Exploring the Antiangiogenic and Anti-Inflammatory Potential of Homoisoflavonoids: Target Identification Using Biotin Probes.

Chemical proteomics using biotin probes of natural products have significantly advanced our understanding of molecular targets and therapeutic potential. This review highlights recent progress in the application of biotin probes of homoisoflavonoids for identifying binding proteins and elucidating mechanisms of action. Notably, homoisoflavonoids exhibit antiangiogenic, anti-inflammatory, and antidiabetic effects. A combination of biotin probes, pull-down assays, mass spectrometry, and molecular modeling has revealed how natural products and their derivatives interact with several proteins such as ferrochelatase (FECH), soluble epoxide hydrolase (sEH), inosine monophosphate dehydrogenase 2 (IMPDH2), phosphodiesterase 4 (PDE4), and deoxyhypusine hydroxylase (DOHH). These target identification approaches pave the way for new therapeutic avenues, especially in the fields of oncology and ophthalmology. Future research aimed at expanding the repertoire of target identification using biotin probes of homoisoflavonoids promises to further elucidate the complex mechanisms and develop new drug candidates.

Challenges and opportunities of developing small-molecule therapies for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of vision loss in senior adults. The disease can be categorized into two types: wet AMD and dry AMD. Wet AMD, also known as exudative or neovascular AMD, is less common but more severe than dry AMD and is responsible for 90% of the visual impairment caused by AMD and affects 20 million people worldwide. Current treatment options mainly involve biologics that inhibit the vascular endothelial growth factor or complement pathways. However, these treatments have limitations such as high cost, injection-related risks, and limited efficacy. Therefore, new therapeutic targets and strategies have been explored to improve the outcomes of patients with AMD. A promising approach is the use of small-molecule drugs that modulate different factors involved in AMD pathogenesis, such as tyrosine kinases and integrins. Small-molecule drugs offer advantages, such as oral administration, low cost, good penetration, and increased specificity for the treatment of wet and dry AMD. This review summarizes the current status and prospects of small-molecule drugs for the treatment of wet AMD. These advances are expected to support the development of effective and targeted treatments for patients with AMD.

Observation and manipulation of quantum interference in a superconducting Kerr parametric oscillator.

Quantum tunneling is the phenomenon that makes superconducting circuits "quantum". Recently, there has been a renewed interest in using quantum tunneling in phase space of a Kerr parametric oscillator as a resource for quantum information processing. Here, we report a direct observation of quantum interference induced by such tunneling and its dynamics in a planar superconducting circuit through Wigner tomography. We experimentally elucidate all essential properties of this quantum interference, such as mapping from Fock states to cat states, a temporal oscillation due to the pump detuning, as well as its characteristic Rabi oscillations and Ramsey fringes. Finally, we perform gate operations as manipulations of the observed quantum interference. Our findings lay the groundwork for further studies on quantum properties of superconducting Kerr parametric oscillators and their use in quantum information technologies.

(S)-3-(3-Fluoro-4-Methoxybenzyl)-5,6,7-Trimethoxychroman-4-One Suppresses the Proliferation of Huh7 Cells by Up-regulating P21 and Inducing G2/M Phase Arrest.

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a prevalent type of cancer worldwide. Although sorafenib is the only chemotherapy agent used for HCC, there is a need to discover a more potent anticancer agent with reduced side-effects. The compound, (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (FMTC), was designed to inhibit tubulin assembly but its specific mechanisms of action have not been previously investigated. Herein, we investigated the regulation mechanisms by which FMTC affects the proliferation of the HCC cell line, Huh7. MATERIALS AND METHODS: The effects of FMTC on cell viability and growth were analyzed in the HCC cell line, Huh7. Cell cycle and apoptosis regulated by FMTC were analyzed using flow cytometry. To verify the regulation of mRNA and protein expression of cell proliferation-related factors by FMTC in Huh7 cells, RT-qPCR and western blot analyses were employed. RESULTS: FMTC suppressed cell division dose-dependently by triggering cell cycle arrest at the G2/M phase via p21 up-regulation. The increased phosphorylation of histone H3 on Ser-10 and the condensation of chromatin in FMTC-treated cells indicated mitotic arrest. Prolonged FMTC-induced cell cycle arrest triggered apoptosis. CONCLUSION: FMTC inhibits the proliferation of human liver cancer cells by up-regulating p21, thereby inducing cell cycle arrest at the G2/M phase. These findings highlight FMTC as a novel agent for HCC treatment.

