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

Ruptured Medullary Hemangioblastoma Mimicking a Craniocervical Junction Dural Arteriovenous Fistula with a Pseudoaneurysm

Hemangioblastomas (HBMs) are rare vascular tumors commonly located in the posterior fossa of adults. A mid-50s patient presented with sudden unconsciousness. Computed tomography scans revealed acute hemorrhages around the posterior fossa, predominantly in the subarachnoid space. Digital subtraction angiography (DSA) revealed an 8-mm round lesion filled with contrast agent, fed by the C1 segmental artery of the left vertebral artery (VA), showing early venous drainage to the spinal cord and brainstem. Emergent embolization was attempted under suspicion of a ruptured dural arteriovenous fistula, resulting in parent artery occlusion due to feeder selection failure. Follow-up DSA after a month depicted a persistent aneurysm via collaterals from both VAs. Consequently, the decision was made to proceed with surgical intervention, leading to the resection of the lesion, confirming its diagnosis as a HBM through histological examination. This case underscores the potential for misdiagnosis when HBMs with an intratumoral shunt mimic vascular shunt lesions

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 anti-angiogenic 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

Valence states and spin structure of spinel FeV2O4 with different orbital degrees of freedom

The electronic structure of spinel FeV2O4, which contains two Jahn-Teller active Fe and V ions, has been investigated by employing soft x-ray absorption spectroscopy (XAS), soft x-ray magnetic circular dichroism (XMCD), and nuclear magnetic resonance (NMR). XAS indicates that V ions are trivalent and Fe ions are nearly divalent. The signs of V and Fe 2p XMCD spectra are opposite to each other. It is found that the effect of the V 3d spin-orbit interaction on the V 2p XMCD spectrum is negligible, indicating that the orbital ordering of V t2g states occurs from the real orbital states and that the orbital moment of a V3+ ion is mostly quenched. NMR shows that V spins are canted to have a Yafet-Kittel-type triangular spin configuration

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

Multiscale modeling and control of crystal shape and size distributions: accounting for crystal aggregation, evaluation of continuous crystallization systems and run-to-run control

Crystallization plays a vital role in separation and purification methods for the production of therapeutic drugs. Considering the fact that crystal size and shape distributions have a significant influence on the bioavailability of drugs such as the dissolution rate, filterability, and stability as a carrier to the target site, the production of crystals with desired size and shape distributions is of particular interest to the pharmaceutical industry. Motivated by these considerations, this dissertation focuses on the development of a multiscale modeling and simulation framework for crystallization processes that elucidates the relationship between molecular-level processes like crystal nucleation, growth and aggregation and macroscopically-observable process behavior and allows computing optimal design and operation conditions. Using protein crystallization as a model system, the multiscale framework encompasses: a) equilibrium Monte-Carlo modeling for computing solid-liquid phase diagrams and determining initial crystallization conditions that favor crystal nucleation, b) kinetic Monte-Carlo modeling for simulating crystal growth and aggregation and predicting the evolution of crystal shape distribution, and c) integrated multiscale computation linking molecular-level models and continuous-phase macroscopic equations, covering both batch and continuous crystallization systems. The multiscale model parameters and predictions are calibrated and tested with respect to available experimental data. Then, this dissertation addresses model predictive controller designs that utilize the insights and results from the multiscale modeling work and real-time measurements of solute concentration and temperature to manipulate crystallizer conditions that lead to the production of crystals with desired size and shape distributions. To enhance the ability of the predictive controller to deal with batch-to-batch parametric drifts, a common problem in industrial crystallization owing to changes, for example, in the pH level or impurity concentration in the feedstock container, a run-to-run-based model parameter estimation scheme will be presented that uses moving horizon estimation principles to update the predictive controller model parameters after each batch and leads to the consistent production of crystals of desired shape at the end of each batch

Multiscale modeling and control of crystal shape and size distributions: accounting for crystal aggregation, evaluation of continuous crystallization systems and run-to-run control

Crystallization plays a vital role in separation and purification methods for the production of therapeutic drugs. Considering the fact that crystal size and shape distributions have a significant influence on the bioavailability of drugs such as the dissolution rate, filterability, and stability as a carrier to the target site, the production of crystals with desired size and shape distributions is of particular interest to the pharmaceutical industry. Motivated by these considerations, this dissertation focuses on the development of a multiscale modeling and simulation framework for crystallization processes that elucidates the relationship between molecular-level processes like crystal nucleation, growth and aggregation and macroscopically-observable process behavior and allows computing optimal design and operation conditions. Using protein crystallization as a model system, the multiscale framework encompasses: a) equilibrium Monte-Carlo modeling for computing solid-liquid phase diagrams and determining initial crystallization conditions that favor crystal nucleation, b) kinetic Monte-Carlo modeling for simulating crystal growth and aggregation and predicting the evolution of crystal shape distribution, and c) integrated multiscale computation linking molecular-level models and continuous-phase macroscopic equations, covering both batch and continuous crystallization systems. The multiscale model parameters and predictions are calibrated and tested with respect to available experimental data. Then, this dissertation addresses model predictive controller designs that utilize the insights and results from the multiscale modeling work and real-time measurements of solute concentration and temperature to manipulate crystallizer conditions that lead to the production of crystals with desired size and shape distributions. To enhance the ability of the predictive controller to deal with batch-to-batch parametric drifts, a common problem in industrial crystallization owing to changes, for example, in the pH level or impurity concentration in the feedstock container, a run-to-run-based model parameter estimation scheme will be presented that uses moving horizon estimation principles to update the predictive controller model parameters after each batch and leads to the consistent production of crystals of desired shape at the end of each batch