Halogen-Bonding-Enabled Photoinduced Atom Transfer Radical Addition/Cyclization Reaction Leading to Tricyclic Heterocycles.

Atom transfer radical addition (ATRA) reactions are crucial for the dual functionalization of unsaturated hydrocarbons. Radical generation, pivotal in ATRA, has seen advancements from thermal to photochemical methods. Recent focus on halogen-bonding-based radical generation, including our group's innovative photochemical approach, offers cost-effective alternatives to transition-metal-dependent photocatalysts. This eliminates the need for high-energy UV light, enhancing the efficiency with noncovalent interactions.

[Development of Molecular Transformation Reactions Using Visible Light and Main Group Elements].

Owing to their ability to induce excitation of specific molecular orbitals or initiate chemical reactions, photochemical reactions have the potential to be more effective at selectively activating target molecules than thermal reactions. The thermal reactions transfer thermal energy to activate molecules, which often leads to the activation of multiple molecular species, including undesired ones, resulting in non-selectivity. This nonselectivity may result in undesirable side reactions or decrease reaction efficiency. Additionally, photochemical reactions can induce selective activation by absorbing specific wavelengths of light. However, visible light-driven photocatalytic reactions typically require expensive transition metal catalysts or organic dyes, leaving plenty of room for improvement. To address the aforementioned issues, the photochemical properties of the main group elements, such as halogens, were optimized and methodologies for visible light-induced reactions were developed. Activation of molecular halogen, halogen-carbon bonds, and halogen bonding interactions were independently investigated and various methodologies were reported. These developed reactions are excellent methodologies that use inexpensive raw materials and are thus predicted to contribute significantly toward sustainability.

Halogen-Bonding-Promoted Photoinduced C-X Borylation of Aryl Halide Using Phenol Derivatives.

This study investigates the photoinduced C-X borylation reaction of aryl halides by forming a halogen-bonding (XB) complex using 2-naphthol as an XB acceptor. The method is chemoselective and broadly functional group tolerant and provides concise access to corresponding boronate esters. Mechanistic studies reveal that forming the XB complex between aryl halide and naphthol acts as an electron donor-acceptor complex to furnish aryl radicals through photoinduced electron transfer.

Visible-Light-Induced Regioselective Functionalization of α-Olefin: Development of One-Pot Photo-Synthesis of C3-Substituted Dihydrobenzofurans.

A method for the catalytic regioselective synthesis of C3-substituted dihydrobenzofurans (DHBs) via [2 + 2] photocycloaddition of alkene and p-benzoquinone is developed. This method realizes the rapid synthesis of DHBs with readily available substrates and simple reaction conditions by using Lewis acid B(C6F5)3 and Lewis base P(o-tol)3 as a catalyst in combination with the classical Paternò-Büchi reaction.

Regulation of adipogenesis through retinoid X receptor and/or peroxisome proliferator-activated receptor by designed lignans based on natural products in 3T3-L1 cells.

We previously synthesized two retinoid X receptor (RXR) agonists, 4'-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid ethyl ester (4'OHE) and 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid ethyl ester (6OHE), based on the structure of magnaldehyde B, a natural product obtained from Magnolia obovata. 4'OHE and 6OHE exhibited different selectivities for peroxisome proliferator-activated receptor (PPAR)/RXR heterodimers. To examine the regulatory effects of these compounds in adipogenesis, 3T3-L1 mouse preadipocytes were treated with a differentiation cocktail with or without test compounds to induce differentiation, and subsequently treated with test compounds in insulin-containing medium every alternate day. Lipid droplets were stained with Oil Red O to examine lipid accumulation. In addition, adipogenesis-related gene expression was measured using RT-qPCR and immunoblotting. The results showed that a PPARγ agonist, 4'OHE, which exerts agonistic effects on PPARγ and RXRα, enhanced adipogenesis similar to rosiglitazone. However, unlike GW501516, a PPARδ agonist, 6OHE and its hydrolysis product (6OHA), which exert agonistic effects on PPARδ and RXRα, suppressed adipogenesis. In a manner similar to 6OHE and 6OHA, bexarotene, an RXR agonist, suppressed adipocyte differentiation, and its anti-adipogenic effect was reversed by an RXR antagonist. Furthermore, 6OHA and bexarotene inhibited the increase in Pparγ2 and Cebpa mRNA levels 2 days after the induction of differentiation. We demonstrated the adipogenic effect of 4'OHE and anti-adipogenic effects of 6OHE and 6OHA in 3T3-L1 cells. Previously, RXR agonists have been reported to positively regulate the differentiation of mesenchymal stem cells into adipocytes, but our current data showed that they inhibited the differentiation of preadipocytes, at least 3T3-L1 cells, into adipocytes.

