2 research outputs found
Synthesis of 7‑Oxabicyclo[2.2.1]heptanes and 8‑Oxabicyclo[3.2.1]octanes from C‑Glycosides via an Intramolecular Cyclization
A simple
and effective method for the synthesis of 7-oxabicyclo[2.2.1]Âheptanes
and 8-oxabicyclo[3.2.1]Âoctanes from acetonyl C-glycoside substrates
is described, which involves an intramolecular cyclization reaction
through a nucleophilic substitution at C-5 or C-6 of C-glycosides
by a 2′-enamine intermediate formed in the presence of pyrrolidine.
Because anomeric epimerization occurs under these conditions, C-glycoside
substrates with either anomeric configuration were converted to the
same product(s) in same stereoselectivity and similar chemical yield
Novel Carvedilol Analogues That Suppress Store-Overload-Induced Ca<sup>2+</sup> Release
Carvedilol
is a uniquely effective drug for the treatment of cardiac
arrhythmias in patients with heart failure. This activity is in part
because of its ability to inhibit store-overload-induced calcium release
(SOICR) through the RyR2 channel. We describe the synthesis, characterization,
and bioassay of ca. 100 compounds based on the carvedilol motif to
identify features that correlate with and optimize SOICR inhibition.
A single-cell bioassay was employed on the basis of the RyR2-R4496C
mutant HEK-293 cell line in which calcium release from the endoplasmic
reticulum through the defective channel was measured. IC<sub>50</sub> values for SOICR inhibition were thus obtained. The compounds investigated
contained modifications to the three principal subunits of carvedilol,
including the carbazole and catechol moieties, as well as the linker
chain containing the β-amino alcohol functionality. The SAR
results indicate that significant alterations are tolerated in each
of the three subunits