Synthesis of proposed structure of ledebourin A.

Naturally occurring homoisoflavonoids have attracted significant attention in the field of medicinal chemistry due to their potential health benefits and diverse range of biological properties. Recently, C-prenylated homoisoflavonoids, namely ledebourin A, B, and C, were isolated from the bulbs of Ledebouria floribunda and have exhibited potent antioxidant activity. In this study, we successfully synthesized ledebourin A and its regioisomer, compounds 1 and 9. By comparing the NMR spectra of the synthesized compounds with those of reported ledebourin A, we observed discrepancies. Nonetheless, our synthesis and subsequent findings offer valuable insights into the structural revision and biological activities of these unique prenylated homoisoflavonoids. Both synthesized compounds 1 and 9 exhibited no toxicity towards Hep-G2 cells and displayed the ability to recover glyceraldehyde-induced cell death, suggesting their potential as protective agents against liver damage.

Cremastranone-Derived Homoisoflavanes Suppress the Growth of Breast Cancer Cells via Cell Cycle Arrest and Caspase-Independent Cell Death.

Breast cancer is the most common cancer and a frequent cause of cancer-related deaths among women wordlwide. As therapeutic strategies for breast cancer have limitations, novel chemotherapeutic reagents and treatment strategies are needed. In this study, we investigated the anti-cancer effect of synthetic homoisoflavane derivatives of cremastranone on breast cancer cells. Homoisoflavane derivatives, SH-17059 and SH-19021, reduced cell proliferation through G2/M cell cycle arrest and induced caspase-independent cell death. These compounds increased heme oxygenase-1 (HO-1) and 5-aminolevulinic acid synthase 1 (ALAS1), suggesting downregulation of heme. They also induced reactive oxygen species (ROS) generation and lipid peroxidation. Furthermore, they reduced expression of glutathione peroxidase 4 (GPX4). Therefore, we suggest that the SH-17059 and SH-19021 induced the caspase-independent cell death through the accumulation of iron from heme degradation, and the ferroptosis might be one of the potential candidates for caspase-independent cell death.

Synthesis and Structure Revision of Naturally Occurring Homoisoflavane (+)-Dracaeconolide B.

Dracaeconolide B (1), a naturally occurring homoisoflavane, was isolated from the red resin of Dracaena cochinchinensis. Efforts have been made to elucidate the exact structure of compound 1 since it was confirmed that dracaeconolide B did not contain a 7-hydroxy-5,8-dimethoxy moiety. The structure of dracaeconolide B was revised by synthesis of three homoisoflavanes containing a 5,6,7-trioxygenated moiety each and analysis by NMR spectroscopy. The revised structure of dracaeconolide B was proposed as 3-(4-hydroxybenzyl)-7-hydroxy-5,6-dimethoxychromane. Noyori's Ru-catalyzed asymmetric transfer hydrogenation was used to synthesize (+)-dracaeconolide B. The absolute configuration of the compound was revised to S based on the results obtained by the electronic circular dichroism calculation. We examined the antiangiogenic activity of (S)- and (R)-dracaeconolide B and of synthetic 5,6,7- and 5,7,8-trioxygenated homoisoflavanes. The results can potentially help in the synthesis of related natural products and support drug discovery to treat neovascular eye diseases.

Mouse Pharmacokinetics and In Vitro Metabolism of SH-11037 and SH-11008, Synthetic Homoisoflavonoids for Retinal Neovascularization.

Cremastranone is a member of the homoisoflavanone family with anti-angiogenic activity in the eyes. SH-11037, a potent and selective synthetic homoisoflavonoid derived from cremastranone, was studied here for pharmacokinetics and metabolism characterization with a special focus on esterase-mediated hydrolysis. SH-11037 was shown to be converted rapidly and nearly completely to SH-11008 following an intravenous dose in mice. SH-11008 showed a high systemic clearance well exceeding the hepatic blood flow in mice. Neither SH-11037 nor SH-11008 were detected in plasma following oral administration of SH-11037 and SH-11008 in mice. Carboxylesterase was shown to be responsible for the rapid and quantitative hydrolysis of SH-11037 to SH-11008 in mouse plasma; the hydrolytic bioconversion was much slower in dog and human plasma, with butyrylcholinesterase and paraoxonase 1 likely being responsible. In vitro metabolism studies with liver S9 fractions suggested that SH-11008 was likely to have a high hepatic metabolic clearance with a predicted hepatic extraction ratio close to 1 in both mouse and human. In conclusion, SH-11037 and SH-11008 both appear to possess pharmacokinetic profiles suboptimal as a systemic agent. SH-11008 is suggested to possess a low potential for systemic toxicity suitable as a topical ocular therapeutic agent.

