Inhaled mRNA Nanoformulation with Biogenic Ribosomal Protein Reverses Established Pulmonary Fibrosis in a Bleomycin-Induced Murine Model.

Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed the alveolar architecture. Here, an inhaled ribosomal protein-based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re-epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein-condensed mRNA core, a bifunctional peptide-modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell. When inhaled via a nebulizer, the nanoformulations carried by microdrops are deposited in the alveoli, and penetrate into fibrotic foci, where the outer KGFs are detached after matrix metalloproteinase 2 (MMP2) triggering. The RGD motif-grafted cores then expose and specifically target the integrin-elevated cells for the intracellular delivery of mRNA. Notably, repeated inhalation of the nanoformulations accelerates the clearance of locoregional collagen by boosting the intralesional expression of MMP13 and alveolar re-epithelialization mediated by KGFs, which synergistically ameliorates the lung function of a bleomycin-induced murine model. Therefore, this work provides an alternative mRNA-inhalation delivery strategy, which shows great potential for the treatment of IPF.

Direct Observation of Aggregation-Induced Emission Mechanism.

The mechanism of aggregation-induced emission, which overcomes the common aggregation-caused quenching problem in organic optoelectronics, is revealed by monitoring the real time structural evolution and dynamics of electronic excited state with frequency and polarization resolved ultrafast UV/IR spectroscopy and theoretical calculations. The formation of Woodward-Hoffmann cyclic intermediates upon ultraviolet excitation is observed in dilute solutions of tetraphenylethylene and its derivatives but not in their respective solid. The ultrafast cyclization provides an efficient nonradiative relaxation pathway through crossing a conical intersection. Without such a reaction mechanism, the electronic excitation is preserved in the molecular solids and the molecule fluoresces efficiently, aided by the very slow intermolecular charge and energy transfers due to the well separated molecular packing arrangement. The mechanisms can be general for tuning the properties of chromophores in different phases for various important applications.

Synthesis of Lactams via Ir-Catalyzed C-H Amidation Involving Ir-Nitrene Intermediates.

x-membered lactams were synthesized via either an amidation of sp3 C-H bonds or an electrophilic substitution of arenes via Ir-nitrene intermediates. With the employment of a readily available iridium catalyst in dichloromethane or hexafluoro-2-propanol, a wide range of lactams were synthesized in good to excellent yields with high selectivity.

Transition metal mediated carbonylative benzannulations.

In carbonylative benzannulations, feedstock carbon monoxide is converted to a benzene ring, which is one of the most fundamentally important and common rings in natural products and pharmaceutical compounds. Carbon monoxide, however, is rather inert in the absence of transition metals. Historically, carbonylative benzannulations have been mediated by stoichiometric chromium and iron in the form of Fischer carbenes. Recently, a number of transition metal-catalyzed carbonylative benzannulations have been developed, and almost all of them involve rhodium catalysts. This review will briefly discuss the mechanism and applications of carbonylative benzannulations involving Fischer carbenes and compare them with the more recent transition metal-catalyzed processes, including [3 + 2 + 1] cycloadditions, [5 + 1] cycloadditions, and other less common cycloadditions.

Total synthesis of diptoindonesin G and its analogues as selective modulators of estrogen receptors.

We have developed a versatile synthetic strategy for the synthesis of the natural product diptoindonesin G and its analogues as selective modulators of estrogen receptors. The strategy involves a regioselective dehydrative cyclization of arylacetals, a regioselective bromination of benzofurans, a sequential cross-coupling of bromo-benzofurans with aryl boronic acids, and a BBr3-mediated tandem cyclization and demethylation. Preliminary biological studies uncovered the critical and dispensable phenolic hydroxyl groups in the natural product and also revealed unexpected selectivity for isoforms of estrogen receptor.

Rhodium(I)-Catalyzed Benzannulation of Heteroaryl Propargylic Esters: Synthesis of Indoles and Related Heterocycles.

A de novo synthesis of a benzene ring allows for the preparation of a diverse range of heterocycles including indoles, benzofurans, benzothiophenes, carbazoles, and dibenzofurans from simple heteroaryl propargylic esters using a unified carbonylative benzannulation strategy. Multiple substituents can be easily introduced to the C4-C7 positions of indoles and related heterocycles.

A highly regio- and stereoselective synthesis of α-fluorinated imides via fluorination of chiral enamides.

A highly π-facial selective and regioselective fluorination of chiral enamides is described. The reaction involves an enantioselective fluorination exclusively at the electron-rich enamide olefin with N-F reagents such as Selectfluor and N-fluoro-benzenesulfonimide [NFSI] accompanied by trapping of the ß-fluoro-iminium cationic intermediate with water. The resulting N,O-hemiacetal could be oxidized using Dess-Martin periodinane, leading to an asymmetric sequence for syntheses of chiral α-fluoro-imides and optically enriched α-fluoro-ketones.

Protecting-group-free total synthesis of aplykurodinone-1.

A concise, stereoselective, and protecting-group-free total synthesis of aplykurodinone-1 from Hajos-Parrish ketone was described. The synthetic approach features a sequence of aerobic allylic oxidation and elimination of alcohol 9. The key intermediate for this synthesis was formed by a stereoselective intramolecular radical cyclization.

Conversion of fructose into 5-hydroxymethylfurfural (HMF) and its derivatives promoted by inorganic salt in alcohol.

The conversion of D-fructose to 5-hydroxymethylfurfural (HMF) on a 1 mmol scale was achieved in good yield (68%) using NH(4)Cl as catalyst in isopropanol at 120°C. About 3% of 5-i-propoxymethylfurfural was formed. The reaction in ethanol at 100°C on a 10g scale gave a total yield of HMF and 5-ethoxymethylfurfural of 42%. No mineral acid such as H(2)SO(4) and HCl are required.

Tetra-µ-acetato-κO:O'-bis-{[2-(2-fur-yl)-1-(2-furylmeth-yl)-1H-benzimidazole-κN]copper(II)}.

The title complex, [Cu(2)(CH(3)COO)(4)(C(16)H(12)N(2)O(2))(2)], forms a dimer of the paddle-wheel type located on a crystallographic inversion centre. The two Cu(II) atoms [Cu⋯Cu = 2.7254 (11) Å] are bridged by four acetate anions. The geometry of the polyhedron around the metal centre can be described as tetra-gonal-pyramidal derived from the calculation of the value τ = 0.0018. The apical positions of the tetra-gonal-pyramidal copper coordination polyhedra are occupied by the N atoms of 2-(2-fur-yl)-1-(2-furylmeth-yl)-1H-benzimidazole ligands. In the crystal structure, mol-ecules are linked into a chain by inter-molecular C-H⋯O hydrogen bonds parallel to [010]. Two furan rings are disordered over two positions in ratios of 0.55:0.45 and 0.69:0.31.