Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe

An effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium–hydride complex (Rh–H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4-reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor

Therapeutic efficacy of lenvatinib for patients with unresectable hepatocellular carcinoma based on the middle-term outcome.

AIM:This study sought to clarify the usefulness of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC). METHODS:The subjects were 69 patients with HCC receiving lenvatinib; the median age was 73 years, and 14 and 67 patients had been previously treated with regorafenib and/or sorafenib and therapies without molecular-targeted agents, respectively. Therapeutic efficacy was evaluated using contrast-enhanced CT images obtained 4-8 weeks after the start of lenvatinib and the middle-term outcome using Kaplan-Meier method. RESULTS:The baseline Child-Pugh scores were 5, 6 and 7 in 31, 32 and 6 patients, respectively, and the modified albumin-bilirubin (mALBI) grades were 1, 2a and 2b in 20, 20 and 29 patients, respectively. The Barcelona Clinic Liver Cancer (BCLC) stages following downsizing after prior treatment were A, B and C in 17, 22 and 30 patients, respectively. The therapeutic efficacy was evaluated in 54 patients, and the percentages of patients achieving CR, PR, SD and PD were 3.7%, 44.4%, 37.0%, and 14.8%, respectively. The ALBI scores deteriorated significantly between 4 and 12 weeks after the start of therapy, compared with the baseline. The cumulative survival rates at 48 weeks were significantly higher among patients achieving CR/PR (95.5%) than among those showing no response (54.3%). Multivariate analyses revealed that the BCLC stages and the serum AFP levels were significantly associated with therapeutic efficacy, while the mALBI grade was associated with the middle-term outcome. CONCLUSIONS:A favorable middle-term outcome was obtained in patients with HCC receiving lenvatinib, especially in those manifesting grades 1/2a mALBI at baseline, despite the deterioration in ALBI scores during treatment

Dietitian‐supported dietary intervention leads to favorable dietary changes in patients with type 2 diabetes: A randomized controlled trial

Abstract Aims/Introduction It remains to be fully elucidated whether nutrition education by dietitians can lead to specific positive changes in the food choices of patients with diabetes. Materials and Methods A total of 96 patients with type 2 diabetes and diabetic kidney disease were randomly assigned to the intensive intervention group that received nutritional education at every outpatient visit and the control group that received nutritional education once a year. The total energy intake, energy‐providing nutrients and 18 food groups were analyzed at baseline, and 1 and 2 years after the intervention in 87 patients. Furthermore, the relationship between the changes in hemoglobin A1c, body composition and changes in the total energy or energy‐producing nutrient intake was analyzed in 48 patients who did not use or change hypoglycemic agents during the study period. Results The total energy intake, carbohydrates, cereals, confections, nuts and seeds, and seasonings significantly decreased, and fish and shellfish intake significantly increased during the study period in the intensive intervention group, whereas these changes were not observed in the control group. The decrease in the total energy intake and carbohydrates after 2 years was significantly greater in the intensive intervention group than in the control group. The change in the total energy and carbohydrate intake showed a significant positive correlation with that in muscle mass. The multivariate analysis showed that the decrease in total energy intake was independently associated with that in muscle mass. Conclusion Dietitian‐supported intensive dietary intervention helps improve the diet of patients with type 2 diabetes

Identification of Novel d‑Aspartate Oxidase Inhibitors by <i>in Silico</i> Screening and Their Functional and Structural Characterization <i>in Vitro</i>

d-Aspartate oxidase (DDO) is a degradative enzyme that is stereospecific for acidic d-amino acids, including d-aspartate, a potential agonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated neurotransmission has been implicated in the onset of various mental disorders, such as schizophrenia. Hence, a DDO inhibitor that increases the brain levels of d-aspartate and thereby activates NMDA receptor function is expected to be a useful compound. To search for potent DDO inhibitor(s), a large number of compounds were screened <i>in silico</i>, and several compounds were identified as candidates. They were then characterized and evaluated as novel DDO inhibitors <i>in vitro</i> (e.g., the inhibitor constant value of 5-aminonicotinic acid for human DDO was 3.80 μM). The present results indicate that some of these compounds may serve as lead compounds for the development of a clinically useful DDO inhibitor and as active site probes to elucidate the structure–function relationships of DDO

Identification of Novel d‑Aspartate Oxidase Inhibitors by <i>in Silico</i> Screening and Their Functional and Structural Characterization <i>in Vitro</i>

d-Aspartate oxidase (DDO) is a degradative enzyme that is stereospecific for acidic d-amino acids, including d-aspartate, a potential agonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated neurotransmission has been implicated in the onset of various mental disorders, such as schizophrenia. Hence, a DDO inhibitor that increases the brain levels of d-aspartate and thereby activates NMDA receptor function is expected to be a useful compound. To search for potent DDO inhibitor(s), a large number of compounds were screened <i>in silico</i>, and several compounds were identified as candidates. They were then characterized and evaluated as novel DDO inhibitors <i>in vitro</i> (e.g., the inhibitor constant value of 5-aminonicotinic acid for human DDO was 3.80 μM). The present results indicate that some of these compounds may serve as lead compounds for the development of a clinically useful DDO inhibitor and as active site probes to elucidate the structure–function relationships of DDO

GPI-anchor synthesis is indispensable for the germline development of the nematode Caenorhabditis elegans

Twenty-four Caenorhabditis elegans genes are involved in GPI-anchor synthesis. Based on the isolation of a deletion allele of the PIGA gene mediating the first step of GPI-anchor synthesis, GPI-anchor synthesis in somatic gonads and/or in germline is shown to be indispensable for the normal development of oocytes and eggs