed. Specific scavengers like tetracyclone (TC) are used to demonstrate it. The efficiency now is 0.85 showing that the sonochemical process is much more efficient that the thermal one. Another endoperoxide, artemisinin was also studied. Unlike the concept of photosensitizer of photodynamic therapy, in spite of large amount of reported results in literature, the term sonosensitizer and the sonosensitization process are not well defined. We define sonosensitized reaction as one in which a chemical species decompose as consequence of cavitation phenomena producing ROS or other radicals and some other target species does undergo a chemical reaction. The concept could be reach rapidly other peroxides which are now under experimental studies. For artemisinin, an important antimalarian and anticancer drug, was established that ultrasound irradiation increases the effectiveness of the treatment but without any explanation. We show that artemisinin is an endoperoxide and behaves as a sonosensitizer in the sense of our definition. [ABSTRACT FROM AUTHOR]

The thermal decomposition of fulvene endoperoxides ordinarily proceeds via an allene oxide intermediate affording oxepin-2(3 H )-one derivatives. We have now uncovered new, unusual pathways in these decompositions where the presence of a hydroxyl group on the alkyl or aryl attached to the fulvene exocyclic double bond has a profound effect on the fate of the reactive intermediates derived from the unstable endoperoxides. Computational work supports the proposed mechanistic pathways. [ABSTRACT FROM AUTHOR]

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]

Twenty previously unknown compounds and two known metabolites, merulin A and merulin D, were isolated from the endophytic fungus Pseudolagarobasidium acaciicola , which was isolated from a mangrove tree, Bruguiera gymnorrhiza . Structures of the 20 compounds were elucidated by analysis of spectroscopic data. The absolute configuration of seven of these compounds was addressed by a single crystal X-ray analysis using CuK α radiation and an estimate of the Flack parameter. Three compounds also possessed a tricyclic ring system. Terpene endoperoxides isolated exhibited cytotoxic activity, while those without an endoperoxide moiety did not show activity. The endoperoxide moiety of sesquiterpenes has significant impact on cytotoxic activity, and thus is an important functionality for cytotoxicity. One terpene endoperoxide displayed potent cytotoxic activity (IC 50 0.28 μM), and selectively exhibited activity against the HL-60 cell line. [ABSTRACT FROM AUTHOR]

Objectives: The development of drugs to reduce malaria transmission is an important part of malaria eradication plans. We set out to develop and validate a combination of new screening assays for prioritization of transmissionblocking molecules. Methods: We developed high-throughput assays for screening compounds against gametocytes, the parasite stages responsible for onward transmission to mosquitoes. An existing gametocyte parasitic lactate dehydrogenase (pLDH) assay was adapted for use in 384-well plates, and a novel homogeneous immunoassay to monitor the functional transition of female gametocytes into gametes was developed. A collection of 48 marketed and experimental antimalarials was screened and subsequently tested for impact on sporogony in Anopheles mosquitoes, to directly quantify the transmission-blocking properties of antimalarials in relation to their effects on gametocyte pLDH activity or gametogenesis. Results and Conclusions: The novel screening assays revealed distinct stage-specific kinetics and dynamics of drug effects. Peroxides showed the most potent transmission-blocking effects, with an intermediate speed of action and IC50 values that were 20-40-fold higher than the IC50s against the asexual stages causing clinical malaria. Finally, the novel synthetic peroxide OZ439 appeared to be a promising drug candidate as it exerted gametocytocidal and transmission-blocking effects at clinically relevant concentrations. [ABSTRACT FROM AUTHOR]