Synthetic Homoisoflavane Derivatives of Cremastranone Suppress Growth of Colorectal Cancer Cells through Cell Cycle Arrest and Induction of Apoptosis.

Colorectal cancer is diagnosed as the third most prevalent cancer; thus, effective therapeutic agents are urgently required. In this study, we synthesized six homoisoflavane derivatives of cremastranone and investigated their cytotoxic effects on the human colorectal cancer cell lines HCT116 and LoVo. We further examined the related mechanisms of action using two of the potent compounds, SH-19027 and SHA-035. They substantially reduced the cell viability and proliferation in a dose-dependent manner. Treatment with SH-19027 and SHA-035 induced cell cycle arrest at the G2/M phase and increased expression of p21 both of which are implicated in cell cycle control. In addition, the apoptotic cell population and apoptosis-associated marker expression were accordingly increased. These results suggest that the synthesized cremastranone derivatives have anticancer effects through the suppression of cell proliferation and induction of apoptosis. Therefore, the synthesized cremastranone derivatives could be applied as novel therapeutic agents against colorectal cancer.

Small-molecule inhibitors of ferrochelatase are antiangiogenic agents.

Activity of the heme synthesis enzyme ferrochelatase (FECH) is implicated in multiple diseases. In particular, it is a mediator of neovascularization in the eye and thus an appealing therapeutic target for preventing blindness. However, no drug-like direct FECH inhibitors are known. Here, we set out to identify small-molecule inhibitors of FECH as potential therapeutic leads using a high-throughput screening approach to identify potent inhibitors of FECH activity. A structure-activity relationship study of a class of triazolopyrimidinone hits yielded drug-like FECH inhibitors. These compounds inhibit FECH in cells, bind the active site in cocrystal structures, and are antiangiogenic in multiple in vitro assays. One of these promising compounds was antiangiogenic in vivo in a mouse model of choroidal neovascularization. This foundational work may be the basis for new therapeutic agents to combat not only ocular neovascularization but also other diseases characterized by FECH activity.

Total Synthesis of Naturally Occurring 5,7,8-Trioxygenated Homoisoflavonoids.

Homoisoflavonoids are in the subclass of the larger family of flavonoids but have one more alkyl carbon than flavonoids. Among them, 5,7,8-trioxygenated homoisoflavonoids have not been extensively studied for synthesis and biological evaluation. Our current objective is to synthesize 2 5,7,8-trioxygenated chroman-4-ones and 12 5,7,8-trioxygenated homoisoflavonoids that have been isolated from the plants Bellevalia eigii, Drimiopsis maculata, Ledebouria graminifolia, Eucomis autumnalis, Eucomis punctata, Eucomis pallidiflora, Chionodoxa luciliae, Muscari comosum, and Dracaena cochinchinensis. For this purpose, 1,3,4,5-tetramethoxybenzene and 4'-benzyloxy-2',3'-dimethoxy-6'-hydroxyacetophenone were used as starting materials. Asymmetric transfer hydrogenation using Noyori's Ru catalyst provided 5,7,8-trioxygenated-3-benzylchroman-4-ones with R-configuration in high yield and enantiomeric excess. By selective deprotection of homoisoflavonoids using BCl3, the total synthesis of natural products including 10 first syntheses and three asymmetric syntheses has been completed, and three isomers of the reported dracaeconolide B could be provided. Our research on 5,7,8-trioxygenated homoisoflavonoids would be useful for the synthesis of related natural products and pharmacological applications.

Interactions in the bond-frustrated helimagnet ZnCr2Se4 investigated by NMR.