Antiandrogenic Effects of a Polyphenol in Carex kobomugi through Inhibition of Androgen Synthetic Pathway and Downregulation of Androgen Receptor in Prostate Cancer Cell Lines.

Prostate cancer (PC) represents the most common cancer disease in men. Since high levels of androgens increase the risk of PC, androgen deprivation therapy is the primary treatment; however this leads to castration-resistant PC (CRPC) with a poor prognosis. The progression to CRPC involves ectopic androgen production in the adrenal glands and abnormal activation of androgen signaling due to mutations and/or amplification of the androgen receptor (AR) as well as activation of androgen-independent proliferative pathways. Recent studies have shown that adrenal-derived 11-oxygenated androgens (11-ketotestosterone and 11-ketodihydrotestosterone) with potencies equivalent to those of traditional androgens (testosterone and dihydrotestosterone) are biomarkers of CRPC. Additionally, dehydrogenase/reductase SDR family member 11 (DHRS11) has been reported to be a 17ß-hydroxysteroid dehydrogenase that catalyzes the production of the 11-oxygenated and traditional androgens. This study was conducted to evaluate the pathophysiological roles of DHRS11 in PC using three LNCaP, C4-2 and 22Rv1 cell lines. DHRS11 silencing and inhibition resulted in suppression of the androgen-induced expression of AR downstream genes and decreases in the expression of nuclear AR and the proliferation marker Ki67, suggesting that DHRS11 is involved in androgen-dependent PC cell proliferation. We found that 5,7-dihydroxy-8-methyl-2-[2-(4-hydroxyphenyl)ethenyl]-4H-1-benzopyran-4-one (Kobochromone A, KC-A), an ingredient in the flowers of Carex kobomugi, is a novel potent DHRS11 inhibitor (IC50 = 0.35 µM). Additionally, KC-A itself decreased the AR expression in PC cells. Therefore, KC-A suppresses the androgen signaling in PC cells through both DHRS11 inhibition and AR downregulation. Furthermore, KC-A enhanced the anticancer activity of abiraterone, a CRPC drug, suggesting that it may be a potential candidate for the development of drugs for the prevention and treatment of CRPC.

Selenonium ylides: synthesis, characterization, and applications to photo-induced cyclopropanation reactions.

Carbenes are important and highly reactive intermediates for the synthesis of various complex molecules. They are now an indispensable chemical species in organic chemistry and are used frequently to synthesize complex compounds in drug discovery chemistry. In general, carbenes are synthesized by a combination of transition metal catalysts and diazo compounds or by the decomposition reactions of diazo compounds. This paper reports the development of the visible light for the photochemical generation of carbenes from a novel C,Se-selenonium ylide. Overall, this photochemical carbene generation method using C,Se-selenonium ylide does not require a catalyst, is simple to perform, and enables highly efficient cyclopropanation reactions with alkenes.

Photoinduced Atom Transfer Radical Addition/Cyclization Reaction between Alkynes or Alkenes with Unsaturated α-Halogenated Carbonyls.

We have developed a photochemical ATRA/ATRC reaction that is mediated by halogen bonding interactions. This reaction is caused by the reaction of malonic acid ester derivatives containing bromine or iodine with unsaturated compounds such as alkenes and alkynes in the presence of diisopropylethylamine under visible light irradiation. As a result of various control experiments, it was found that the formation of complexes between amines and halogens by halogen-bonding interaction occurs in the reaction system, followed by the cleavage of the carbon-halogen bonds by visible light, resulting in the formation of carbon radicals. In this reaction, a variety of substrates can be used, and the products, cyclopentenes and cyclopentanes, were obtained by intermolecular addition and intramolecular cyclization.

Photoinduced Atom Transfer Radical Addition Reaction of Olefins with α-Bromo Carbonyls.