The artemisinin resistance has posed a serious threat against malaria elimination lately. Past few years have seen important development of several peroxide based medicinal compounds and their derivatives such as trioxanes and tetraoxanes. Here, we report a rapid, one-pot method for synthesizing a new series of N -sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogs with diverse substitution on the tetraoxane ring i.e., various substituted alkyl and aryl sulfonyl chlorides, as well as cyclic, acyclic and aryl substituted ketones. All the synthesized tetraoxanes were characterized by spectroscopic (1H NMR,13C NMR), and spectrometric (High-resolution mass spectrometry) techniques and quantify by High Performance Liquid Chromatography (HPLC) analysis. The structure of compound 19 was confirmed by single crystal XRD. From the overall preliminary in vitro data, analogs 14, 16, 19, 20, 24, 41, and 44 exhibited potential IC 50 values in the nanomolar range between 4.7 ± 0.3 to 12.9 ± 1.1 nM against P. falciparum (Pf 3D7) strains of human malaria parasite. Furthermore, these selective analogs were evaluated in vivo for their antimalarial potential against P. berghei and results revealed that analogue 24 rapidly kills the infected cell at asexual erythrocytic stage, with activity comparable to positive control chloroquine. [Display omitted] • Synthesis ofg N -sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogs. • Compounds were characterized by various techniques such as 1H NMR, 13C NMR, HRMS (High-resolution mass Spectrometry) and single crystal X-ray diffraction (XRD) analysis. • Anti-plasmodial activities of the 41 analogs were evaluated against P. falciparum in vitro. • Selective analogs 14, 16, 19, 20, 24, 41 , and 44 were evaluated in vivo for their antimalarial potential against P. berghei and compound 24 exhibited the most potent fast killing antimalarial efficacy against asexual erythro-cytic stage. [ABSTRACT FROM AUTHOR]

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC 50 value, 50% of killing concentration for T. vaginalis , was very low for metronidazole-sensitive isolates (11.7 to 22.8 μM), but was high for metronidazole-resistant ones (182.9 to 730.4 μM). The IC 50 values of N-89 and N-251 were 41.0 to 60.0 μM, and 82.0 to 300.0 μM for metronidazole-sensitive and -resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-trichomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole. [ABSTRACT FROM AUTHOR]

A series of substituted 3-azabicyclo[4.1.0]hept-4-ene derivatives were prepared and analysed by cyclic voltammetry. Preparative aerobic electrochemical oxidation reactions were then carried out. Three original endoperoxides were isolated, characterised and subjected to antimalarial and cytotoxicity activity assays. [ABSTRACT FROM AUTHOR]

A series of endoperoxides ( 3a – j ) were synthesized and evaluated for cytotoxic activity against four human cancer cell lines by using SRB dye assay. All the compounds displayed moderate to high cytotoxic effect against almost all investigational cancer cells. Particularly, compounds bearing electron withdrawing groups such as nitro substituted compound 3j (IC 50 = 0.001 μM) and fluoro substituted compound 3i (IC 50 = 0.003 μM) showed comparatively more cytotoxic potential than standard drugs against lung cancer cell line (A549). All synthesized endoperoxides ( 3a – j ) were further evaluated for their apoptotic potential through various parameters such as flow-cytometric analysis of nuclear DNA, flow-cytometric determination of mitochondrial membrane potential (ΔΨ m ), spectrofluorimetric estimation of intracellular ROS level and caspase-3 & 9 assays in treated lung cancer cells (A549); results reveal that endoperoxides induce apoptosis in cancer cells via mitochondrial pathway. [ABSTRACT FROM AUTHOR]

Background: The global burden of leishmaniasis is exacerbated by the limited repertoire of drugs, resulting in an urgent need to develop new therapeutic alternatives. Endoperoxides like ascaridole have emerged as promising anti-parasitic candidates, and its effectiveness was established in an animal model of cutaneous leishmaniasis (CL). However, its impact on Leishmania donovani parasites, causative of visceral leishmaniasis (VL) remains to be established.Purpose: This study aimed to delineate the underlying mechanisms contributing towards the leishmanicidal effect of ascaridole in terms of its impact on the cellular redox status and metabolic bioenergetics of L. donovani parasites.Methodology: The anti-promastigote activity of ascaridole was established by a cell viability assay in L. donovani [MHOM/IN/1983/AG83] and anti-amastigote activity by microscopy and ddPCR (droplet digital polymerase chain reaction). The cellular redox status, mitochondrial membrane potential (MMP), annexin V positivity and cell cycle arrest was evaluated by flow cytometry, while cellular and mitochondrial bioenergetics was assessed using Agilent XFp Analyzer, and the levels of ATP was measured by chemiluminescence.Results: Ascaridole demonstrated strong anti-promastigote and anti-amastigote activities in l. donovani, IC50 (half maximal Inhibitory concentration) being 2.47 ± 0.18 µM and 2.00±0.34 µM respectively, while in J774.A1 and murine peritoneal macrophages, the CC50 (half maximal cytotoxic concentration) was 41.47 ± 4.89 µM and 37.58 ± 5.75 µM respectively. Ascaridole disrupted the redox homeostasis via an enhanced generation of reactive oxygen species (ROS), lipid peroxidation and concomitant depletion of thiols. However, it failed to increase the generation of mitochondrial superoxide, which minimally impacted on mitochondrial respiration and was corroborated by energy metabolism studies. Instead, ascaridole inhibited glycolysis of promastigotes, caused a loss in MMP, which translated into ATP depletion. In promastigotes, ascaridole enhanced annexin-V positivity and caused a cell cycle arrest at sub- G0/G1 phase.Conclusion: In summary, ascaridole displays its leishmanicidal activity possibly due to its ability to auto-generate free radicals following cleavage of its endoperoxide bridge that led to disruption of the redox homeostasis, inhibition of glycolysis and culminated in an apoptotic like cell death. [ABSTRACT FROM AUTHOR]

