Small molecule mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ...ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia-reperfusion injury, and neurodegenerative diseases. This communication will review the small molecule mitochondrial uncouplers reported to date and explore their potential as therapeutics.
We present dye-doped polymer nanoparticles that are able to detect mercury in aqueous solution at parts per billion levels via fluorescence resonance energy transfer (FRET). The nanoparticles are ...prepared by reprecipitation of highly fluorescent conjugated polymers in water and are stable in aqueous suspension. They are doped with rhodamine spirolactam dyes that are nonfluorescent until they encounter mercury ions, which promote an irreversible reaction that converts the dyes to fluorescent rhodamines. The rhodamine dyes act as FRET acceptors for the fluorescent nanoparticles, and the ratio of nanoparticle-to-rhodamine fluorescence intensities functions as a ratiometric fluorescence chemodosimeter for mercury. The light harvesting capability of the conjugated polymer nanoparticles enhances the fluorescence intensity of the rhodamine dyes by a factor of 10, enabling sensitive detection of mercury ions in water at levels as low as 0.7 parts per billion.
Predator-prey interactions shape ecosystem stability and are influenced by changes in ecosystem productivity. However, because multiple biotic and abiotic drivers shape the trophic responses of ...predators to productivity, we often observe patterns, but not mechanisms, by which productivity drives food web structure. One way to capture mechanisms shaping trophic responses is to quantify trophic interactions among multiple trophic groups and by using complementary metrics of trophic ecology. In this study, we combine two diet-tracing methods: diet DNA and stable isotopes, for two trophic groups (top predators and intermediate predators) in both low- and high-productivity habitats to elucidate where in the food chain trophic structure shifts in response to changes in underlying ecosystem productivity. We demonstrate that while top predators show increases in isotopic trophic position (
N) with productivity, neither their isotopic niche size nor their DNA diet composition changes. Conversely, intermediate predators show clear turnover in DNA diet composition towards a more predatory prey base in high-productivity habitats. Taking this multi-trophic approach highlights how predator identity shapes responses in predator-prey interactions across environments with different underlying productivity, building predictive power for understanding the outcomes of ongoing anthropogenic change.
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P1–5) to regulate cell growth and survival and has been implicated in a ...variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this article, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK. Surprisingly, combining features of reported SphK1 inhibitors generated SphK1/2 dual inhibitor 20l (SLC4011540) (hSphK1 K i = 120 nM, hSphK2 K i = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (K i = 90 nM, 100-fold SphK2 selectivity). These compounds effectively decrease S1P levels in vitro. In vivo administration of 20dd validated that inhibition of SphK2 increases blood S1P levels.
Here we report the first synthesis of a family of novel heterocyclic compounds based on a 5-dihydropyrazolo3',4':5,6pyrano3,4- bpyridine core. In the course of our drug discovery programs, we had ...need to access the previously unknown 5-dihydropyrazolo3',4':5,6pyrano3,4- bpyridine core. Initial attempts required long reaction times, which led to degradation and side products. Reaction optimization identified a Pd-catalyzed, microwave-assisted C-H heteroarylation protocol for the rapid, general, and high yielding synthesis of this tricyclic core (as well as related analogs) suitable to drive optimization efforts.
Fluorescent systems that can undergo intensity photomodulation in aqueous environments are finding increasing applications, particularly in high-resolution imaging of biological samples. We seek to ...develop conjugated polymer nanoparticles (CPNs) with bright fluorescence that can be modulated with a light signal. Here, we present CPNs, doped with a photochromic diarylethene dye, that exhibit efficient fluorescence photomodulation that is thermally irreversible. In their UV-absorbing open form, the diarylethenes have no effect on the fluorescence properties of the bright CPNs. A brief period of UV irradiation converts the dyes to their visible-absorbing closed form, which is an efficient fluorescence quencher for the CPNs, likely via a fluorescence resonance energy transfer mechanism. Aqueous suspensions of dye-doped CPNs prepared from the homopolymer poly2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene (MEH-PPV) or a polyfluorene-phenylenevinylene copolymer (PFPV) exhibit thermally stable bright and dark levels. The dye-doped MEH-PPV CPNs also exhibit photomodulation in single-nanoparticle imaging experiments, which reveal that nearly all CPNs retain a small amount of residual emission in the dark state. Their PFPV counterparts undergo irreversible fluorescence photobleaching rather than photomodulation in single-nanoparticle studies. The photostability of the CPNs under the UV irradiation conditions required for photochromic conversion is investigated on the single-particle level, and PFPV CPNs are found to be particularly susceptible to photobleaching upon 254 nm irradiation. These results will guide the selection of polymers and photochromes for CPNs intended for single-particle photomodulation.
Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the ...mitochondria without depolarizing the plasma membrane, as a lead compound for structure–activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N–H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.
Predator–prey interactions shape ecosystems and can help maintain biodiversity. However, for many of the earth's most biodiverse and abundant organisms, including terrestrial arthropods, these ...interactions are difficult or impossible to observe directly with traditional approaches. Based on previous theory, it is likely that predator–prey interactions for these organisms are shaped by a combination of predator traits, including body size and species‐specific hunting strategies. In this study, we combined diet DNA metabarcoding data of 173 individual invertebrate predators from nine species (a total of 305 individual predator–prey interactions) with an extensive community body size data set of a well‐described invertebrate community to explore how predator traits and identity shape interactions. We found that (1) mean size of prey families in the field usually scaled with predator size, with species‐specific variation to a general size‐scaling relationship (exceptions likely indicating scavenging or feeding on smaller life stages). We also found that (2) although predator hunting traits, including web and venom use, are thought to shape predator–prey interaction outcomes, predator identity more strongly influenced our indirect measure of the relative size of predators and prey (predator:prey size ratios) than either of these hunting traits. Our findings indicate that predator body size and species identity are important in shaping trophic interactions in invertebrate food webs and could help predict how anthropogenic biodiversity change will influence terrestrial invertebrates, the earth's most diverse animal taxonomic group.
Here, we report the first total synthesis of hinduchelins A–D, a family of nontoxic catechol derivatives from Streptoalloteichus hindustanus, possessing a druglike chemotype and modest iron-chelating ...ability. A concise synthesis was developed employing methyl 5-methyloxazole-4-carboxylate as a single starting material to provide hinduchelins A–D (and unnatural analogues) in only four steps and 5–15% overall yields; moreover, the stereochemistry of hinduchelin A was reassigned from (S) to (R). Biological evaluation confirmed that natural and unnatural hinduchelins are weak iron chelators (siderophores).
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Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling ...pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure–activity relationship studies of the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1.
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