Enantioselective Synthesis of α-Aryl-ß-Aminocyclopropane Carboxylic Acid Derivatives via Rh(II)-Catalyzed Cyclopropanation of Vinylsulfonamides with α-Aryldiazoesters.

The reaction of vinylsulfonamides with donor-acceptor carbenes derived from α-aryldiazoesters, catalyzed by the tert-butyl glycine-derived dirhodium complex Rh2(S-4-Br-NTTL)4, has been reported. This method provides a variety of α-aryl-ß-aminocyclopropane carboxylic acid derivatives bearing one quaternary carbon stereogenic center vicinal to the amino-substituted carbon in high yields with excellent diastereo- and enantioselectivities. Vinylsulfonamides showed complementary advantages over the well-developed vinylamides or vinylcarbamates for this Rh(II)-catalyzed cyclopropanation strategy. Moreover, these conformationally restricted α-aryl-ß-aminocyclopropyl carboxylic acid derivatives can be readily incorporated into dipeptides.

Insulin Resistance-Related Proteins Are Overexpressed in Patients and Rats Treated With Olanzapine and Are Reverted by Pueraria in the Rat Model.

BACKGROUND: Olanzapine, a commonly used second-generation antipsychotic, causes severe metabolic adverse effects, such as elevated blood glucose and insulin resistance (IR). Previous studies have proposed that overexpression of CD36, GGPPS, PTP-1B, GRK2, and adipose triglyceride lipase may contribute to the development of metabolic syndrome, and Pueraria could eliminate the metabolic adverse effects. The study aimed to investigate the association between olanzapine-associated IR and IR-related proteins (IRRPs) and determine the role of Pueraria in protection against the metabolic adverse effects of olanzapine. METHODS: The expression levels of IRRPs were examined in schizophrenia patients and rat models with long-term olanzapine treatment. The efficacy of Pueraria on anti-IR by reducing the expression of IRRPs was comprehensively evaluated. RESULTS: Our study demonstrated that in schizophrenia patients chronically treated with olanzapine, the expression levels of IRRPs in patients with a high IR index significantly increased, and these phenomena were further confirmed in a rat model. The expression levels of IRRPs were reduced significantly in Pueraria-treated IR rat models. The body weight, blood glucose, and IR index were restored to levels similar to those of normal controls. CONCLUSIONS: The IRRPs are closely related to IR induced by olanzapine, and Pueraria could interfere with olanzapine-associated IR and revert overexpressed IRRPs. These findings suggest that IRRPs are key players in olanzapine-associated IR and that Pueraria has potential as a clinical drug to prevent the metabolic adverse effects of olanzapine, further improving compliance of schizophrenia patients.

Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model.

Defective lysosomal acidification contributes to virtually all lysosomal storage disorders (LSDs) and to common neurodegenerative diseases like Alzheimer's and Parkinson's. Despite its fundamental importance, the mechanism(s) underlying this defect remains unclear. The v-ATPase, a multisubunit protein complex composed of cytosolic V1-sector and lysosomal membrane-anchored V0-sector, regulates lysosomal acidification. Mutations in the CLN1 gene, encoding PPT1, cause a devastating neurodegenerative LSD, INCL. Here we report that in Cln1-/- mice, which mimic INCL, reduced v-ATPase activity correlates with elevated lysosomal pH. Moreover, v-ATPase subunit a1 of the V0 sector (V0a1) requires palmitoylation for interacting with adaptor protein-2 (AP-2) and AP-3, respectively, for trafficking to the lysosomal membrane. Notably, treatment of Cln1-/- mice with a thioesterase (Ppt1)-mimetic, NtBuHA, ameliorated this defect. Our findings reveal an unanticipated role of Cln1 in regulating lysosomal targeting of V0a1 and suggest that varying factors adversely affecting v-ATPase function dysregulate lysosomal acidification in other LSDs and common neurodegenerative diseases.