2 research outputs found
Aqueous Glycosylation of Unprotected Sucrose Employing Glycosyl Fluorides in the Presence of Calcium Ion and Trimethylamine
We
report a synthetic glycosylation reaction between sucrosyl acceptors
and glycosyl fluoride donors to yield the derived trisaccharides.
This reaction proceeds at room temperature in an aqueous solvent mixture.
Calcium salts and a tertiary amine base promote the reaction with
high site-selectivity for either the 3′-position or 1′-position
of the fructofuranoside unit. Because nonenzymatic aqueous oligosaccharide
syntheses are underdeveloped, mechanistic studies were carried out
in order to identify the origin of the selectivity, which we hypothesized
was related to the structure of the hydroxyl group array in sucrose.
The solution conformation of various monodeoxysucrose analogs revealed
the co-operative nature of the hydroxyl groups in mediating both this
aqueous glycosyl bond-forming reaction and the site-selectivity at
the same time
Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach
Using
the collective body of known (CETP) inhibitors as inspiration for
design, a structurally novel series of tetrahydroquinoxaline CETP
inhibitors were discovered. An exemplar from this series, compound <b>5</b>, displayed potent in vitro CETP inhibition and was efficacious
in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay.
However, an undesirable metabolic profile and chemical instability
hampered further development of the series. A three-dimensional structure
of tetrahydroquinoxaline inhibitor <b>6</b> was proposed from <sup>1</sup>H NMR structural studies, and this model was then used in
silico for the design of a new class of compounds based upon an indoline
scaffold. This work resulted in the discovery of compound <b>7</b>, which displayed potent in vitro CETP inhibition, a favorable PK–PD
profile relative to tetrahydroquinoxaline <b>5</b>, and dose-dependent
efficacy in the transgenic cynomologus-CETP mouse HDL PD assay