Abstract: The reactions of 1,1-disubstituted alkenes with 4-hydroxyquinolin-2(1H)-ones under both Mn(III)-catalyzed aerobic oxidation conditions at room temperature and Mn(III)-mediated oxidation conditions at reflux temperature are described. The Mn(III)-catalyzed aerobic oxidation afforded bis(hydroperoxyethyl)quinolinones and azatrioxa[4.4.3]propellanes, while the oxidation with Mn(OAc)3·2H2O produced furo[3,2-c]quinolin-4-one analogues. The existence of a substituent at the 3-position of the 4-hydroxyquinolin-2(1H)-ones prevented a double reaction with the alkenes, and (endoperoxy)quinolinones and/or (hydroperoxyethyl)quinolinones were obtained under the Mn(III)-catalyzed aerobic conditions, while furo[3,2-c]quinolinone hemiacetals and vinylquinolinones were selectively produced under the Mn(III)-mediated oxidation conditions depending on the reaction temperature and times. Cyclic assembly of quinolinone-related 1,3-dicarbonyl compounds such as dihydropyridinones, pyranones, and dimedone derivatives was also examined under elevated temperature conditions. [Copyright &y& Elsevier]

Highlights: [•] Artemisinins are our most important class of antimalarial drugs. [•] PfATP6, a SERCA pump, is a proposed target for artemisinins in parasites. [•] Recent expression studies in yeast support this suggestion. [•] Other recent studies on PfATP6 are reviewed. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of 1,2,4-trioxanes were synthesized from 2H-pyrans via photooxidation, and their antiproliferative and growth factor inhibitory activity has been investigated across a variety of human cancer cell lines. Compounds 5k, 5l, 5s, 7a and 7c exhibited the highest activity and selectivity against a human leukemia (MV4-11) cell line (IC50 = 0.5 μM). Compound 5o showed the highest growth factor inhibitory activity against a melanoma (LOX-IMVI) cancer cell line (GI50 = 1.0 μM). A SAR study has confirmed the importance of the 1,2,4-trioxane unit as a pharmacophore for anticancer activity. The computer-assisted database analysis, COMPARE, has suggested that the compounds have unique mechanisms of actions that were different from those of known anticancer drugs. Some of the selected trioxanes were tested against the NF54 strain, albeit showing weak antiplasmodial activity. The molecular docking of trioxanes and hemin reveals that a short distance (1.30 Å) leads to their physical contact. The UV–vis spectroscopic analysis ensured the definite complexation between 1,2,4-trioxanes and hemin. The role of hemin–trioxane interaction in the hemin-induced oxidative damage has been studied using methylene blue as a substrate by UV–vis spectroscopy. [Copyright &y& Elsevier]

