Ligand-Enabled Pd-Catalyzed sp3 C‒H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease.

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalysed sp3 C‒H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C‒H activation is also demonstrated by an unprecedented enantioselective sp3 C‒H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

The prevalence of generalized and syndromic hypermobility in elite Australian dancers.

OBJECTIVES: To determine the prevalence of Generalized Joint Hypermobility (GJH) and Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobility Type (JHS/EDS-HT) among dancers using established validated measures. DESIGN: Observational Cohort Study. SETTING: Laboratory. PARTICIPANTS: 85 dancers from two dance institutions. MAIN OUTCOME MEASURES: GJH was determined using the Beighton score (cut-point ≥5/9) and the Lower Limb Assessment Scale (LLAS) (cut-point ≥7/12). Presence of JHS/EDS-HT was assessed using the Brighton and Villefranche criteria. Paired sample t-test was performed to compare LLAS side-to-side scores, and percentage disagreements calculated to determine differences between the two GJH and the two JHS/EDS-HT measures. RESULTS: 72% of dancers met the Beighton cut-point for GJH, while 38% and 42% met the LLAS cut-point on the left and right respectively. The proportion of dancers identified with GJH was different when assessed using the Beighton compared to the left and right LLAS (both p < 0.001), a disagreement of 48% and 46% respectively, with Beighton classifying more participants as having GJH. The Villefranche identified more dancers with JHS/EDS-HT than the Brighton (84% vs 31%, p < 0.001), with 54% disagreement. CONCLUSIONS: High prevalence of generalized and syndromic hypermobility was found regardless of the criteria used. A higher Beighton cut-point, e.g. ≥6/9, to identify true GJH amongst dancers maybe warranted.

Organized Aggregation Makes Insoluble Perylene Diimide Efficient for the Reduction of Aryl Halides via Consecutive Visible Light-Induced Electron-Transfer Processes.

The consecutive photo-induced electron-transfer (conPET) process found with perylene diimide (PDI) overcomes the limitation of visible-light photocatalysis and sheds light on effective solar energy conversion. By the incorporation of PDI into a metal-organic polymer Zn-PDI, a heterogeneous approach was achieved to tackle the poor solubility and strong tendency to aggregate of PDIs that restricted the exploitation of this outstanding homogeneous process. The interplay between metal-PDI coordination and π···π stacking of the organized PDI arrays in Zn-PDI facilitates the conPET process for the visible light-driven reduction of aryl halides by stabilizing the radical-anion intermediate and catalyst-substrate interacted moiety. These synergistic effects between the PDI arrays and Zn sites further render Zn-PDI photoactivity for fundamental oxidation of benzyl alcohols and amines. The tunable and modular nature of the two-dimensional metal-organic polymers makes the catalyst-embedding strategy promising for the development of ideal photocatalysts toward the better utilization of solar energy.