Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair.

Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to lower airway repair. Agents that promote the selective expansion of these cells might stimulate regeneration of the compromised alveolar epithelium, an etiology-defining event in several pulmonary diseases. From a high-content imaging screen of the drug repurposing library ReFRAME, we identified that dipeptidyl peptidase 4 (DPP4) inhibitors, widely used type 2 diabetes medications, selectively expand AEC2s and are broadly efficacious in several mouse models of lung damage. Mechanism of action studies revealed that the protease DPP4, in addition to processing incretin hormones, degrades IGF-1 and IL-6, essential regulators of AEC2 expansion whose levels are increased in the luminal compartment of the lung in response to drug treatment. To selectively target DPP4 in the lung with sufficient drug exposure, we developed NZ-97, a locally delivered, lung persistent DPP4 inhibitor that broadly promotes efficacy in mouse lung damage models with minimal peripheral exposure and good tolerability. This work reveals DPP4 as a central regulator of AEC2 expansion and affords a promising therapeutic approach to broadly stimulate regenerative repair in pulmonary disease.

Treatment of MRSA Infection: Where are We?

Staphylococcus aureus is a leading cause of septicemia, endocarditis, pneumonia, skin and soft tissue infections, bone and joint infections, and hospital-acquired infections. In particular, methicillin-resistant Staphylococcus aureus (MRSA) is associated with high morbidity and mortality, and continues to be a major public health problem. The emergence of multidrug-resistant MRSA strains along with the wide consumption of antibiotics has made anti-MRSA treatment a huge challenge. Novel treatment strategies (e.g., novel antimicrobials and new administrations) against MRSA are urgently needed. In the past decade, pharmaceutical companies have invested more in the research and development (R&D) of new antimicrobials and strategies, spurred by favorable policies. All research articles were collected from authentic online databases, including Google Scholar, PubMed, Scopus, and Web of Science, by using different combinations of keywords, including 'anti-MRSA', 'antibiotic', 'antimicrobial', 'clinical trial', 'clinical phase', clinical studies', and 'pipeline'. The information extracted from articles was compared to information provided on the drug manufacturer's website and Clinical- Trials.gov (https://clinicaltrials.gov/) to confirm the latest development phase of anti- MRSA agents. The present review focuses on the current development status of new anti-MRSA strategies concerning chemistry, pharmacological target(s), indications, route of administration, efficacy and safety, pharmacokinetics, and pharmacodynamics, and aims to discuss the challenges and opportunities in developing drugs for anti-MRSA infections.

Construction of Bridged-Ring-Fused Naphthalenone Derivatives Through an Unexpected Zn(OTf)2-Catalyzed Cascade Transformation.

An unexpected cascade transformation of aminonaphthoquinones with N-substituents bearing a p-methoxybenzyl ether into bridged-ring-fused naphthalenone derivatives is reported. This cascade transformation was initiated by a catalytic amount of Zn(OTf)2 and involved with subsequent functional group migration and cyclization. The process proceeded through the cleavage of two bonds and the formation of three new bonds in one pot and was proven to be efficient and tolerant to various substituents.

Synthesis of Bioactive 3,4-Dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-dione and 2,3,4,5-Tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-dione Derivatives via the Copper-Catalyzed Intramolecular Coupling Reaction.

A convenient synthesis of 3,4-dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-diones and 2,3,4,5-tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-diones via the copper-catalyzed intramolecular C-O/C-C coupling reaction is described. This method showed a good tolerance for functional groups and was applied to the synthesis of natural product core structures. Some coupling products exhibited moderate activities against lung cancer A549 cells.

Transition-Metal-Free Cascade Synthesis of 4-Quinolones: Umpolung of Michael Acceptors via Ene Reaction with Arynes.

A novel "one-pot" aryne transformation is described that affords various 4-quinolone derivatives without recourse to transition-metal catalysis. Arynes react with aza-Morita-Baylis-Hillman (AMBH) adducts through a cascade sequence involving an insertion/cyclization/ene reaction process to afford 4-quinolones in high yields with a broad substrate scope under mild reaction conditions. Essentially, an umpolung of reactivity at the ß carbon of α,ß-unsaturated ketone has been achieved by an inverse electron demand aryne-ene reaction to provide a C-arylated product.