Visible and near-IR chemiluminescence was observed upon the decomposition of 1,4-dimethylnaphthalene endoperoxide applied to silica gel in the presence of the β-diketonate complexes Nd(L)3· nHO, Yb(L)3· nHO, and Eu(L)3· nHO (L is 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyloctane-3,5-dionate, 1,1,1-trifluoro-3-thenoylacetonate, and acetylacetonate). Excited lanthanide ions serve as luminescent emitters with emission maxima at λ = 870 and 1060 nm for Nd, 990 nm for Yb, and 615 nm for Eu. Singlet oxygen generated by decomposing endoperoxide was found to play a key role in the chemiluminescence mechanism. [ABSTRACT FROM AUTHOR]

Abstract: The first total synthesis of andavadoic acid, a naturally occurring five-membered ring peroxide, and its absolute configuration assignment are reported. Central to this venture was the development of an effective synthesis of a key β-hydroperoxy epoxy ester from (R)-epichlorohydrin via chemoselective methylenation with Nysted reagent in the presence of Ti(Oi-Pr)2Cl2 and chemo- and regioselective Mukaiyama–Isayama peroxidation. This approach also featured the construction of the 1,2-dioxolane ring system by an efficient base-promoted 5-exo epoxide opening by a hydroperoxy group. [Copyright &y& Elsevier]

Abstract: Background: Oxidative stress occurs through free radical- and non-radical-mediated oxidative mechanisms, but these are poorly discriminated by most assays. A convenient assay for oxidants in human serum is based upon the Fe2+-dependent decomposition of peroxides to oxidize N,N′-diethyl-1,4-phenylenediamine (DEPPD) to a stable radical cation which can be measured spectrophotometrically. Methods: We investigated modification of the DEPPD oxidation assay to discriminate color formation due to non-radical oxidants, including hydroperoxides and endoperoxides, which are sensitive to ebselen. Results: Use of serum, which has been pretreated with ebselen as a reference, provides a quantitative assay for non-radical, reactive oxidant species in serum, including hydroperoxides, endoperoxides and epoxides. In a set of 35 human serum samples, non-radical oxidants largely accounted for DEPPD oxidation in 86% of the samples while the remaining 14% had considerable contribution from other redox-active chemicals. Conclusions: The simple modification in which ebselen-pretreated sample is used as a reference provides means to quantify non-radical oxidants in human serum. Application of this approach could enhance understanding of the contribution of different types of oxidative stress to disease. [Copyright &y& Elsevier]

The electronic excited states corresponding to singlet oxygen generation versus O-O splitting in o-fluorine-phenyl-9-anthracene-9,10-endoperoxide 1 and its 9,10-bisarylanthracene analog 2 have been investigated using theoretical methods. In the case of the smaller endoperoxide 1, the recently developed second-order perturbation theory restricted active space (RASPT2) method has been employed and the results are compared to those from the complete active space (CASPT2), second-order approximated coupled cluster (CC2), and time-dependent density functional theory (TD-DFT) approaches. In addition to the vertical excited states, the photochemical path leading to homolytic O-O dissociation has been computed. This process is governed by a point, where four singlet and four triplet states are almost degenerate and show substantial spin-orbit coupling. The results obtained with RASPT2 indicate that the S state is of πσ character, corresponding to the O-O homolytic dissociation, while higher excited states S ( n ≥ 2) correspond to local and charge transfer excitations and should be correlated to the generation of singlet molecular oxygen. A similar photochemical picture is obtained with CASPT2, although two different active spaces are required to describe different parts of the spectrum. The calculations carried out with CC2 as well as the functionals CAM-B3LYP and the B3LYP(32) containing 32 % of exact exchange show good agreement with the RASPT2 energies, but present a strong mixing of πσ and π π excitations in the lowest S state, contradicting the assignment of RASPT2/CASPT2. The use of BP86 is strongly discouraged since it misplaces a large number of charge transfer states below the πσ state. The excited states of 2, calculated with B3LYP(32) are very similar to those of 1, leading to the conclusion that both endoperoxides should show a similar photochemistry, that is, the O-O cleavage seems to be partially quenched and singlet oxygen generation is enhanced, in comparison with the parent compound, anthracene-9,10-endoperoxide. Graphical abstract: The different electronic excited states of o-fluorine-phenyl-9-anthracene-9,10-endoperoxide have been benchmarked with RASPT2. The lowest excited state corresponds to the homolytic O-O dissociation and higher excited states are connected to singlet oxygen generation. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]