The
overaccumulation of glycogen appears as a hallmark in various
glycogen storage diseases (GSDs), including Pompe, Cori, Andersen,
and Lafora disease. Accumulating evidence suggests that suppression
of glycogen accumulation represents a potential therapeutic approach
for treating these GSDs. Using a fluorescence polarization assay designed
to screen for inhibitors of the key glycogen synthetic enzyme, glycogen
synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class
inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography
at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p.
The high conservation of residues between human and yeast GS in direct
contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure–activity
relationship profile that led to the identification of a substituted
pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against
human GS. These substituted pyrazoles possess a promising scaffold
for drug development efforts targeting GS activity in GSDs associated
with excess glycogen accumulation.
A wide
set of 65 diverse Ru metathesis catalysts was investigated
in the ethenolysis reaction of biosourced ethyl oleate to allow the
comparison between the catalyst structure and its activity and selectivity.
Handling of the oleic substrate, weighing of the catalysts, and charging
the reactor were done in air, with exclusion of a glovebox or Schlenk
techniques. A catalyst bearing the unsymmetrical N-heterocyclic ligand
featuring a thiophene fragment (
Ru-63
) was selected to
offer the best combination between high selectivity and sufficient
activity under conditions mimicking oil industry practice. A proof-of-concept
large-scale ethenolysis experiment was also done with the selected
catalyst to prove its high selectivity at the 1 L scale reaction with
a 90% pure non-distilled substrate.
A selective electrophilic nitration of meso-tetraarylporphyrin copper(II) and nickel(II) complexes, bearing in meso-aryl rings a variety of substituents (3- NO 2, 3- CH 3, 3- Cl , 2,3,4,5,6-pentafluoro-, and 2,6-dichloro-), is described. The reactions of the above porphyrinates, carried out in CHCl 3 at room temperature, with aqueous HNO 3 (concentration 15-50%), resulted in the formation of the respective mono-β-nitrated products, in good or very good yield (74-93%). All the synthesized compounds were demetallated in CF 3 CO 2 H/H 2 SO 4 mixture to give β-nitro-substituted porphyrin free bases – very versatile substrates for further chemical transformations.
Robust, selective, and stable in the presence of ethylene, ruthenium olefin metathesis pre‐catalyst, {[3‐benzyl‐1‐(10‐phenyl‐9‐phenanthryl)]‐2‐imidazolidinylidene}dichloro(o‐isopropoxyphenylmethylene)ruthenium(II), Ru‐3, bearing an unsymetrical N‐heterocyclic carbene (uNHC) ligand, has been synthesized. The initiation rate of Ru‐3 was examined by ring‐closing metathesis and cross‐metathesis reactions with a broad spectrum of olefins, showing an unprecendented selectivity. It was also tested in industrially relevant ethenolysis reactions of olefinic substrates from renewable feedstock with very good yields and selectivities.
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