Influence of peak inspiratory flow rates and pressure drops on inhalation performance of dry powder inhalers

The aim of this study was to reveal the relationship between human inspiratory flow patterns and the concomitant drops in pressure in different inhalation devices, and the influence of the devices on inhalation performance. As a model formulation for inhalers, a physically mixed dry powder composed of salbutamol sulfate and coarse lactose monohydrate was selected. The drops in pressure at 28.3?L/min of three inhalation devices, Single-type, Dual-type, and Reverse-type, was 1.0, 5.1, and 8.7?kPa, respectively. Measurements of human inspiratory patterns revealed that although the least resistant device (Single) had large inter- and intra-individual variation of peak flow rate (PFR), the coefficients of variation of PFR of the three devices were almost the same. In tests with a human inspiratory flow simulator in vitro, inhalation performance was higher, but the variation in inhalation performance in the range of human flow patterns was wider, for the more resistant device. To minimize the intra- and inter-individual variation in inhalation performance for the model formulation in this study, a formulation design that allows active pharmaceutical ingredient to detach from the carrier with a lower inhalation flow rate is needed.     

The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy

The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients’ quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic nephropathy patients. Impaired lipid signaling, especially abnormal protein kinase C (PKC) activation by de novo-synthesized diacylglycerol (DG) under high blood glucose, is one of the causes of diabetic nephropathy. DG kinase (DGK) is an enzyme that phosphorylates DG and generates phosphatidic acid, i.e., DGK can inhibit PKC activation under diabetic conditions. Indeed, it has been proven that DGK activation ameliorates diabetic nephropathy. In this review, we summarize the involvement of PKC and DGK in diabetic nephropathy as therapeutic targets, and its mechanisms, by referring to our recent study.     

Iridium-Catalyzed Reductive (3+2) Annulation of Lactams Enabling the Rapid Total Synthesis of (±)-Eburnamonine

A reductive (3+2) annulation of lactams through iridium-catalyzed hydrosilylation and photoredox coupling with α-bromoacetic acid was developed. The iridium-catalyzed hydrosilylation of the lactam carbonyl group and subsequent elimination provide a transient cyclic enamine, which undergoes iridium-catalyzed photoredox coupling with α-bromoacetic acid in a one-pot process. The developed conditions show high functional-group tolerance and provide cyclic N,O-acetals containing a quaternary carbon center. The resulting N,O-acetals undergo a variety of acid-mediated nucleophilic addition reactions via iminium ions to give substituted cyclic amines. The developed sequence including reductive (3+2) annulation and acid-mediated nucleophilic addition was successfully applied to the four-step total synthesis of (±)-eburnamonine.     

Atomically Precise Alloy Nanoclusters

Metal nanoclusters (NCs) have a particle size of about one nanometer, which makes them the smallest unit that can give a function to a substance. In addition, metal NCs possess physical and chemical properties that are different from those of the corresponding bulk metals. Metal NCs with such characteristics are expected to be important for use in nanotechnology. Research on the precise synthesis of metal NCs and elucidation of their physical/chemical properties and functions is being actively conducted. When metal NCs are alloyed, it is possible to obtain further various electronic and geometrical structures and functions. Thus, research on alloy NCs has become a hot topic in the study of metal NCs and the number of publications on alloy NCs has increased explosively in recent years. Such publications have provided much insight into the effects of alloying on the electronic structure and function of metal NCs. However, the rapid increase in knowledge has made it difficult for researchers (especially those new to the field) to grasp all of it. Therefore, in this review, we summarize the reported chemical composition, geometrical structure, electronic structure, and physical and chemical properties of Au_n−xM_x(SR)_m, Ag_n−xM_x(SR)_m, Au_n−xM_x(PR₃)_l(SR)_m, and Ag_n−xM_x(PR₃)_l(SR)_m (Au=gold, Ag=silver, M=heteroatom, PR₃=phosphine, and SR=thiolate) NCs. This review is expected to help researchers understand the characteristics of alloy NCs and lead to clear design guidelines to develop new alloy NCs with intended functions.     

