Application of (S,S)-Pentacycloundecane bis(4-Phenyloxazoline) as a Novel Chiral Ligand for Catalysis of the Asymmetric Diels-Alder Reaction of Cyclopentadiene with 3-Acryloyl-2-oxazolidinone

The synthesis of the novel C1 symmetric (S,S)-pentacycloundecane bis(4-phenyloxazoline) ligand 5 and its evaluation as a chiral Lewis acid catalyst in the benchmark asymmetric Diels-Alder reaction between 3-acryloyloxazolidin-2-one (6) and cyclopentadiene (7) is reported. From the various metal salts screened the anhydrous magnesium perchlorate complex emerged as the best catalyst. The endo-cycloadduct product 8 was afforded in 81% enantiomeric excess with an endo:exo ratio of 98:2. An extensive screening of various metal ions as complexing agents was performed and is also reported.Keywords: Pentacycloundecane, oxazolines, chiral catalysis, Diels-Alder reactionPDF and Supplementry file attache

Accuracy of SenseWear Pro2 armband to predict resting energy expenditure in childhood obesity.

OBJECTIVE: We evaluate the accuracy of the SenseWear Pro2 Armband (SWA) in estimating resting energy expenditure (REE) in children and adolescents with obesity, using indirect calorimetry (IC) as a reference. DESIGN AND METHODS: REE was assessed using both the SWA and IC in 40 obese subjects (26 M/14 F, age 11.5±2.57 years, z-score BMI 3.14±0.53). The agreement between methods was assessed by the Bland-Altman procedure. The relationship between REE assessments and patients' characteristics was also analyzed. RESULTS: SWA- and IC-derived estimates of REE showed a significant correlation (r=0.614; P<0.001), but the SWA overestimated mean REE by 13% (P<0.001). Age and kg of fat-free mass (kgFFM) were significantly correlated with both REE estimation by SWA (r=0.434 and r=0.564; respectively) and IC (r=0.401 and r=0.518; respectively). Only kgFFM was demonstrated to be the main predictor factor of REE variability (r2 79% SWA; 75% IC). CONCLUSIONS: The SWA overestimated mean REE in childhood obesity, suggesting that the SWA and IC are not yet interchangeable methods. This would require improving the SWA by developing better algorithms for predicting REE and, probably, bias in each individual REE could be reduced by an adjustment for subjects' kgFFM

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors

Dynamics of the Lithium Amide/Alkyllithium Interactions: Mixed Dimers and Beyond

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