The irradiation of halogen-bonded complexes with light leads to the homolysis of carbon-halogen bonds and the formation of the corresponding carbon radical species. However, the only methodology reported for these halogen-bonding complexes is using CBr4 as the halogen-bond donor and its applicability is of great interest. In this study, the atom transfer radical addition (ATRA) reaction of olefins using bromomalonates as halogen-bonding donors was developed. Using 4-phenylpyridine as the halogen-bonding acceptor, the desired reaction proceeded well under external irradiation of 380 nm light to furnish the corresponding ATRA reaction product. The ATRA reaction was effective in generating the corresponding products for a variety of olefins. Furthermore, the ATRA reaction was applicable to bulky ketones, substrates, and malonate esters. The intermediates of the reaction were identified and a plausible reaction mechanism was proposed.

Three-Component Iminolactonization Reaction via Bifunctionalization of Olefins Using Molecular Iodine and Visible Light.

A novel three-component γ-iminolactonization reaction was developed, which relied on the C-C/C-O bond-forming bifunctionalization of olefins using molecular iodine and visible light. This strategy did not require any (heavy) metal reagents for double-bond activation because molecular iodine acted as a rare-metal-alternative reagent through visible light irradiation. In addition, the preactivation of amines and other substrates is not required. The mechanistic investigation revealed that the generated iodine radicals under visible light irradiation reacted with alkenes to form a highly reactive intermediate; then, the three-component reaction of diiodide, malonate, and amine furnished iminolactone. Of note, the developed reaction is simple and realized the diversity-oriented synthesis innovative methodology of γ-iminolactone derivatives in drug discovery chemistry.

In Situ-Generated Halogen-Bonding Complex Enables Atom Transfer Radical Addition (ATRA) Reactions of Olefins.

Although organic-based photocatalysts provide an inexpensive, environmentally friendly alternative, many are incapable of absorption within the visible wavelength range; this ultimately influences their effectiveness. Photocatalytic reactions usually proceed via single electron transfer (SET) or energy transfer (ET) processes from the photoexcited molecules to the various substrates. In our study, the carbohalogenation of olefins was accomplished by combining CBr4 and 4-Ph-pyridine under irradiation. The atom transfer radical addition reaction of olefins was catalyzed by an in situ-formed photocatalyst via halogen bonding to afford a variety of products in moderate to good yields. Essential to the reaction is the formation of a CT complex with the haloalkene, which triggers charge separation processes and, ultimately, leads to the formation of the C-centered radical. While taking advantage of relatively inexpensive, readily available, and environmentally friendly reagents, the indirect activation of the substrate via the photoexcited catalyst paves the way for more efficient routes, especially for otherwise challenging chemical syntheses.

The Novel gem-Dihydroperoxide 12AC3O Suppresses High Phosphate-Induced Calcification via Antioxidant Effects in p53LMAco1 Smooth Muscle Cells.

The excessive intake of phosphate (Pi), or chronic kidney disease (CKD), can cause hyperphosphatemia and eventually lead to ectopic calcification, resulting in cerebrovascular diseases. It has been reported that reactive oxygen species (ROS), induced by high concentrations of Pi loading, play a key role in vascular calcification. Therefore, ROS suppression may be a useful treatment strategy for vascular calcification. 12AC3O is a newly synthesized gem-dihydroperoxide (DHP) that has potent antioxidant effects. In the present study, we investigated whether 12AC3O inhibited vascular calcification via its antioxidative capacity. To examine whether 12AC3O prevents vascular calcification under high Pi conditions, we performed Alizarin red and von Kossa staining, using the mouse aortic smooth muscle cell line p53LMAco1. Additionally, the effect of 12AC3O against oxidative stress, induced by high concentrations of Pi loading, was investigated using redox- sensitive dyes. Further, the direct trapping effect of 12AC3O on reactive oxygen species (ROS) was investigated by ESR analysis. Although high concentrations of Pi loading exacerbated vascular smooth muscle calcification, calcium deposition was suppressed by the treatment of both antioxidants and 12AC3O, suggesting that the suppression of ROS may be a candidate therapeutic approach for treating vascular calcification induced by high concentrations of Pi loading. Importantly, 12AC3O also attenuated oxidative stress. Furthermore, 12AC3O directly trapped superoxide anion and hydroxyl radical. These results suggest that ROS are closely involved in high concentrations of Pi-induced vascular calcification and that 12AC3O inhibits vascular calcification by directly trapping ROS.

Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ-RXR.

A known natural product, magnaldehyde B, was identified as an agonist of retinoid X receptor (RXR) α. Magnaldehyde B was isolated from Magnolia obovata (Magnoliaceae) and synthesized along with more potent analogs for screening of their RXRα agonistic activities. Structural optimization of magnaldehyde B resulted in the development of a candidate molecule that displayed a 440-fold increase in potency. Receptor-ligand docking simulations indicated that this molecule has the highest affinity with the ligand binding domain of RXRα among the analogs synthesized in this study. Furthermore, the selective activation of the peroxisome proliferator-activated receptor (PPAR) δ-RXR heterodimer with a stronger efficacy compared to those of PPARα-RXR and PPARγ-RXR was achieved in luciferase reporter assays using the PPAR response element driven reporter (PPRE-Luc). The PPARδ activity of the molecule was significantly inhibited by the antagonists of both RXR and PPARδ, whereas the activity of GW501516 was not affected by the RXR antagonist. Furthermore, the molecule exhibited a particularly weak PPARδ agonistic activity in reporter gene assays using the Gal4 hybrid system. The obtained data therefore suggest that the weak PPARδ agonistic activity of the optimized molecule is synergistically enhanced by its own RXR agonistic activity, indicating the potent agonistic activity of the PPARδ-RXR heterodimer.

Inhibitory effects of 4-hydroperoxy-2-decenoic acid ethyl ester on phorbol ester- and TGF-ß1-induced MMPs expression.

Matrix metalloproteinases (MMPs), zinc-containing proteinases, play a critical role in tumour progression by degrading extracellular matrix components. MMP2 and MMP9 are secreted from tumour-associated macrophages as well as tumour cells and have been implicated in the formation of the tumour microenvironment. Therefore, the inhibition of these MMPs may suppress tumour progression and metastasis. 4-Hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE) is known to cause apoptosis in the human lung cancer cell line A549 by inducing endoplasmic reticulum (ER) stress. However, the effects of HPO-DAEE on tumour progression remain unclear. HPO-DAEE pre-treatment significantly suppressed phorbol 12-myristate 13-acetate (TPA)-triggered MMP activation in human monocytic THP-1 cells. It also enhanced the expression of haem oxygenase-1, an antioxidant enzyme, and suppressed the TPA-triggered intracellular accumulation of reactive oxygen species (ROS). Furthermore, HPO-DAEE suppressed transforming growth factor-ß1-triggered human prostate cancer PC3 cell migration and this was accompanied by the inhibition of MMP expression and activities. The present results indicate that HPO-DAEE may exert inhibitory effects on tumour progression by suppressing MMP expression and activities.

trans-Diastereoselective Syntheses of γ-Lactones by Visible Light-Iodine-Mediated Carboesterification of Alkenes.

This study aims to develop an intermolecular lactonization reaction of alkenes with carbonyls mediated by visible light and molecular iodine. The one-step reaction involved the carboesterification of alkenes to produce the corresponding lactones in moderate to good yield. It was also revealed that it is possible to control the diastereoselectivity of the reaction by altering the base used and the reaction conditions. When water was added as a solvent, the reaction resulted in the formation of lactones with trans-selectivity. A mechanistic investigation was undertaken and it was found that the reaction requires the generation of an iodine radical from molecular iodine, driven by visible light irradiation, and proceeds via the formation of an iodine radical alkene adduct. The proposed reaction is an example of a rare-metal free intermolecular addition cyclization reaction, which is an environment-friendly chemical process that only uses molecular iodine. In addition, since diastereoselectivity was observed without the use of any specific reagents, the developed methodology is an example of a novel stereoselective transformation using only cost-effective reagents.

Visible Light/Molecular-Iodine-Mediated Intermolecular Spirolactonization Reaction of Olefins with Cyclic Ketones.

In this study, intermolecular spirolactonization via an iodine/visible-light-mediated C-C/C-O bond formation reaction was developed. The developed reaction proceeded to form quaternary carbon centers via carboesterification between cyclic ß-keto esters and olefins, affording spirolactone derivatives in a single step. In addition, the mechanistic investigation revealed that the generation of iodine radicals from molecular iodine driven by visible-light irradiation is a crucial step. The developed reaction proceeded under milder conditions than previously reported procedures as iodine played a role of a conventional transition-metal catalyst, realizing an environmentally friendly, novel molecular transformation.

