Design, Synthesis, Computational and Biological Evaluation of Novel Structure Fragments Based on Lithocholic Acid (LCA).

The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar "oxygen atom" into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a-1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a-1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.

Concentrations of Tire Additive Chemicals and Tire Road Wear Particles in an Australian Urban Tributary.

Tire road wear particles (TRWPs) are one of the largest sources of microplastics to the urban environment with recent concerns as they also provide a pathway for additive chemicals to leach into the environment. Stormwater is a major source of TRWPs and associated additives to urban surface water, with additives including the antioxidant derivative N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) demonstrating links to aquatic toxicity at environmentally relevant concentrations. The present study used complementary analysis methods to quantify both TRWPs and a suite of known tire additive chemicals (including 6PPD-quinone) to an urban tributary in Australia during severe storm events. Concentrations of additives increased more than 40 times during storms, with a maximum concentration of 2760 ng/L for ∑15additives, 88 ng/L for 6PPD-quinone, and a similar profile observed in each storm. TRWPs were detected during storm peaks with a maximum concentration between 6.4 and 18 mg/L, and concentrations of TRWPs and all additives were highly correlated. Contaminant mass loads to this catchment were estimated as up to 100 g/storm for ∑15additives, 3 g/storm for 6PPD-quinone, and between 252 and 730 kg of TRWPs/storm. While 6PPD-quinone concentrations in this catchment were lower than previous studies, elevated concentrations post storm suggest prolonged aquatic exposure.

Cannabichromene Racemization and Absolute Stereochemistry Based on a Cannabicyclol Analog.

Cannabichromene (CBC) is unusual among cannabinoids in having been described as both a racemic and a scalemic compound from natural Cannabis sources. Several explanations are available for this circumstance, including facile racemization. Cannabichromene was resolved chromatographically, and the enantiomer matching CBC from local Cannabis was identified. To preclude racemization, CBC was converted to cannabicyclol for further stereochemical analysis. This permitted the (R) absolute stereochemistry to be assigned to natural CBC based on chiroptical data for related natural products and the absolute configuration of a cannabicyclol analog determined by X-ray crystallography. The racemization of CBC was found to be rather slow in the laboratory, but handling practices for natural cannabis products can be inferred to promote the process.

Correction to "Investigation of 6PPD-Quinone in Rubberized Asphalt Concrete Mixtures".

[This corrects the article DOI: 10.1021/acsenvironau.3c00023.].

Anti-adipogenic properties of clock activator chlorhexidine and a new derivative.

Background: The circadian clock exerts temporal control of metabolic pathways to maintain homeostasis, and its disruption leads to the development of obesity and insulin resistance. In adipose tissue, key regulators of clock machinery orchestrate adipogenic processes via the Wnt signaling pathway to impact mature adipocyte development. Methods: Based on the recent finding of chlorhexidine as a new clock activator, we determined its potential anti-adipogenic activities in distinct adipogenic progenitor models. Furthermore, we report the structural optimization of chlorhexidine leading to the discovery of analogs with improved efficacy in inhibiting adipogenesis. Results: In adipogenic progenitors with Per2::dLuc luciferase reporter, Chlorhexidine shortened clock period length with induction of core clock components. Consistent with its clock-activating function, Chlorhexidine robustly suppressed the lineage commitment and maturation of adipogenic mesenchymal precursors, with comparable effect on inhibiting preadipocyte terminal differentiation. Mechanistically, we show that Chlorhexidine induces signaling components of the Wnt pathway resulting in activation of Wnt activity. Via modification of its chemical scaffold, we generated analogs of chlorhexidine that led to the identification of CM002 as a new clock- activating molecule with improved anti-adipogenic activity. Conclusions: Collectively, our findings uncovered the anti-adipogenic functions of a new class of small molecule clock activators. These compounds provide novel chemical probes to dissect clock function in maintaining metabolic homeostasis and may have therapeutic implications in obesity and associated metabolic disorders.

A Direct Mass Spectrometry Method for the Rapid Analysis of Ubiquitous Tire-Derived Toxin N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine Quinone (6-PPDQ).

The oxidative transformation product of a common tire preservative, identified as N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ), has recently been found to contribute to "urban runoff mortality syndrome" in Coho salmon at nanogram per liter levels. Given the number of fish-bearing streams with multiple stormwater inputs, large-scale campaigns to identify 6-PPDQ sources and evaluate mitigation strategies will require sensitive, high-throughput analytical methods. We report the development and optimization of a direct sampling tandem mass spectrometry method for semiquantitative 6-PPDQ determinations using a thin polydimethylsiloxane membrane immersion probe. The method requires no sample cleanup steps or chromatographic separations, even in complex, heterogeneous samples. Quantitation is achieved by the method of standard additions, with a detection limit of 8 ng/L and a duty cycle of 15 min/sample. High-throughput screening provides semiquantitative concentrations with similar sensitivity and a full analytical duty cycle of 2.5 min/sample. Preliminary data and performance metrics are reported for 6-PPDQ present in representative environmental and stormwater samples. The method is readily adapted for real-time process monitoring, demonstrated by following the dissolution of 6-PPDQ from tire fragments and subsequent removal in response to added sorbents.

Photooxidation of mixed aryl and biarylphosphines.

Arylphosphines and dialkylbiarylphosphines react with singlet oxygen to form phosphine oxides and phosphinate esters. For mixed arylphosphines, the most electron-rich aryl group migrates to form the phosphinate, while for dialkylbiarylphosphines migration of the alkyl group occurs. Dialkylbiarylphosphines also yield arene epoxides, especially in electron-rich systems. Phosphinate ester formation is increased at high temperature, while protic solvents increase the yield of epoxide. The product distribution provides evidence for Buchwald's recent conformational model for the aerobic oxidation of dialkylbiarylphosphines.