Stereocontrolled access to the hexacyclic core of FD-594 has been achieved. The key steps include the intramolecular S(N)Ar reaction for construction of the densely functionalized xanthone skeleton, the stereoselective lactone cleavage using a chiral nucleophile to induce the axial stereochemistry, and the SmI(2)-mediated pinacol cyclization for the stereocontrolled conversion of axially chiral biaryl dialdehyde into the corresponding trans diol.

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity, but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (M pro , also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to sub-micromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern (VOCs), including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

Drug absorption via the intestinal tissue is modulated by membrane permeability and metabolism in intestinal epithelial cells (IECs). In drug discovery research, using human IECs to evaluate membrane permeability and metabolic stability can offer very useful information when exploring for drug candidate compounds that have good bioavailability and when trying to predict the fraction absorbed and intestinal availability in humans. Here, we evaluated the pharmacokinetic functions of human IECs differentiated from human induced pluripotent stem cells (hiPSCs) in 3D cultures. As human IECs differentiated in 3D cultures form intestinal organoids and spheroids (herein termed organoids), their morphology makes it difficult to evaluate their pharmacokinetic functions. Therefore, we dissociated intestinal organoids into single cells and attempted to purify human IECs. We found that hiPSC-derived IECs (hiPSC-IECs) expressed the epithelial cell adhesion molecule (EpCAM) and could be highly purified by sorting EpCAM+ cells. The hiPSC-IEC monolayer showed a high TEER value (approximately 350 Ω × cm 2). In addition, hiPSC-IECs oxidatively metabolized terfenadine (CYP3A and CYP2J2 substrate) and midazolam (CYP3A substrate). These results indicated that hiPSC-IECs form tight-junction and have cytochrome P450 enzymatic activities. In conclusion, we developed a novel application of hiPSCderived intestinal organoids for drug testing.

We examined the degradation of amaranth, a representative azo dye, by Bjerkandera adusta Dec 1. The degradation products were analyzed by high performance liquid chromatography (HPLC), visible absorbance, and electrospray ionization time-of-flight mass spectroscopy (ESI-TOF-MS). At the primary culture stage (3 days), the probable reaction intermediates were 1-aminonaphthalene-2,3,6-triol, 4-(hydroxyamino) naphthalene-1-ol, and 2-hydroxy-3-[2-(4-sulfophenyl) hydrazinyl] benzenesulfonic acid. After 10 days, the reaction products detected were 4-nitrophenol, phenol, 2-hydroxy-3-nitrobenzenesulfonic acid, 4-nitrobenzene sulfonic acid, and 3,4'-disulfonyl azo benzene, suggesting that no aromatic amines were created. Manganese-dependent peroxidase activity increased sharply after 3 days culture. Based on these results, we herein propose, for the first time, a degradation pathway for amaranth. Our results suggest that Dec 1 degrades amaranth via the combined activities of peroxidase and hydrolase and reductase action.

We successfully developed a new achromatic quarter wave film for anti-reflection of OLEDs, consisting of multiple layers of liquid crystal materials. Applying an original optical design, a new liquid crystal compound, and multi-layer coating technology, we realized OLEDs with very low reflection in all viewing angles. This new film can be produced in a rolled single-sheet state, which enables the manufacture of a circular polarizer with high productivity by a conventional roll-to-roll process. Author Keywordsliquid crystals; quarter wave film; wide viewing angle; OLED; optical compensation film; discotic material. Objectives and BackgroundThe rapid spread of mobile devices, led by smartphones and tablet PCs, is progressing. OLEDs are growing in popularity as the display technology for these applications. OLEDs are well suited for mobile devices due to the high color saturation in their light emission, large field of view, and thin profile. However, a circular polarizing film is indispensable for OLEDs to obtain good black mode performance.Conventionally, achromatic quarter wave films (QWFs) have been used for the circular polarizing film. A superposition of a /4 and a /2 film or a polycarbonate-derivative QWF has been used because of their achromatic optical performance. However, these films' drawbacks include a narrow anti-reflection viewing angle and a complicated production process.To solve these problems, we developed a new achromatic QWF consisting of multiple layers of liquid crystal (LC) materials. We extended the alignment technologies of discotic and calamitic (rod-shaped) LC materials which we have been developing for many years [1,2], and succeeded in controlling the multi-layer alignment. Further, we applied a new optical design that allows adjustment of the total out-of-plane retardation of the multiple layers so that a wide anti-reflection viewing angle is obtained. This achromatic QWF can be produced by a roll-to-roll process because the alignment direction of each of the two LC layers is independently controllable. Results and DiscussionOptical Design: A circular polarizer in combination with a reflector prevents reflection by suppressing the exit of incident light. The black mode of OLEDs, which is derived from the light shielding characteristics of the circular polarizer, has a great influence on display performance properties such as contrast and color. The QWF is characterized by the wavelength dispersion of its birefringence. It is not easy to provide the same characteristics over the entire range of visible light.There are two ways to control the wavelength dispersion. One is to use reverse wavelength dispersion materials [3], and the other is to stack retardation films with an axial design (a superposition of a /4 and a /2 film) [4]. It is reported that some materials exhibit this reverse wavelength dispersion. However, the dispersion obtained by a single sheet of retardation film is not enough to achieve achromaticity. Therefore, we attempted the second approach, stacking retardati...

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In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622, a novel inhibitor of SARS-CoV-2 main protease (Mpro, also known as 3C-like protease), decreases viral load and ameliorates the disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to sub-micromolar concentrations in cells. Oral administration of S 217622 demonstrated eminent pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern (VOCs), including the highly pathogenic Delta variant and the recently emerged Omicron variant. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase II/III clinical trial, possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.