Olefin Bifunctionalization: A Visible-light Photoredox-catalyzed Aryl Alkoxylation of Olefins.

Olefin bifunctionalization is a facile route to obtain complex molecules from abundant and commercially available olefin feedstocks. Visible light together with a catalytic amount of tris(bipyridine)ruthenium salt catalyzes the aryl alkoxylation of styrenes with aryl diazonium salts in alcohol solvents via a photoredox process. The scope of this proposed reaction with respect to various aryl diazonium salts and styrenes has been investigated.

Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4-Hydroperoxy-2-decenoic Acid Ethyl Ester through Intracellular ROS Accumulation and the Induction of Proapoptotic CHOP Expression.

Royal jelly, a natural product secreted by honeybees, contains several fatty acids, such as 10-hydroxy-2-decenoic acid (DE), and shows anti- and pro-apoptotic properties. 4-Hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE), a DE derivative, exhibits potent antioxidative activity; however, it currently remains unclear whether HPO-DAEE induces cancer-cell death. In the present study, treatment with HPO-DAEE induced human-lung-cancer-A549-cell death (52.7 ± 10.2%) that was accompanied by DNA fragmentation. Moreover, the accumulation of intracellular reactive oxygen species (ROS, 2.38 ± 0.1-fold) and the induction of proapoptotic CCAAT-enhancer-binding-protein-homologous-protein (CHOP) expression (18.4 ± 4.0-fold) were observed in HPO-DAEE-treated cells. HPO-DAEE-elicited CHOP expression and cell death were markedly suppressed by pretreatment with N-acetylcysteine (NAC), an antioxidant, by 2.40 ± 1.57-fold and 5.7 ± 1.6%, respectively. Pretreatment with 4-phenylbutyric acid (PBA), an inhibitor of endoplasmic reticulum stress, also suppressed A549-cell death (38.4 ± 1.1%). Furthermore, we demonstrated the involvement of extracellular-signal-regulated protein kinase (ERK) and p38-related signaling in HPO-DAEE-elicited cell-death events. Overall, we concluded that HPO-DAEE induces A549-cell apoptosis through the ROS-ERK-p38 pathway and, at least in part, the CHOP pathway.

Visible-Light-Mediated Iminyl Radical Generation from Benzyl Oxime Ether: Synthesis of Pyrroline via Hydroimination Cyclization.

The treatment of an  O-(4-methoxybenzyl) oxime ether bearing an olefin substituent and 1-chloroanthraquinone (1-Cl-AQN) catalyst in 2-butanone under visible-light irradiation affords pyrroline via an iminyl radical intramolecular hydroimination. Mechanistic studies indicate that iminyl radical generation mainly proceeds by hydrogen abstraction of the photocatalyst from the benzyl position of the oxime. Moreover, the hydrogen atom was identified in circulation from the benzylic position of the substrates between AQN and 2-butanone to quench the carbon radical without requiring any additional reagents.

Effects of gem-dihydroperoxides against mutant copper­zinc superoxide dismutase-mediated neurotoxicity.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis, and death. Although its neuropathology is well investigated, currently, effective treatments are unavailable. The mechanism of ALS involves the aggregation and accumulation of several mutant proteins, including mutant copper­zinc superoxide dismutase (SOD1), TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) proteins. Previous reports have shown that excessive oxidative stress, associated with mitochondrial dysfunction and mutant protein accumulation, contributes to ALS pathology. The present study focuses on the promotion of SOD1 misfolding and aggregation by oxidative stress. Having recently synthesized novel organic gem-dihydroperoxides (DHPs) with high anti-oxidant activity, we now examined whether DHPs reduce the mutant SOD1-induced intracellular aggregates involved in oxidative stress. We found that, among DHPs, 12AC2O significantly inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Moreover, immunofluorescence staining with redox-sensitive dyes showed that 12AC2O reduced the excessive level of intracellular mutant SOD1-induced reactive oxygen species (ROS). Additionally, ESR analysis showed that 12AC2O exerts a direct scavenging effect against the hydroxyl radical (OH) and the superoxide anion (O2-). These results suggest that 12AC2O is a very useful agent in combination with other agents against ALS.