Development of fluorous boronic acid catalysts integrated with sulfur for enhanced amidation efficiency.

A thermally stable, fluorous sulfur-containing boronic acid catalyst has been developed and was shown to efficiently promote dehydrative condensation between carboxylic acids and amines under environmentally friendly conditions. The methodology can be applied to aliphatic, aromatic and heteroaromatic acids as well as primary and secondary amines. N-Boc protected amino acids were also successfully coupled in good yields with very little racemization. The catalyst could be reused four times with no significant loss of activity.

Alkyltriphenylphosphonium turns naphthoquinoneimidazoles into potent membrane depolarizers against mycobacteria.

Due to its central role in energy generation and bacterial viability, mycobacterial bioenergetics is an attractive therapeutic target for anti-tuberculosis drug discovery. Building upon our work on antimycobacterial dioxonaphthoimidazoliums that were activated by a proximal positive charge and generated reactive oxygen species upon reduction by Type II NADH dehydrogenase, we herein studied the effect of a distal positive charge on the antimycobacterial activity of naphthoquinoneimidazoles by incorporating a trialkylphosphonium cation. The potency-enhancing properties of the linker length were affirmed by structure-activity relationship studies. The most active compound against M. tb H37Rv displayed good selectivity index (SI = 34) and strong bactericidal activity in the low micromolar range, which occurred through rapid bacterial membrane depolarization that resulted in depletion of intracellular ATP. Through this work, we demonstrated a switch of the scaffold's mode-of-action via relocation of positive charge while retaining its excellent antibacterial activity and selectivity.

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury through a sirtuin-3 mediated increase in fatty acid oxidation.

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury (IRI) but the mechanisms are unknown. Here, we investigate the role of the mitochondrial NAD+-dependent deacetylase, Sirtuin-3 (SIRT3), which has been shown to influence fatty acid oxidation and cardiac outcomes, as a potential mediator of this effect. Fasting was shown to shift metabolism from glucose towards fatty acid oxidation. This change in metabolic fuel substrate utilisation increased myocardial infarct size in wild-type (WT), but not SIRT3 heterozygous knock-out (KO) mice. Further analysis revealed SIRT3 KO mice were better adapted to starvation through an improved cardiac efficiency, thus protecting them from acute myocardial IRI. Mitochondria from SIRT3 KO mice were hyperacetylated compared to WT mice which may regulate key metabolic processes controlling glucose and fatty acid utilisation in the heart. Fasting and the associated metabolic switch to fatty acid respiration worsens outcomes in WT hearts, whilst hearts from SIRT3 KO mice are better adapted to oxidising fatty acids, thereby protecting them from acute myocardial IRI.

Dissecting Clinical and Metabolomics Associations of Left Atrial Phasic Function by Cardiac Magnetic Resonance Feature Tracking.

Among community cohorts, associations between clinical and metabolite factors and complex left atrial (LA) phasic function assessed by cardiac magnetic resonance (CMR) feature tracking (FT) are unknown. Longitudinal LA strain comprising reservoir strain (εs), conduit strain (εe) and booster strain (εa) and their corresponding peak strain rates (SRs, SRe, SRa) were measured using CMR FT. Targeted mass spectrometry measured 83 circulating metabolites in serum. Sparse Principal Component Analysis was used for data reduction. Among community adults (n = 128, 41% female) (mean age: 70.5 ± 11.6 years), age was significantly associated with εs (ß = -0.30, p < 0.0001), εe (ß = -0.3, p < 0.0001), SRs (ß = -0.02, p < 0.0001), SRe (ß = 0.04, p < 0.0001) and SRe/SRa (ß = -0.01, p = 0.012). In contrast, heart rate was significantly associated with εa (ß = 0.1, p = 0.001) and SRa (ß = -0.02, p < 0.0001). Serine was significantly associated with εs (ß = 10.1, p = 0.015), SRs (ß = 0.5, p = 0.033) and SRa (ß = -0.9, p = 0.016). Citrulline was associated with εs (ß = -4.0, p = 0.016), εa (ß = -3.4, p = 0.002) and SRa (ß = 0.4, p = 0.019). Valine was associated with ratio of SRe:SRa (ß = -0.4, p = 0.039). Medium and long chain dicarboxyl carnitines were associated with εs (ß = -0.6, p = 0.038). Phases of LA function were differentially associated with clinical and metabolite factors. Metabolite signals may be used to advance mechanistic understanding of LA disease in future studies.

Metabolomic profile of arterial stiffness in aged adults.

BACKGROUND: Increasing arterial stiffness is an important contributor to declining cardiovascular health in ageing. Changes in whole-body fuel metabolism could be related to alterations in arterial stiffness in ageing adults. METHODS: Targeted high-performance liquid and gas chromatography mass spectrometry were used to measure 84 circulating metabolites in a group of community elderly adults ( n = 141, 58% men; mean age = 70.6 ± 11.2 years) without cardiovascular disease. In basic and adjusted models, we correlated the measured metabolites to carotid-femoral pulse wave velocity assessed by applanation tonometry. RESULTS: Age ( ß = 0.10, p < 0.0001), smoking status ( ß = 1.32, p = 0.02), dyslipidemia ( ß = 1.22, p = 0.01), central systolic blood pressure ( ß = 0.05, p < 0.0001), central mean arterial pressure ( ß = 0.04, p = 0.03) and central pulse pressure ( ß = 0.05, p < 0.0001) were significantly associated with pulse wave velocity. Amino acids such as histidine, methionine and valine correlated with pulse wave velocity. In multivariable models adjusted for clinical covariates, only Factor 5, comprising the medium- and long-chain dicarboxyl and hydroxyl acylcarnitines was independently associated with pulse wave velocity ( ß = 0.24, p = 0.015). CONCLUSION: An upstream metabolic perturbation comprising medium- and long-chain dicarboxyl and hydroxyl acylcarnitines, likely reflecting changes in cellular fatty acid oxidation, was associated with arterial stiffness among aged adults. This advances mechanistic understanding of arterial stiffness among aged adults before clinical disease.