Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke-Blackburn-Bienaymé reaction on a range of α-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner.
SummaryEnantiomerically pure β-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multicomponent reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three stereogenic centers, allowing the introduction of five diversity inputs.
Sphingolipids
(SphLs) are a diverse class of molecules that are
regulated by a complex network of enzymatic pathways. A disturbance
in these pathways leads to lipid accumulation and initiation of several
SphL-related disorders. Acid ceramidase is one of the key enzymes
that regulate the metabolism of ceramides and glycosphingolipids,
which are important members of the SphL family. Herein, we describe
the lead optimization studies of benzoxazolone carboxamides resulting
in piperidine
22m
, where we demonstrated target engagement
in two animal models of neuropathic lysosomal storage diseases (LSDs),
Gaucher’s and Krabbe’s diseases. After daily intraperitoneal
administration at 90 mg kg
–1
,
22m
significantly
reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph)
in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice.
We believe that
22m
is a lead molecule that can be further
developed for the correction of severe neurological LSDs where GluSph
or GalSph play a significant role in disease pathogenesis.
Chiral, enantiopure 1,3‐amino alcohols, obtained through an organocatalytic Mannich reaction, have been used as starting materials for a concise sequence involving a diastereoselective Ugi reaction followed by various types of SN2 cyclization. In this way, different enantiopure heterocycles have been prepared, with both scaffold and decoration diversity (up to four diversity inputs).
Graphene oxide is exploited as a heterogeneous, metal-free and sustainable catalyst for the three-component Povarov reaction and subsequent oxidation. The multistep synthesis can also be performed as a one-pot procedure.
Acid
ceramidase (AC) is a cysteine hydrolase that plays a crucial
role in the metabolism of lysosomal ceramides, important members of
the sphingolipid family, a diversified class of bioactive molecules
that mediate many biological processes ranging from cell structural
integrity, signaling, and cell proliferation to cell death. In the
effort to expand the structural diversity of the existing collection
of AC inhibitors, a novel class of substituted oxazol-2-one-3-carboxamides
were designed and synthesized. Herein, we present the chemical optimization
of our initial hits, 2-oxo-4-phenyl-
N
-(4-phenylbutyl)oxazole-3-carboxamide
8a
and 2-oxo-5-phenyl-
N
-(4-phenylbutyl)oxazole-3-carboxamide
12a
, which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo-
N
-pentyl-oxazole-3-carboxamide
32b
as a potent
AC inhibitor with optimal physicochemical and metabolic properties,
showing target engagement in human neuroblastoma SH-SY5Y cells and
a desirable pharmacokinetic profile in mice, following intravenous
and oral administration.
32b
enriches the arsenal of
promising lead compounds that may therefore act as useful pharmacological
tools for investigating the potential therapeutic effects of AC inhibition
in relevant sphingolipid-mediated disorders.
Enantiomerically pure β‐amino alcohols undergo Ugi reactions under classic or Lewis‐acid‐promoted conditions to give polyfunctionalized peptidomimetics with moderate to good diastereoselectivities.
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