Chiral Template-Directed Regio‑, Diastereo‑, and Enantioselective Photodimerization of an Anthracene Derivative Assisted by Complementary Amidinium–Carboxylate Salt Bridge Formation

A series of optically active amidine dimers composed of <i>m</i>-terphenyl backbones joined by a variety of linkers, such as achiral and chiral <i>p</i>-phenylene and chiral amide linkers, were synthesized and used as templates for the regio- (head-to-tail (HT) or head-to-head (HH)), diastereo- (<i>anti</i> or <i>syn</i>), and enantioselective [4 + 4] photocyclodimerization of an achiral <i>m</i>-terphenyl-based carboxylic acid monomer bearing a prochiral 2-substituted anthracene at one end (<b>1</b>) through complementary amidinium–carboxylate salt bridges. The amidine dimers linked by <i>p</i>-phenylene linkages almost exclusively afforded the chiral <i>syn</i>-HT and <i>anti</i>-HH dimers at 25 °C, while those joined by amide linkers produced all four dimers. The <i>p</i>-phenylene-linked templates tended to enhance the <i>syn</i>-HT-photodimer formation at high temperatures with no significant changes in the product enantiomeric excess (ee), while the <i>anti</i>-HH-photodimer formation remarkably increased with the decreasing temperature accompanied by a significant enhancement of the product ee up to −86% at −50 °C. Temperature-dependent inversion of the chirality of the <i>anti</i>-HH dimer was observed when the chiral phenylene-linked amidine dimer was used and the product ee was changed from 22% at 50 °C to −86% at −50 °C. A similar enhancement of the enantioselectivity of the <i>anti</i>-HH dimer was also observed for the chiral amide-linked template, producing the <i>anti</i>-HH dimer with up to −88% ee at −50 °C. The observed difference in the regio-, diastereo-, and enantioselectivities due to the difference in the linker structures of the amidine dimers during the template-directed photodimerization of <b>1</b> was discussed on the basis of a reversible conformational change in the amidine dimers complexed with <b>1</b>

Cobalt(II)-Salen-Linked Complementary Double-Stranded Helical Catalysts for Asymmetric Nitro-Aldol Reaction

Double-helical, bimetallic chiral Co­(II)-salen complexes stabilized by chiral amidinium–carboxylate salt bridges efficiently catalyzed the asymmetric nitro-aldol (Henry) reaction, producing products with up to an 89% enantiomeric excess (ee); the reactivity and enantioselectivity were higher than those catalyzed by the corresponding single strands. The key role of the chiral double-helical framework for the supramolecular bimetallic catalysis has been revealed by a double-helical catalyst carrying achiral Co­(II)-salen units that promoted the Henry reaction, yielding the product with a 50%–45% ee, while the corresponding single strands showed poor or no enantioselectivity

Cobalt(II)-Salen-Linked Complementary Double-Stranded Helical Catalysts for Asymmetric Nitro-Aldol Reaction

Double-helical, bimetallic chiral Co­(II)-salen complexes stabilized by chiral amidinium–carboxylate salt bridges efficiently catalyzed the asymmetric nitro-aldol (Henry) reaction, producing products with up to an 89% enantiomeric excess (ee); the reactivity and enantioselectivity were higher than those catalyzed by the corresponding single strands. The key role of the chiral double-helical framework for the supramolecular bimetallic catalysis has been revealed by a double-helical catalyst carrying achiral Co­(II)-salen units that promoted the Henry reaction, yielding the product with a 50%–45% ee, while the corresponding single strands showed poor or no enantioselectivity

Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation:A Prespecified Subanalysis of the ELDERCARE-AF Randomized Clinical Trial

IMPORTANCE: Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated. OBJECTIVE: To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE–AF) trial. DESIGN, SETTING, AND PARTICIPANTS: This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo. INTERVENTIONS: Edoxaban (15 mg once daily) or placebo. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis–defined major bleeding. RESULTS: A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n = 181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n = 184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n = 127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P = .13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata. CONCLUSIONS AND RELEVANCE: Results of this subanalysis of the ELDERCARE–AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0280166

The Effect of Maternal Exposure to Dioxin on Fetal Steroidogenesis in the Steroidogenic Organs