The zero field 53Cr nuclear magnetic resonance was measured at low temperatures to investigate the interactions in the bond-frustrated S = 3/2 Heisenberg helimagnet ZnCr2Se4. A quadratic decrease of the sublattice magnetization was determined from the temperature dependence of the isotropic hyperfine field. We calculated the magnetization using linear spin wave theory for the incommensurate spiral spin order and compared this outcome with experimental results to estimate the coupling constants. The hyperfine fields at Cr and Se ions provide evidences that the spin polarization of Cr ions is transferred to neighboring Se ions due to the covalent bonding between them, resulting in reduced magnetic moment in the Cr ion. This observation indicates that the Jahn-Teller effect, which leads to distortion inducing spin-lattice coupling, is not completely missing in ZnCr2Se4.

Enantioselective Synthesis of Homoisoflavanones by Asymmetric Transfer Hydrogenation and Their Biological Evaluation for Antiangiogenic Activity.

Neovascular eye diseases are a major cause of blindness. Excessive angiogenesis is a feature of several conditions, including wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity. Development of novel antiangiogenic small molecules for the treatment of neovascular eye disease is essential to provide new therapeutic leads for these diseases. We have previously reported the therapeutic potential of anti-angiogenic homoisoflavanone derivatives with efficacy in retinal and choroidal neovascularization models, although these are racemic compounds due to the C3-stereogenic center in the molecules. This work presents asymmetric synthesis and structural determination of anti-angiogenic homoisoflavanones and pharmacological characterization of the stereoisomers. We describe an enantioselective synthesis of homoisoflavanones by virtue of ruthenium-catalyzed asymmetric transfer hydrogenation accompanying dynamic kinetic resolution, providing a basis for the further development of these compounds into novel experimental therapeutics for neovascular eye diseases.

Fe and Co NMR studies of magnetoelectric Co2 Y-type hexaferrite BSCFAO.

The Fe3+ and Co2+ NMR spectra for Ba0.3Sr1.7Co2(Fe0.96Al0.04)12O22 (BSCFAO) and Ba0.3Sr1.7Co2Fe12O22 (BSCFO) were obtained in a zero magnetic field at a low temperature. We observed change in the enhancement effect of the NMR signals depending on the setting field, which was varied when applied along the b-axis and then turned off before the measurement was taken. The experimental results indicate that the magnetic structure changes from an alternating longitudinal cone to a transverse cone when the setting field is 250 mT. They also show that the spins of Co2+ ions together with those of Fe3+ ions constitute a part of the overall magnetic structure and that the substitution of Al3+ for Fe3+ weakens the magnetic anisotropy within the easy plane. From a comparison of the enhancement factors of the Fe3+ NMR obtained with the RF pulse applied along the a-axis and the c-axis, we found that the magnetic easy plane anisotropy is approximately 16 times greater than the anisotropy within the easy plane. No changes of the NMR spectra were observed under an electric field of 1.2 MV m-1.

Phonon engineering in proximity enhanced superconductor heterostructures.

In this research, we tailor the phonon density of states (DOS) in thin superconducting films to suppress quasiparticle losses. We examine a model system of a proximity-enhanced three-layered Al/Nb/Al heterostructure and show that the local quantized phonon spectrum of the ultrathin Al cladding layers in the heterostructure has a pronounced effect on the superconducting resonator's quality factors. Instead of a monotonic increase of quality factors with decreasing temperatures, we observe the quality factor reaches a maximum at 1.2 K in 5/50/5 nm Al/Nb/Al microstrip resonators, because of a quantized phonon ladder. The phonon DOS may be engineered to enhance the performance of quantum devices.

Characterization of particulate matter from diesel passenger cars tested on chassis dynamometers.

Emission characterization of particle number as well as particle mass from three diesel passenger cars equipped with diesel particulate filter (DPF), diesel oxidation catalyst (DOC) and exhaust gas recirculation (EGR) under the vehicle driving cycles and regulatory cycle. Total particle number emissions (PNEs) decreased gradually during speed-up of vehicle from 17.3 to 97.3km/hr. As the average vehicle speed increases, the size-segregated peak of particle number concentration shifts to smaller size ranges of particles. The correlation analysis with various particulate components such as particle number concentration (PNC), ultrafine particle number concentration (UFPNC) and particulate matter (PM) mass was conducted to compare gaseous compounds (CO, CO2, HC and NOx). The UFPNC and PM were not only emitted highly in Seoul during severe traffic jam conditions, but also have good correlation with hydrocarbons and NOx influencing high potential on secondary aerosol generation. The effect of the dilution temperature on total PNC under the New European Driving Cycle (NEDC), was slightly higher than the dilution ratio. In addition, the nuclei mode (DP: ≤13nm) was confirmed to be more sensitive to the dilution temperature rather than other particle size ranges. Comparison with particle composition between vehicle speed cycles and regulatory cycle showed that sulfate was slightly increased at regulatory cycle, while other components were relatively similar. During cold start test, semivolatile nucleation particles were increased due to effect of cold environment. Research on particle formation dependent on dilution conditions of diesel passenger cars under the NEDC is important to verify impact on vehicular traffic and secondary aerosol formation in Seoul.