Stable meso–meso-Linked 2NH-Corrole Radical Dimers as a Key Intermediate to Corrole Tape

While oxidation of 5,5′,15,15′-tetramesityl-10-10′-linked 3NH-corrole dimer with DDQ gave the corresponding triply linked 2NH-corrole tape, the use of an equimolar amount of p-chloranil as a milder oxidant resulted in the formation of a 10-10′-linked neutral 2NH-corrole radical dimer as a stable product. The stability of this peculiar product is ascribed largely to strong antiferromagnetic interaction of the two spins. Further oxidation of this diradical produced corrole tape, suggesting its involvement as a reaction intermediate to the corrole tape. Oxidation of 10-10′-linked bis-pyridine-coordinated Co^III corrole dimer with DDQ produced a cobalt corrole radical dimer and a doubly linked corrole dimer both as stable compounds bearing pyridine and cyanide axial ligands. This type of oxidative transformation involving neutral diradical intermediates is a unique reaction mechanism specific for corrole dimers.     

Cyclophane‐Type Chlorin Dimers from Dynamic Covalent Chemistry of 2,18‐Porphyrinyl Dicyanomethyl Diradicals

2,18‐Bis(dicyanomethyl)‐substituted Ni^II porphyrin 8 and Zn^II porphyrin 11 were prepared and subjected to oxidation with PbO₂ in CH₂Cl₂ at 298 K to give cyclophane‐type chlorin dimers ( 9 )₂ and ( 12 )₂ as a consequence of double recombination of biradicals 9 and 12 , respectively. Dimer ( 9 )₂ takes a syn‐conformation of two distorted Ni^II chlorins but ( 12 )₂ takes an anti‐conformation of relatively planar Zn^II chlorins. At 298 K, dimer ( 9 )₂ is stable and its ¹H NMR spectrum is sharp but becomes broad at high temperature, while the ¹H NMR spectrum of ( 12 )₂ is considerably broad even at 298 K but becomes sharper at low temperature. These results indicate that the chlorin dimers dissociate to radical species, but the activation barrier of the dissociation of ( 12 )₂ is much less than that of ( 9 )₂. The involvement of diradicals in dynamic covalent chemistry has been suggested by thermal scrambling of hetero dimer ( 16 )₂ to give homo dimers ( 9 )₂ and ( 15 )₂.     

Selective Formation of Helical Tetrapyrrin-Fused Porphyrins by Oxidation of β-to-β Linked meso-Aminoporphyrin Dimers

Oxidation of β-to-β directly linked and sulfur-bridged meso-amino Ni^II-porphyrin dimers with PbO₂ gave helical tetrapyrrin (biliverdin analogue)-fused Ni^II-porphyrins. These ring cleaving reactions differ markedly from the previously reported oxidation of a β–β linked Ni^II-porphyrin dimer carrying one amino group, which gave an azepine-fused porphyrin dimer. The tetrapyrrin-fused Ni^II-porphyrins display intense NIR absorption bands at 1200–1400 nm and reversible redox processes because of the highly π-conjugated networks and rigid structures. These tetrapyrrin-fused Ni^II-porphyrins were separated to stable enantiomers, which showed clear Cotton effects in their CD spectra with Δϵ of 10² order.     

Synthesis and properties of 1,6,7,12,13,18,19,24-octamethylacenaphthyleno[b,l]tetraphenylene

The X-ray crystal structure and photophysical properties of 1,6,7,12,13,18,19,24-octamethylacenaphthyleno[b,l]tetraphenylene, which has been synthesized via a Diels-Alder reaction of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene and 6,7-dihydro-6-hydroxy-7,9-dimethyl-8H-cyclopenta[a]acenaphthylene-8-one, are reported.     

A Benzene‐1,3,5‐Triaminyl Radical Fused with ZnII‐Porphyrins: Remarkable Stability and a High‐Spin Quartet Ground State

A benzene‐1,3,5‐triaminyl radical fused with three Zn^II‐porphyrins was synthesized through a three‐fold oxidative fusion reaction of 1,3,5‐tris(Zn^II‐porphyrinylamino)benzene followed by oxidation with PbO₂ as key steps. This triaminyl radical has been shown to possess a quartet ground state with a doublet–quartet energy gap of 3.1 kJ mol^?1 by superconducting quantum interference device (SQUID) studies. Despite its high‐spin nature, this triradical is remarkably stable, which allows its separation and recrystallization under ambient conditions. Moreover, this triradical can be stored as a solid for more than one year without serious deterioration. The high stability of the triradical is attributed to effective spin delocalization over the porphyrin segments and steric protection at the nitrogen centers and the porphyrin meso positions.     

Memory of chirality in intramolecular conjugate addition of enolates: a novel access to nitrogen heterocycles with contiguous quaternary and tertiary stereocenters

Nitrogen heterocycles with contiguous quaternary and tertiary stereocenters have been prepared in high enantiomeric purity by intramolecular conjugate addition of enolates generated from alpha-amino acid derivatives via memory of chirality.