特集号 油症とPCB及びダイキシン関連化合物 研究報告 第23集 責任編集者 古江増隆The Twenty-third Reports of the Study on Yusho―PCBs and Dioxin-Related Compounds―Guest Editor Furue Masutaka2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposed to pregnant or lactational mother impairs the reproduction and development of the pups. The defect is a serious problem, because it is caused by TCDD at much lower doses than that needed for acute toxicity in the mother. However, the toxic mechanism underlying the defect remains to be obscure. We have previously revealed that maternal exposure to TCDD (1 μg/kg) causes a reduction in luteinizing hormone in the fetal pituitary, leading to the reduced expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17. In addition, we have provided evidence that such a reduction imprints defects in sexual behaviors at adulthood. In this study, we investigated TCDD effect on fetal steroidogenesis in the extra-gonadal tissues. Even when pregnant Wistar rats at gestational day (GD) 15 were orally treated with TCDD (0.25, 1 or 3 μg/kg), neither expression of StAR nor CYP17 mRNA was affected in the adrenal gland, placenta and hypothalamus of male fetuses (GD20). However, TCDD induced placental StAR (3 μg/kg) and adrenal CYP17 mRNAs (0.25 μg/kg) in female fetuses. Therefore, our study suggests that while TCDD gives damage to male fetal steroidogenesis in a testis-specific manner, the dioxin enhances the steroidogenesis of the fetal adrenal gland and placenta in females. Thus, the mechanism whereby TCDD exerts its endocrine-disrupting properties is considered to differ, at least partially, between male and female fetuses

The Effect of Maternal Exposure to Dioxins on the Level of Thyroid Hormone in Developing Pups

特集号 油症とPCB及びダイキシン関連化合物 研究報告 第25集 責任編集者 古江増隆The Twenty-fifth Reports of the Study on Yusho―PCBs and Dioxin-Related Compounds―Editor Furue MasutakaMaternal exposure to dioxins causes a number of developmental disorders in the offspring. Previous studies have suggested that lactational exposure to 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) reduces the pup level of thyroid hormone after weaning, leading to the damage to their development including neural maturation. However, the specificity for age and dioxin congeners as well as dose dependency in terms of a reduction in pup thyroid hormone remains to be clarified. To address this issue, we investigated whether TCDD or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), one of the dioxins which caused \u27Yusho\u27 incident, affects the status of thyroid hormone during the fetal and neonatal periods. Treating pregnant rats at gestational day (GD) 15 with 1μg/kg TCDD scarcely affected the serum concentration of thyroxine, although a significant reduction by TCDD was detected at limited endpoints [GD21 and postnatal day (PND) 21]. In addition, maternal exposure to TCDD (0.05-30μg/kg) or PenCDF (1-1,000μg/kg) did not have any change in the serum level of thyroxine in GD20 fetuses even at the maximum dose. Neither the expression of pituitary thyroid-stimulating hormone β (TSHβ) nor hypothalamic thyrotropin-releasing hormone was sensitive to TCDD treatment. In pregnant dams, TCDD decreased the serum level of thyroxine at GD20 and 21, while the pituitary expression of TSHβ was induced. These results suggest that a single administration of dioxins to pregnant rats at GD15 have little effect on the level of thyroxine in the fetuses and infants, while a reduced level of this hormone observed in the offspring at GD21 and PND21 and pregnant dams at GD20 and 21

The Gender-Specific Effect of Maternal Exposure to Dioxin on Fetal Steroidogenesis in the Adrenal Gland

特集号 油症とPCB及びダイキシン関連化合物 研究報告 第24集 責任編集者 古江増隆The Twenty-four Reports of the Study on Yusho―PCBs and Dioxin-Related Compounds―Guest Editor Furue MasutakaMaternal exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin(TCDD) causes a number of toxic effects on development such as growth retardation and sexual immaturity in the offspring. However, the toxic mechanism remains unknown. Our previous studies have revealed that single oral administration of TCDD (1µg/kg) to pregnant rats at gestational day (GD) 15 attenuates the fetal expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17 by targeting the fetal production of pituitary gonadotropins. In addition, we provided evidence that TCDD-produced damage on the fetal pituitary-gonad axis leads to imprint defects in sexual behaviors at adulthood. In this study, we investigated whether TCDD also affects fetal steroidogenesis in the adrenal gland. When pregnant Wistar rats were orally treated with TCDD, the fetal expression of CYP21, CYP11B1 and CYP11B2 mRNAs was either induced or tended to be induced in the male adrenal gland during GD17 and GD19, while the expression of mRNAs coding for StAR, CYP11A1 and 3β-hydroxysteroid dehydrogenase was insensitive to TCDD treatment. The above alterations did not seem to be caused through a change in the upstream regulator, because TCDD exhibited little ability to attenuate the expression of adrenocorticotropin, a pituitary hormone stimulating adrenal steroidogenesis, in the male and female fetuses. In contrast to the males, TCDD effect on the adrenal gland was not observed in the female fetuses. These results suggest that maternal exposure to TCDD disrupts fetal steroidogenesis in adrenal as well as gonadal glands in a male specific manner, and the mechanism underlying the effect on adrenal gland is independent of the alteration of pituitary regulator