Characteristics of on-road NOx emissions from Euro 6 light-duty diesel vehicles using a portable emissions measurement system.

This paper presents the on-road nitrogen oxides (NOx) emissions measurements from Euro 6 light-duty diesel vehicles using a portable emissions measurement system on the predesigned test routes in the metropolitan area of Seoul, Korea. Six diesel vehicles were tested and the NOx emissions results were analyzed according to the driving routes, driving conditions, data analysis methods, and ambient temperatures. Total NOx emissions for route 1, which has higher driving severity than route 2, differed by -4-60% from those for route 2. The NOx emissions when the air conditioner (AC) was used were higher by 68% and 85%, on average, for routes 1 and 2, respectively, compared to when the AC was not used. The analytical results for NOx emissions by the moving averaging window method were higher by 2-31% compared to the power binning method. NOx emissions at lower ambient temperatures (0-5°C) were higher by 82-192% compared to those at higher ambient temperatures (15-20°C). This result shows that performance improvements of exhaust gas recirculation and the NOx after-treatment system will be needed at lower ambient temperatures.

Overestimation of on-road air quality surveying data measured with a mobile laboratory caused by exhaust plumes of a vehicle ahead in dense traffic areas.

The unintended influence of exhaust plumes emitted from a vehicle ahead to on-road air quality surveying data measured with a mobile laboratory (ML) at 20-40 km h-1 in dense traffic areas was investigated by experiment and life-sized computational fluidic dynamics (CFD) simulation. The ML equipped with variable sampling inlets of five columns by four rows was used to measure the spatial distribution of CO2 and NOx concentrations when following 5-20 m behind a sport utility vehicle (SUV) as an emitter vehicle equipped with a portable emission monitoring system (PEMS). The PEMS measured exhaust gases at the tailpipe for input data of the CFD simulations. After the CFD method was verified with experimental results of the SUV, dispersion of exhaust plumes emitted from a bus and a sedan was numerically analyzed. More dilution of the exhaust plume was observed at higher vehicle speeds, probably because of eddy diffusion that was proportional to turbulent kinetic energy and vehicle speed. The CO2 and NOx concentrations behind the emitter vehicle showed less overestimation as both the distance between the two vehicles and their background concentrations increased. If the height of the ML inlet is lower than 2 m and the ML travels within 20 m behind a SUV and a sedan ahead at 20 km h-1, the overestimation should be considered by as much as 200 ppb in NOx and 80 ppm in CO2. Following a bus should be avoided if possible, because effect of exhaust plumes from a bus ahead could not be negligible even when the distance between the bus and the ML with the inlet height of 2 m, was more than 40 m. Recommendations are provided to avoid the unintended influence of exhaust plumes from vehicles ahead of the ML during on-road measurement in urban dense traffic conditions.

Electrical control of large magnetization reversal in a helimagnet.

Reversal of magnetization M by an electrical field E has been a long-sought phenomenon in materials science because of its potential for applications such as memory devices. However, the phenomenon has rarely been achieved and remains a considerable challenge. Here we report the large M reversal by E in a multiferroic Ba0.5Sr1.5Zn2(Fe0.92Al0.08)12O22 crystal without any external magnetic field. Upon sweeping E through the range of ±2 MV m(-1), M varied quasi-linearly in the range of ±2 µB per f.u., resulting in the M reversal. Strong electrical modulation of M at zero magnetic field were observable up to ~\n150 K. Nuclear magnetic resonance measurements provided microscopic evidence that the electric field and the magnetic field play equivalent roles in modulating the volume of magnetic domains. Our results suggest that the soft ferrimagnetism and the associated transverse conical state are key ingredients to achieve the large magnetization reversal at fairly high temperatures.