ダイオキシン母体曝露による発達児の甲状腺ホルモンへの影響

Maternal exposure to dioxins causes a number of developmental disorders in the offspring. Previous studies have suggested that lactational exposure to 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) reduces the pup level of thyroid hormone after weaning, leading to the damage to their development including neural maturation. However, the specificity for age and dioxin congeners as well as dose dependency in terms of a reduction in pup thyroid hormone remains to be clarified. To address this issue, we investigated whether TCDD or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), one of the dioxins which caused 'Yusho' incident, affects the status of thyroid hormone during the fetal and neonatal periods. Treating pregnant rats at gestational day (GD) 15 with 1μg/kg TCDD scarcely affected the serum concentration of thyroxine, although a significant reduction by TCDD was detected at limited endpoints [GD21 and postnatal day (PND) 21]. In addition, maternal exposure to TCDD (0.05-30μg/kg) or PenCDF (1-1,000μg/kg) did not have any change in the serum level of thyroxine in GD20 fetuses even at the maximum dose. Neither the expression of pituitary thyroid-stimulating hormone β (TSHβ) nor hypothalamic thyrotropin-releasing hormone was sensitive to TCDD treatment. In pregnant dams, TCDD decreased the serum level of thyroxine at GD20 and 21, while the pituitary expression of TSHβ was induced. These results suggest that a single administration of dioxins to pregnant rats at GD15 have little effect on the level of thyroxine in the fetuses and infants, while a reduced level of this hormone observed in the offspring at GD21 and PND21 and pregnant dams at GD20 and 21.特集号 油症とPCB及びダイキシン関連化合物 研究報告 第25集 責任編集者 古江増隆The Twenty-fifth Reports of the Study on Yusho―PCBs and Dioxin-Related Compounds―Editor Furue Masutak

ダイオキシン母体曝露が胎児ステロイド産生臓器の性ステロイドホルモン合成系に及ぼす影響

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposed to pregnant or lactational mother impairs the reproduction and development of the pups. The defect is a serious problem, because it is caused by TCDD at much lower doses than that needed for acute toxicity in the mother. However, the toxic mechanism underlying the defect remains to be obscure. We have previously revealed that maternal exposure to TCDD (1 μg/kg) causes a reduction in luteinizing hormone in the fetal pituitary, leading to the reduced expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17. In addition, we have provided evidence that such a reduction imprints defects in sexual behaviors at adulthood. In this study, we investigated TCDD effect on fetal steroidogenesis in the extra-gonadal tissues. Even when pregnant Wistar rats at gestational day (GD) 15 were orally treated with TCDD (0.25, 1 or 3 μg/kg), neither expression of StAR nor CYP17 mRNA was affected in the adrenal gland, placenta and hypothalamus of male fetuses (GD20). However, TCDD induced placental StAR (3 μg/kg) and adrenal CYP17 mRNAs (0.25 μg/kg) in female fetuses. Therefore, our study suggests that while TCDD gives damage to male fetal steroidogenesis in a testis-specific manner, the dioxin enhances the steroidogenesis of the fetal adrenal gland and placenta in females. Thus, the mechanism whereby TCDD exerts its endocrine-disrupting properties is considered to differ, at least partially, between male and female fetuses.特集号 油症とPCB及びダイキシン関連化合物 研究報告 第23集 責任編集者 古江増隆The Twenty-third Reports of the Study on Yusho―PCBs and Dioxin-Related Compounds―Guest Editor Furue Masutak